Leptin : Hormonal Functions, Dysfunctions and Clinical Uses [1 ed.] 9781613247518, 9781611228915

Citation preview

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

CELL BIOLOGY RESEARCH PROGRESS

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

LEPTIN: HORMONAL FUNCTIONS, DYSFUNCTIONS AND CLINICAL USES

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

CELL BIOLOGY RESEARCH PROGRESS Additional books in this series can be found on Nova‘s website under the Series tab.

Additional E-books in this series can be found on Nova‘s website under the E-book tab.

METABOLIC DISEASES - LABORATORY AND CLINICAL RESEARCH Additional books in this series can be found on Nova‘s website under the Series tab.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Additional E-books in this series can be found on Nova‘s website under the E-book tab.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

CELL BIOLOGY RESEARCH PROGRESS

LEPTIN: HORMONAL FUNCTIONS, DYSFUNCTIONS AND CLINICAL USES

ROSE M. HEMLING AND

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ARTHUR T. BELKIN EDITORS

Nova Science Publishers, Inc. New York Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers‘ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA Leptin : hormonal functions, dysfunctions, and clinical uses / editors, Rose M. Hemling and Arthur T. Belkin. p. ; cm. Includes bibliographical references and index. ISBN:  (eBook)

1. Leptin. I. Hemling, Rose M. II. Belkin, Arthur T. [DNLM: 1. Leptin. WK 185] QP572.L48L47 2010 612.4--dc22 2010043905

Published by Nova Science Publishers, Inc. † New York Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

CONTENTS

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Preface

vii

Chapter 1

Interplay of Leptin with the Stress System Components George Soulis and Efthymia Kitraki

Chapter 2

The Effect of Drugs on Leptin Metabolism Irem Fatma Uludag

Chapter 3

Leptin: A Novel Therapeutic Target in the Fight against Neuro-Degeneration? G. H. Doherty

Chapter 4

Role of Leptin in the Activation of the Immune System Patricia Fernández-Riejos, Souad Najib, José Santos-Alvarez, Consuelo Martín-Romero, Antonio Pérez-Pérez, Carmen González-Yanes and Víctor Sánchez-Margalet

Chapter 5

Role of Leptin in the Mammary Gland Development, Lactation and in Neonatal Physiology Mario Baratta

Chapter 6

Gender Difference in Leptin Production and Leptin Sensitivity Haifei Shi

Chapter 7

The Role and Application of Leptin in Control of Female Reproductive Functions Alexander V. Sirotkin

Chapter 8

Leptin in Breast Milk and Infancy Francesco Savino, Stefania Alfonsina Liguori and Maria Maddalena Lupica

Chapter 9

Risk of Primary Hypogonadism in Patients with Obstructive Sleep Apnea due to High Leptin Levels Madalina Minciu Macrea, Thomas J Martin and Leon Zagrean

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

1 33

55 71

89 107

123 141

155

vi Chapter 10

Chapter 11

Chapter 12

Contents Leptin - A Cardioprotective Hormone Following CPB or an Innocent Bystander? Dalit Modan-Moses and Gideon Paret

165

Interaction Between Leptin and Gut Hormones in the Regulation of Food Intake and Body Weight Tooru M. Mizuno

187

Fructose Consumption and Leptin Resistance: What Have We Learnt from Animal Studies? Marta Alegret, Núria Roglans and Juan C. Laguna

209

Chapter 13

Neonatal Leptin Surge Takashi Higuchi

Chapter 14

Adipokines in Human Pregnancy: The Role of Leptin and Adiponectin Shali Mazaki-Tovi, Edi Vaisbuch, Juan Pedro Kusanovic, Roberto Romero

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Index

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

231

239

283

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

PREFACE This book presents topical research in the study of leptin, including the interaction of leptin with stress system components; the effects of serum leptin levels of some drugs; leptin as a novel therapeutic reagent in the fight against neurodegenerative diseases; the role of leptin in the activation of the immune system; gender difference in leptin production and leptin senstitivity and neonatal leptin surge. Chapter 1 - During the last decade research in the field of metabolism has incorporated studies on the interactions of leptin with components of the stress response system and their impact in situations such as the metabolic syndrome. Today, accumulating evidence suggest the existence of a bidirectional interplay between leptin and stress hormones of sympathoadrenal or neuroendocrine origin that extends beyond the metabolic control. In the central nervous system, the aforementioned interplay appears to be also implicated in the neuroendocrine and behavioral stress response, synaptic plasticity, mood and neuroprotection. In the periphery, leptin - stress hormones‘ interactions are essential in adiposity and obesityrelated hypertension. These interactions are influenced by sex hormones. On most occasions leptin and glucocorticoids show antagonistic effects, whereas estrogens mimic some of the central leptin actions. Furthermore, leptin‘s trophic and programming effects on the developing organism are amenable to environmental stimuli including stress. Chapter 2 - The continuing epidemics of obesity worldwidegave rise to the studies investigating the drugs used for the treatment of obesity as well as the drugs inducing weight gain as an metabolic adverse effect and the invention of the leptin, one of the more important molecules in the pathogenesis of obesity, introduced a new direction for these studies.This chapter focused on the results of previous studies providing information about the effects on serum leptin levels of some drugs. Chapter 3 - Neurodegenerative diseases present one of the greatest ongoing challenges to modern medicine with a paucity of therapies available and a lack of understanding as to why many patients develop these disorders. Given that neurodegeneration largely affects the elderly and that the world is seeing a marked demographic shift towards an ageing population, the need to better understand and treat these conditions is becoming ever more urgent. Recent research has implicated low levels of the anti-obesity hormone leptin in the development of neurodegeneration and has suggested that exogenous leptin may offer protection from the loss of neurons associated with this process. At the moment our understanding of leptin‘s potential in this field is very much in its infancy, thus it seems timely to bring the emerging evidence together. Therefore, this chapter considers the data

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

viii

Rose M. Hemling and Arthur T. Belkin

revealing that leptin deficiency can play a key role in degenerative changes in the central nervous system and investigates the potential of leptin as a novel therapeutic reagent in the fight against neurodegenerative diseases. Chapter 4 - Adipose tissue is an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that may be present in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Leptin is one of the most important hormones secreted by the adipocyte, with a variety of physiological roles related with the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. The adipocyte-derived hormone leptin has been shown to regulate the immune response, innate and adaptative response, both in normal as well as in pathological conditions. The role of leptin in regulating immune response has been assessed in vitro as well as in clinical studies. It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility. On the other hand, leptin can promote autoreactivity. As a pro-inflammatory adipokine, it can induce T helper 1 cells and may contribute to the development and progression of autoimmune responses. A number of studies have implicated a role of leptin in the pathogenesis of several autoimmune diseases, including type 1 diabetes, inflammatory bowel disease, and possibly rheumatoid arthritis. This aspect is also of interest in relation to the well-known gender bias in susceptibility to autoimmunity. Autoimmune diseases are frequently more prevalentin females, and females are relatively hyperleptinemic. The modulation of circulating leptin levels has a pivotal role on some inflammatory and autoimmune conditions. Chapter 5 - The biology of leptin has been studied most extensively in the central nervous system for the regulation of food intake and energy balance. In recent years, a growing number of publications have reported several activities of this adipose-secreted protein in different organs. These effects appear to be independent of the regulation of food intake or at least not directly correlated to it, but rather related to the hormonal regulation of these particular tissues. Thus leptin is now also considered to be a hormonal factor that informs several hormonal circuits and biological peripheral functions of the nutrition status of the organism. Evidences are reported the role of leptin to regulate mammogenesis during a virgin, pregnancy and involution. In mammary gland, leptin has been observed to exert also an autocrine and/or paracrine activity which affects the development of duct, formation of gland alveolus, expression of milk protein gene and onset involution of mammary gland. Findings with experimental rodent models reveal that exposures to leptin during the in utero and pubertal periods when the mammary gland is undergoing extensive modeling and remodeling, may alter susceptibility to develop mammary tumors. Leptin synthesis has been found also in the placenta both in human and in livestock animals suggesting a role in controlling growth of the foetus and neonate. Furthermore, colostrum and milk contain high amounts of leptin, in particular during the first few days of lactation, that cause a correlation between milk leptin and plasma leptin, body weight and body mass index. Furthermore, other studies suggest that milk leptin may control appetite. Lastly, since nutrition or neonatal stress can program the immune system, leptin change that occurs in mothers and neonates can imprint hormonal or metabolic changes that influence later life degenerative and chronic diseases.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Preface

ix

Chapter 6 - Obesity and its related health disorders are increasing. Leptin, a hormone product of the obese (ob) gene, is proportional to peripheral energy stores, provides negative feedback signals to the central nervous system, plays a key role in the regulation of caloric intake and energy expenditure, and thus regulates body weight and body fat. Men and women become overweight or obese in different ways, and suffer different consequences. Specifically, men and women differ in terms of how and where they store body fat, the levels of leptin they synthesize and secrete in proportion to their body fat, and the way they respond to endogenous and exogenous leptin to regulate energy balance and body fat. Leptin is mainly produced in adipose (fat) tissues, and its level is associated with adiposity. Interestingly, serum leptin levels are greater in females than in males with equivalent amount of body fat. There are several possible reasons for the gender difference in circulating leptin levels. One contributing factor is that leptin gene is expressed predominantly in subcutaneous compared to visceral omental fat tissue. Women are more likely to deposit fat subcutaneously; whereas men are more likely to deposit fat in the abdominal region. The health risks associated with obesity vary depending on the location of adipose tissue. Excess fat mass in the abdominal region, especially visceral omental fat, carries a much greater risk for metabolic disorders than does fat tissue distributed subcutaneously. A second contributing factor is that the reproductive hormones influence leptin production. Estrogens stimulate, whereas androgens suppress, leptin synthesis and secretion. Another potential contributing factor is that males and females respond differentially to certain conditions, such as over or under nutrition or stress, to change their circulating leptin levels. Besides gender differences in leptin production, secretion, and circulating levels, males and females respond differentially to leptin. Female brains are relatively sensitive to leptin, and females are more reliant on leptin as an adiposity negative feedback signal. Males are more reliant on insulin, another adiposity signal. Estrogens enhance leptin sensitivity and thus its function, whereas androgens induce leptin resistance and thus its dysfunction. Reviewing the gender differences in the regulation of leptin production, secretion and its sensitivity under normal physiological or pathophysiological conditions is the focus of this chapter. Chapter 7 - Leptin, a product of adipose and some other tissues, which production is promoted by food intake and other stimuli, can be an important hormone through which different external factors affect reproductive processes. Leptin can affect reproduction through the hypothalamo-hypophysial system and by direct action on gonads. Regarding the effects of leptin at CNS level, some reports demonstrated a stimulatory influence of leptin on production of hypothalamic GnRH and hypophysial hormones. Regarding direct effects on the ovary, leptin was found to affect growth, ovulation of ovarian follicles and corpus luteum development, ovarian cell proliferation, apoptosis, secretory activity, oocyte maturation and developmental competence, as well as fecundity. Extra- and intracellular mechanisms of leptin action at central and ovarian level can include hormones (GnRH, gonadotropins and other pituitary hormones, pro-opiomelanocortin, kisspeptin and neuropeptide Y, steroid and nonapeptide hormones, prostaglandins, IGF-I/IGFBP system, VEGF and their receptors), several protein kinases and transcription factors. Serum leptin level can be used to predict development of a number of reproductive disorders including ovarian cancer. Chapter 8 - Leptin, the product of the ob gene, is a 167 amino acid peptide hormone mainly synthesized by the white adipose tissue and released in circulation proportionally to the amount of body fat mass. It is involved in the regulation of energy balance, reducing

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

x

Rose M. Hemling and Arthur T. Belkin

appetite and increasing energy expenditure by acting on the arcuate nucleus in the hypothalamus. Leptin is also produced by human placenta and seems to play a role in foetal and neonatal growth. Recently it has been implicated in the neonatal development of hypothalamic pathways involved in the central regulation of energy balance and appetite. Moreover leptin is present in human milk, both produced by mammary epithelial cells and transferred by secretory epithelial cells from blood to milk. Leptin concentration is higher in whole than in skimmed samples of human milk, probably because a portion of leptin could be associated with the milk fat droplet or fat-associated proteins. Leptin is present also in preterm human breast milk with similar levels to those noted in term breast milk, even though also lower levels have been detected after preterm than after term delivery. Leptin receptors have been identified in gastric epithelial cells and in the absorptive cells of mouse and human small intestine, which suggests that leptin could pass from milk to infant blood. The observation of leptin synthesis by the placenta and the presence of leptin in breast milk suggest a materno-fetal supportive role of this hormone, beginning in early gestation and persisting through lactation. Breast milk leptin may be involved in the short-term control of food intake by acting as a satiety signal, and it may prime or set the endocrinal system at homeostatic regulation balance. Moreover it could also exert a long-term effect on energy balance and body weight regulation. Considering the presence of leptin in breast milk and these possible implications for metabolism, leptin has been evaluated in exclusively breast-fed (BF) and formula fed infants in the first months of life, showing higher serum leptin values in the first ones. A positive correlation has been also detected between breast milk leptin levels and BF infants‘ serum leptin concentration. Leptin levels have been investigated also in serum of lactating mothers, showing a positive correlation between leptin in breast milk and leptin in maternal serum. The presence of leptin in breast milk might have a significant role in growth, appetite and regulation of nutrition in infancy, especially during the early lactation period. Breastfeeding seems to have a small but consistent protective effect against obesity in children who have been breast fed in early infancy. Chapter 9 - Study Objective: Hyperleptinemia inhibits the testicular Leydig and ovarian granulosa cell function directly. As obstructive sleep apnea (OSA) disease is known to be associated with hyperleptinemia, we hypothesize that OSA patients may be at risk of developing primary hypogonadism. Design: Cross-sectional Setting: Academic Sleep Center Methods: Fifteen patients were recruited from those scheduled at the Salem Veterans Affairs Medical Center (VAMC) for a diagnostic polysomnogram. Fasting venous blood samples for testosterone, leptin, luteinizing hormone, follicle stimulating hormone, sex hormone binding globulin, estradiol and glucose were drawn after completion of the PSG. Results: Leptin correlated significantly with serum LH (r = 0.525) and Test (r = -0.687). Conclusions: OSA patients who are hyperleptinemic may be at risk of developing primary hypogonadism. Further studies are needed in these patients to assess the association, if any, between hyperleptinemia and infertility. Chapter 10 - Leptin, the adipocyte-derived peptide encoded by the ob gene, promotes weight loss by reducing appetite and increasing energy expenditure. However, it has multiple other physiological functions, including regulation of neuroendocrine, reproductive,

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Preface

xi

hemopoietic and metabolic pathways. Multiple studies suggest that leptin may be involved in the acute stress response, and that its interaction with the hypothalamic-pituitary-adrenal axis and inflammatory cytokines may be of clinical importance. A wealth of studies defined a close relationship between cardiovascular function and leptin. Leptin receptors as well as leptin mRNA have been identified in myocardial tissue, and it has been suggested that the hormone may have a cardioprotective effect. Several studies suggested that open heart surgery (OHS) and cardiopulmonary bypass (CPB), a well-recognized initiator of a systemic inflammatory response, is associated with acute changes in circulating leptin levels. CPB resulted in a bi-phasic pattern of change in leptin levels – an initial decrease followed by an increase in leptin levels that was sustained up to 24 hours postoperatively. Leptin levels were inversely correlated with IL-6, the main cytokine released after cardiac surgery. A negative correlation between cortisol and leptin levels was also observed. Administration of exogenous glucocorticoid affected the amplitude, but not the pattern, of plasma leptin levels following CPB. A more complicated post-operative course may be associated with lower leptin levels. Furthermore, there was a negative association between leptin levels and troponin levels following OHS with CPB, suggesting an association between myocardial injury and attenuation of leptin levels. In keeping with these findings, leptin deficiency is linked to worse outcomes in chronic ischemic injury. The apparent beneficial role of leptin in the recovery from CPB may be attributed to enhancement of the anti-inflammatory response, as well as to its OHS with CPB is still associated with significant morbidity and mortality, measurement of leptin levels may enhance risk stratification, and the modulation of leptin through current and future therapies could possibly contribute to reducing morbidity and mortality following cardiac surgery. Chapter 11 - Leptin is the adipocyte-derived hormone which is released into the circulation in direct proportion to adiposity and participates in the long-term regulation of body weight. Leptin treatment is effective in reversing metabolic impairments in leptindeficient mice and humans. However, the majority of human obesity is associated with elevated circulating leptin levels and leptin resistance, limiting the weight-lowering effect of leptin. Therefore, establishment of a strategy to reverse leptin resistance is urgent. Mealassociated gastrointestinal hormones have been proven to be effective in reducing short-term food intake. However, the effect of gastrointestinal hormones on long-term food intake and body weight is limited in both magnitude and duration in general. Leptin and gastrointestinal satiety-promoting hormones reduce food intake and body weight by activating the central nervous system (CNS) cells through their synergistic interaction. Combined treatment of leptin and gastrointestinal hormone produces greater reductions in food intake and body weight compared to the treatment with leptin alone or gastrointestinal hormone alone in both normal and leptin-resistant animals. Pre-treatment with gastrointestinal hormone restores leptin-induced activation of CNS signaling in obese leptin-resistant animals. Thus, leptin amplifies feeding inhibition and neural activation produced by gut-derived hormones, suggesting that leptin may increase the efficacy of gastrointestinal meal-related signals. Alternatively, gut-derived hormones may enhance responsiveness to leptin in CNS cells. It is proposed that the interactions between leptin and gastrointestinal hormones participate in the regulation of both short-term feeding and long-term body weight and that the combination treatment of leptin and gastrointestinal hormones is an effective strategy for the treatment of obesity, in particular leptin-resistant obesity.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

xii

Rose M. Hemling and Arthur T. Belkin

Chapter 12 - In recent decades human population has markedly increased consumption of hypercaloric diets enriched in saturated fats and simple sugars, such as fructose. High fructose intake in humans increases body weight, plasma lipids and fat tissue mass. Furthermore, a high intake of energy from fructose-sweetened beverages seems to increase the risk of type 2 diabetes mellitus and cardiovascular diseases. The rat is a good model for the study of fructose metabolism in humans. Several animal species transform a substantial part of ingested fructose into glucose, a situation that does not occur in rats and humans. Solid diets that contain 50-60% of calories as fructose induce hypertriglyceridemia and a marked state of insulin resistance. Diets that incorporate lower fructose concentrations in drinking water (10 % weight/volume) induce hypertriglyceridemia and fatty liver in a short period of time (from days to two weeks), but they take far longer to induce insulin resistance. The administration of fructose in liquid form to rats mimics the human pattern of fructose consumption, with daily fructose intake equivalent to that found in the upper quartile of fructose consumption in human populations. By using this model, the authors have shown that the appearance of hypertriglyceridemia and liver steatosis is exclusive to rats supplemented with fructose, and is absent in rats supplemented with glucose, even though they consumed exactly the same amount of liquid diet. Fructose, but not glucose, simultaneously induced: an increase in the expression and activity of the transcription factor carbohydrate response element binding protein, which controls the expression of lipogenic enzymes; and a reduction in the hepatic activity of the fatty acid -oxidation system, which is related to reduced expression and transcriptional activity of the peroxisome proliferator activated receptor (PPAR administration to healthy young men increases plasma leptin concentrations. Leptin is an adipocytokine that can activate PPAR and increase fatty acid -oxidation activity through activation by phosphorylation of the transcription factor signal transducer and activator of transcription-3 (STAT-3). In our studies, only fructose-supplemented rats showed marked hyperleptinemia, which could be related to a deficit of cellular signalling of leptin. The authors also demonstrated that hepatic leptin resistance was related to two molecular changes. The first was an increase in liver expression of the protein suppressor of cytokine signalling3, which blocks the activation of Janus activated kinase-2 and the phosphorylation in position tyrosine 985 of the long form of the leptin receptor. The second was a generalized deficit of phosphorylation of the serine/threonine residues involved in the activation of proteins such as STAT-3, which are transducers of leptin signalling. This deficit of phosphorylation was attributed to the activation in liver tissue of serine/threonine phosphatase 2A by fructose metabolites. At molecular level, these changes could explain the hypertrilgyceridemia and hepatic steatosis observed in frequent consumers of fructose-sweetened beverages. Chapter 13 - An under- or over-nutritional intrauterine environment and over-nutrition in early postnatal period is associated with long-term metabolic consequences, including obesity, insulin resistance, and type 2 diabetes in adulthood. At least in rodents, leptin surge in neonatal pups may be involved in mediating this programming. Fetal under-nutrition results in reduced or premature leptin surge and maternal obesity induces exaggerated or premature leptin surge. Administration of leptin to neonatal pups to induce premature or supraphysiological leptin surge may cause hypothalamic programming that brings about metabolic abnormality in adulthood. Although there are many problems to be clarified, neonatal leptin surge may be involved in establishing hypothalamic neuronal system that controls food intake and energy expenditure.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Preface

xiii

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Chapter 14 - What are adipokines? During the last decade, accumulating evidence has demonstrated that adipose tissue is an important endocrine organ involved in the regulation of systemic metabolism, as well as in the orchestration of the immune response.1-9 Adipose tissue can exert its systemic effects through several mechanisms, the most important of which is the secretion of bioactive mediators from adipocytes and other cells, collectively termed ―adipokines.‖ The adipokines family includes structurally and functionally diverse proteins. Indeed, the adipokines encompass cytokines [e.g. tumor necrosis factor (TNF)-α10-14 and interleukin (IL)-615-20], chemokines (e.g. monocyte chemoattractant protein-1),21;22 mediators of vascular hemostasis (e.g. plasminogen activator inhibitor-1),23-25 blood pressure (e.g. angiotensinogen),26;27 and angiogenesis (e.g. vascular endothelial growth factor),28;29 as well as hormones regulating glucose homeostasis (e.g. leptin,30-36 adiponectin,37-41 resistin,42-46 visfatin47 and retinol binding protein 4 48-51).

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

In: Leptin: Hormonal Functions, Dysfunctions and Clinical Uses ISBN: 978-1-61122-891-5 Editors: Rose M. Hemling and Arthur T. Belkin ©2011 Nova Science Publishers, Inc.

Chapter 1

INTERPLAY OF LEPTIN WITH THE STRESS SYSTEM COMPONENTS George Soulis 1 and Efthymia Kitraki 2 1. Ippokratio General Hospital, Athens, Greece 2. Lab of Basic Sciences, Dept of Basic Sciences and Oral Biology, School of Dentisty, University of Athens, Greece

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ABSTRACT During the last decade research in the field of metabolism has incorporated studies on the interactions of leptin with components of the stress response system and their impact in situations such as the metabolic syndrome. Today, accumulating evidence suggest the existence of a bidirectional interplay between leptin and stress hormones of sympathoadrenal or neuroendocrine origin that extends beyond the metabolic control. In the central nervous system, the aforementioned interplay appears to be also implicated in the neuroendocrine and behavioral stress response, synaptic plasticity, mood and neuroprotection. In the periphery, leptin - stress hormones‘ interactions are essential in adiposity and obesity-related hypertension. These interactions are influenced by sex hormones. On most occasions leptin and glucocorticoids show antagonistic effects, whereas estrogens mimic some of the central leptin actions. Furthermore, leptin‘s trophic and programming effects on the developing organism are amenable to environmental stimuli including stress.

Corresponding Author: Efthymia Kitraki, Mailing address: Thivon 2 str., Athens 11527, Greece. Tel/Fax: 00302107461323. Email address: [email protected].

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

2

George Soulis and Efthymia Kitraki

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

INTRODUCTION Leptin is secreted by adipocytes in proportion to body fat mass and serves as a sensor of the organism‘s energy stores, transmitting this information to satiety centers in the central nervous system (CNS). Leptinemia increases following a meal, leptin reaches the hypothalamic arcuate nucleus (ARC) and through its receptors activates the adipokine negative feedback loop: it decreases appetite and increases energy expenditure. This homeostatic mechanism is often impaired in obesity due to alterations in leptin availability or signaling. Apart from the rare mutations that deplete leptin or diminish its circulating levels, in obese subjects leptin levels are not low and in several cases obesity coincides with hyperleptinemia and leptin resistance (Kelesidis et al 2010). Resistance to anorexic leptin‘s actions is a common mechanism for weight gain and obesity-related pathologies, such as hypertension, cardiovascular disease, dyslipidemia and diabetes. Interplay of leptin with the stress system components significantly influences its functions and adds to the aggravation of many obesity-associated features. Several observations have shown a regulation of leptin expression by the stress hormones. Sympathetic nervous system (SNS) activation regulates leptin production and secretion by the adipocytes. Exposure to stressors (like cold or fasting) that enhance SNS activity in adipose tissue lowers leptin production, in order to increase appetite and replenish the stress-induced energy loss. Conversely, inhibition of SNS increases leptin‘s gene expression and release. On the other hand, leptin acts within the hypothalamus to increase sympathetic outflow and thus energy expenditure, implying the existence of a regulatory feedback loop in SNS - leptin interactions (Rayner and Trayhurn 2001). In contrast to sympathetic actions, glucocorticoids increase both leptin‘s synthesis and secretion (Slieker et al 1996). Studies in humans support the stimulatory role of glucocorticoids on leptin secretion. The synthetic glucocorticoid dexamethasone potentiates the food-induced increase in serum leptin levels (Laferrere et al 1998) and the same holds true for hydrocortisone that increases plasma leptin and mRNA levels in subcutaneous fat (Askari et al 2000). On the other hand, glucocorticoids override the effects of leptin on food intake, by promoting feeding. Hypercortisolism in humans is associated with central obesity linked to hyperinsulinemia and hyperleptinemia (Leal-Cerro et al 1996). Similarly, in rodents central glucocorticoid administration increases feeding and induces obesity related to hyperleptinemia (Zakrzewska et al 1999). Conversely, elimination of glucocorticoids by adrenalectomy enhances leptin‘s inhibitory effects on food intake and body weight gain (Zakrzewska et al 1997).

INTERACTIONS WITHIN THE CENTRAL NERVOUS SYSTEM Brain is the central coordinator of feeding behavior. Hypothalamic and hindbrain centers constitute the neuroanatomical substrate where satiety and adiposity signals from the periphery, along with environmental stimuli perceived by other brain areas, converge to control food intake and energy expenditure. Following a meal, nutrient-derived satiety signals from the gastrointestinal tract, such as cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), amylin and peptide YY (PYY),

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Interplay of Leptin with the Stress System Components

3

reach the hindbrain satiety center mainly through the vagus nerve. The same route is used by the orexigenic gut signal, ghrelin that is released from an empty stomach. From the nucleus of the solitary tract the information on nutrient levels is transduced to the arcuate nucleus (ARC) of the hypothalamus. There, it is integrated with the information on adiposity status conveyed mainly from the periphery by leptin and insulin, as well as with other relevant inputs from higher brain centers (Valassi et al 2008). ARC contains two groups of neurons: The one is secreting orexigenic peptides like neuropeptide Y (NPY) and agouti-related peptide (AgRP). The other group secretes anorexigenic peptides, such as pro-opiomelanocortin (POMC, precursor for alpha- and betamelanocortin stimulating hormone, a-, β- MSH) and cocaine- and amphetamine-regulated transcript (CART). These groups of neurons project to paraventricular (PVN) hypothalamic neurons that secrete anorexigenic peptides (including corticotropin releasing hormone, CRH, and oxytocin) and to lateral hypothalamic (LH) neurons secreting orexigenic signals, like melanin concentrating hormone (MCH) and orexins. Orexigenic (NPY-releasing) and anorexigenic (POMC-releasing) neurons from the ARC also project to the ventromedial hypothalamus (VMH), an important satiety center that mediates leptin‘s actions on energy control (Bingham et al 2008).

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Positive Energy Balance When total energy intake prevails expenditure and glucose levels are high, the adiposity negative feedback system is set in operation, driven mainly by leptin and insulin. These hormones reach the brain via the circulation in proportion to their plasma concentrations. In the ARC, at the base of the hypothalamus, they exert their catabolic actions, by stimulating the production of the abovementioned anorexigenic peptides and reducing the production of the orexigenic ones. Leptin in particular is able to control both long term adiposity balance and short term energy intake following a meal. Increased leptin levels, reflecting a positive energy balance, activate the catabolic circuit to restore fuel homeostasis (Valassi et al 2008). POMC neurons that localize close to the blood brain barrier in the ARC, express leptin receptors and respond to this adipokine by producing POMC, the precursor for a- and β- MSH (melanocortins). In turn, melanocortins bind to their receptors (MC3/4 R) in second order hypothalamic neurons to induce anorexigenic responses (Sanchez-Lasheras et al 2010). POMC neurons in ARC are also sensing the increase in brain glucose levels by raising their fire rate. Impairment of this sensing mechanism has been reported to contribute in obesity (Parton et al 2007). The anorexic signals originating in the ARC, project to the LH to block MCH/Orexins release and to the PVN to stimulate CRH and oxytocin release. CRH is considered an important mediator of the anorexic actions of leptin. Intracerebroventricular CRH administration in rats attenuates feeding (Benoit et al 2000) probably by inhibiting the NPY-activated orexigenic circuits. CRH and oxytocin also lead to activation of the SNS that contributes to leptin-induced anorexia. (Yokotani et al 2001).

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

4

George Soulis and Efthymia Kitraki

Negative Energy Balance Conversely, a negative energy equilibrium will mobilize orexigenic gut-derived signals like ghrelin that stimulate the brainstem satiety center. The latter feeds back to the hypothalamus to stimulate the release of orexigenic neuropeptides. The anabolic circuit of NPY/AgRP in the arcuate and the MCH/Orexins circuit in LH will be activated. NPY is a powerful appetite enhancer secreted mainly in the ARC, but also in other brain areas including the brainstem. In the ARC, NPY promotes food intake by enhancing the release of anabolic signals from the second order neurons and by reducing the release of catabolic ones. For example, NPY-containing axons that derive from the ARC exert a negative regulatory control on the secretion of CRH from PVN neurons (Valassi et al 2008). Importantly, fasting characterized by reduced leptin, insulin and POMC levels, increases glucocorticoids that exert anabolic actions in the brain and promote food intake. Among the orexigenic peptides potentiated by glucocorticoids are AgRP and NPY. In fact, elevated glucocorticoids are necessary for the induction of both peptides in the fasting state, but they only suffice for the induction of AgRP mRNA (Makimura et al 2003), implying that an interaction of glucocorticoids with other metabolic regulators, including leptin and insulin, is required for the final control of satiety peptides.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Glucoregulation In cases of negative energy equilibrium, hypoglycaemia is also triggering food intake since glucose represents the main fuel of the brain. Glucose-sensitive neurons in the ventromedial hypothalamus will be set in operation to promote food intake and restore glucose levels. This circuit consists of neurons that increase their firing rate following glucose depletion and lead to the production of MCH and orexins. Conversely, other glucose-excited neurons mainly in the LH that are activated by increased glucose levels, maintain brain glucose homeostasis (Levin et al 2004). A significant glucoregulation center resides in the hindbrain. In response to hypoglycaemia, this center increases adrenal catecholamine and corticosterone secretion to promote feeding, as well as glycolysis and gluconeogenesis in the periphery (Ritter et al 2006). At this point it should be noted that SNS and catecho-adrenal systems do not always act in concert to regulate feeding (Landsberg 2006). A concerted action is exerted during the first steps of the stress response, where sympathoadrenal activation mobilizes substrate utilization to compensate the increased metabolic needs of ‗fight or flight‘ reaction. However, during fasting SNS activity is low whilst adrenal medulla secretion is increased to help substrate mobilization. Indeed, moderate hypoglycaemia, in conjunction with insulin drop, stimulates an inhibitory pathway from the ventromedial hypothalamus to the brainstem that decreases central SNS activity (Landsberg 2006). Nevertheless hindbrain epinephrine (E) and norepinephrine (NE) neurons projecting back to adrenals promote the secretion of catecholamines. Additionally, other hindbrain NE/NPY ascending neurons project to the PVN to stimulate CRH secretion from the PVN and subsequent glucocorticoid release by the adrenals (Füzesi et al 2007). Thus, the catecholaminergic NPY innervation seems to activate CRH neurons in cases of glucoprivation or infection, whereas the NPY input from the ARC nucleus contributes to inhibition of CRH neurons. Interestingly, activation of this

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Interplay of Leptin with the Stress System Components

5

glucoregulation circuit also leads to the activation of the hypothalamic pituitary adrenal (HPA) axis, the neuroendocrine stress response system.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Brain Metabolic Syndrome Inadequate activation of the two main stress response systems, SNS and hypothalamic pituitary adrenal (HPA) axis has been proposed to contribute in the appearance of the metabolic syndrome, characterized by visceral fat accumulation, dyslipidemia, hypertension, cardiovascular disease, leptin and insulin resistance (Fehm et al 2006). Converging evidence over the last years support the hypothesis that the metabolic syndrome originates as a brain dysfunction (Van Dijk and Buwalda 2008). In the emergence of this pathology, leptin and the stress hormones are important contributors. Following stress, SNS activation and catecholamine release shortly precede the HPA axis response. Nevertheless, in the first phase of the stress response both systems collaborate to increase blood flow, cardiovascular tone and energy mobilization. Glucocorticoids, released by the adrenal cortex, also attenuate feeding, reproduction and growth during the ‗fight or flight‘ response (Sapolsky et al 2000). Glucocorticoids‘ actions at this phase are exerted by their classical glucocorticoid receptors (GR), widely distributed over the whole body and the brain, as well as by membrane mineralocorticoid receptors (MR), selectively located in the limbic system of the brain (De Kloet et al 2008). During the delayed response phase, exerted mainly by glucocorticoids through GRs and nuclear MRs, negative feedback mechanisms are activated to counteract HPA axis activation and restore homeostasis. At this phase, glucocorticoids enhance feeding to replenish energy loss during the ‗fight or flight‘ response. In cases of prolonged or unmanageable stress, the response system might fail to return to the previous homeostatic equilibrium, thus leading to allostasis. Allostasis is defined as achieving stability through change (McEwen and Wingfield 2003). The neuroendocrine axis remains at an active state, characterized by chronically elevated plasma glucocorticoid levels that continue to potentiate feeding. This state may ablate both neuroendocrine and metabolic functions within the brain, leading to stress-related disorders and obesity. In humans, a typical paradigm of the effects of chronically elevated corticosteroids on both systems is Cushing‘s disease, where hypercortisolemia, hyperglycemia, hypertension, insulin resistance and central obesity coexist with mood disorders, depression and memory dysfunction (Bornstein et al 2006). In a retrospective cohort study investigating the association between work stress and the metabolic syndrome, it was shown that employees experiencing chronic stress at work were more prone to develop the syndrome than those without stress (Chandola et al 2006). Several studies in rodents have shown that chronic stress exposure apart from hypercortisolemia often results in altered levels of glucocorticoid receptors in relevant brain areas, including the hypothalamus (Gómez et al 1996; Karandrea et al 2000, 2002). The altered levels of GR and of GR/MR ratio in the limbic system of chronically stressed animals (Kitraki et al 2004a), imply inability of the neuroendocrine axis to terminate the stress response and probably inability of glucocorticoids to exert metabolic control. Changes in glucocorticoid receptors‘ signalling in the brain by stress may thus also contribute to the mechanisms of stress-induced metabolic disturbances. The neuroanatomical substrates for metabolic and stress - related glucocorticoid actions are largely identical. Glucocorticoid receptors are abundant in many hypothalamic nuclei, the

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

6

George Soulis and Efthymia Kitraki

hippocampus and amygdala. GRs localized in CRH-producing neurons of the PVN are particularly important for the integration of HPA axis inputs with the metabolic signals. In the acute phase of stress response, the stress-induced CRH release in the PVN leads to increased ACTH release from the pituitary and glucocorticoid secretion by the adrenal cortex. Elevated glucocorticoids act in the periphery to promote glycolysis and gluconeogenesis, potentiating the sympathoadrenal - driven mobilization of the energy stores following stress. Apart from being a major component of HPA axis activation, CRH is an important anorexigenic signal activated by leptin and insulin. Thus, stress-stimulated CRH release in the acute phase of the stress response transiently reduces food intake. Similarly, glucocorticoid rise immediately following stress induces POMC and a-MSH expression in the ARC (Larsen and Mau 1994) that also contribute to the attenuation of food intake. Hence, initially -and transiently- elevated glucocorticoids reduce food intake in synergy with leptin and insulin. However, in the delayed phase of stress response, glucocorticoids oppose to the anorexic actions of leptin. By exerting a negative feedback on HPA axis activation, they halt CRH release, reduce POMC mRNA and inhibit the central menalocortin system that mediates leptin‘s anorexigenic actions (Drazen et al 2003). In parallel they promote the expression of orexigenic signals in the hypothalamus that enhance feeding (Nieuwenhuizen and Rutters 2008). Several studies support the opposing interplay between leptin and glucocorticoids in feeding control. For example, leptin insufficiency leads to increased glucocorticoid release (Dallman et al 1993). In ob/ob leptin deficient mice, removal of the adrenals can normalize obesity and the leptin - induced derangement in hypothalamic gene expression (Makimura et al 2000). Glucocorticoids given in adrenalectomized rats can reverse the anorexic effect of leptin in these animals (Zakrzewska et al 1997). Glucocorticoids increase leptin levels but suppress the effect of leptin in the reduction of food intake, promoting the emergence of leptin resistance. This explains why in cases of leptin resistance, glucocorticoid administration in humans increases circulating leptin, while in parallel it enhances feeding (Tataranni et al 1996). An increased glucocorticoid to leptin signaling ratio has been suggested to be the initiative step to the metabolic syndrome (Zakrzewska et al 1997). Elevated glucocorticoids and HPA hyperactivity, met in stressful situations, may promote a state of leptin resistance and obesity (Nieuwenhuizen and Rutters 2008). Prolonged activation of the HPA axis activation, as is the case of chronic stress with an impaired feedback mechanism, can thus lead to hyperphagia, visceral obesity and the metabolic syndrome. Studies in humans have shown that food intake following stress is higher in women and positively relates to the cortisol increase following stress (Epel et al 2001). The risk for the appearance of the metabolic syndrome as a consequence of stress exposure is highly increased in the environment of an unhealthy diet. Animal studies have shown that high fat diets in particular lead to increased HPA activation (Tannenbaum et al 1997), impaired stress responses (Kitraki et al 2004b) and an early down regulation of leptin receptors in the hypothalamus (Boukouvalas et al 2010), implying resistance to central leptin‘s actions. Notably, the effect of glucocorticoids in the stimulation of food intake following stress appears macronutrient specific. Evidence from experimental animals indicates that if given a choice, stressed rats preferentially consume carbohydrate - and lipid - enriched foods (Tempel and Leibowitz 1989; La Fleur et al 2004). Leptin insensitivity induced by unhealthy diets could further dampen the metabolic load, by lowering the leptin-dependent central anorexic tone of melanocortins and SNS. Humans at

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Interplay of Leptin with the Stress System Components

7

stress also tend to consume palatable foods, saturated in fat and sugars and / or to increase comfort snack intake (Zellner et al 2006). It has been proposed that such foods can ameliorate the anxiety levels and emotional load from the stressful situation, contrasting their deleterious effects on metabolism (Van Dijk and Buwalda 2008).

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Non-Homeostatic Feeding In addition to the well established role of leptin in homeostatic regulation of feeding (i.e upon metabolic demands), this adipokine has been implicated in the attenuation of nonhomeostatic feeding that relates to pleasure or reward. The neuronal circuitry transforming motivation into action and connecting hedonic stimuli with associative learning comprises of the striatum / substantia nigra and parts of the cerebral cortex, hippocampus, and amygdala. Dopamine releasing neurons in the mesolimbic brain consist the major neurotransmitter system contributing to the reward. Leptin can reduce food reward behaviors by modulating the function of dopaminergic and opioidergic neurotransmitter systems in this area. These effects of leptin, that are independent of its actions in adiposity control, can be exerted either through hypothalamic afferents that reduce for example orexin levels, or through a JAK2/STAT3 pathway directly acting in the ventral tegmental area (Figlewicz and Benoit 2009). Glucocorticoids contradict these actions of leptin as well. Studies in humans (Pruessner et al 2004) and rats (Rouge-Pont et al 1998) have shown that increased glucocorticoids following stress can increase dopamine release in the mesolimbic area, promoting a non-homeostatic food intake that can potentially link the deleterious effects of chronic stress on the settlement of obesity. The interrelated brain circuits of energy homeostasis and stress response should act in concert to satisfy the energy needs of this organ, to keep the peripheral energy stores stable and at the same time to achieve resilience following stress. Insulin resistance and a prolonged activation of the SNS by leptin (that represent counter regulatory mechanisms aiding brain glucose homeostasis), as well as stress-induced overfeeding may explain how a central energy disequilibrium can become the sequel of the metabolic syndrome.

INTERPLAY IN SIGNALING PATHWAYS The reciprocal leptin and stress hormones‘ interactions entail shared signal transduction pathways or mediators. Though the typical signaling pathways for these hormones are distinct, recent data have provided evidence for converging processes that enable important cross talk among them.

Leptin Soon after leptin was discovered, leptin‘s receptor (ObR) was biochemically identified and characterized as a member of class I cytokine receptor family. Leptin receptor gene is expressed broadly and its mRNA undergoes alternative splicing, producing different ObR isoforms which are designated as ObR (a-f). These isoforms are classified into three classes:

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

8

George Soulis and Efthymia Kitraki

short, long and secreted. The long full length receptor (ObRb) is considered the functional receptor in signaling that mediates tissues‘ energy homeostasis. (Fruhbeck 2006). The JAK2/STAT3 is the major signaling pathway utilized by leptin to exert its metabolic actions. Leptin binding to ObRb activates the receptor associated cytoplasmic tyrosine kinase molecule Janus Kinase 2 (JAK2). JAK2 bound to the receptor is autophosphorylated and consequently phosphorylates multiple tyrosine residues on the intracellular domain of ObRb, each of which propagates a different set of downstream signaling mediators. In the JAK/STAT pathway, JAK2 activates, by phosphorylation, STAT molecules that dimerize and translocate to the nucleus to regulate the transcription of target genes. Phosphorylated Tyr1138 is essential for activation of STAT3. Among the genes activated by the canonical JAK2/STAT3 pathway are pomc mediating the anorexic actions of leptin in the hypothalamus, as well as bcl2, cyclin D and myc, encoding for survival and proliferation promoting factors. Activated STATS also control the duration of own signaling by inducing genes that inhibit the pathway, such as Protein Inhibitor of Activated Stats (PIAS), Protein Tyrosin Phosphatases (PTPS) and Suppressors of Cytokine Signaling (SOCS) (Fruhbeck 2006). Other phosphorylated tyrosines on JAK2 are participating in the recruitment of STAT5 and SHP2/GRB2 adapter proteins of the RAS/RAF/MAPK pathway and its ramifications. Activation of MAPK pathway leads to the expression of target genes, such as c-fos and egr-1 which participate in proliferation and differentiation processes. Leptin also increases phosphorylation of p38 MAPK and has the ability to fire c-Jun N-terminal kinase (JNK), with the effectors of the latter cascades not fully elucidated as yet (Cui et al 2006). The PI3K pathway, the main signal transduction pathway activated by insulin is also turned on by leptin, both in the CNS and the periphery (Fruhbeck 2006). The conjunction is achieved via JAK2 and insulin receptor substrate 2 (IRS2) - dependent routes and the activity of this signaling cascade is essential for the mediation of leptin‘s actions in the sympathetic system, leading to the reduction of feeding. The PI3K pathway transduces the action of leptin on SNS activation and on the excitability of hypothalamic and hippocampal neurons. In the hypothalamus, this pathway is implicated in the reduction of excitation of glucose-sensitive neurons by leptin. In the hippocampus, the pathway is involved on leptin‘s actions concerning the development of long term potentiation (LTP) and long term depression (LTD) and the facilitation of NMDA-mediated synaptic transmission (Morrison 2009). Leptin‘s ability to activate intracellular pathways used in growth factor signaling, especially PI3K and MAPK, confer the molecular basis for leptin‘s neuroprotective action. These actions include for example the attenuation by leptin of dopamine neurons‘ loss in an animal model of Parkinson‘s disease, and the reduction of infract volume upon middle cerebral artery occlusion.

Glucocorticoids Glucocorticoids‘ signal transduction is typically mediated by intracellular receptors (GR), belonging to the nuclear receptor superfamily of steroid and thyroid receptors. Upon steroid hormone binding to its cytoplasmic receptor, the receptor undergoes conformational changes that enable translocation to the nucleus, where receptor dimmers act as transcription factors. In the brain, two types of receptors bind glucocorticoids with different affinity: The classical

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Interplay of Leptin with the Stress System Components

9

receptor (GR) and the mineralocorticoid receptor (MR) that binds the hormone with higher affinity than GR. GR are widely distributed in the brain and mediate the metabolic and negative feedback actions in the hypothalamus, whereas MR, selectively located in the limbic system, control basal HPA axis excitability and immediate neuronal firing at stress (De Kloet et al 2008). Apart from binding to specific DNA sequences (hormone responsive elements) in target genes, steroid receptors are known to interact with other transcription regulators, including the AP1 complex and NFkB (Smoak and Cidlowski 2004). Furthermore, membrane actions of both glucocorticoids and estrogens have been reported that relay on either membrane types of own receptors and/or steroid interactions with other membrane receptors (Buttgereit and Scheffold 2002; Joëls et al 2008). These quick actions are particularly involved in neuronal plasticity. Importantly, steroid receptors can also interact with signal transducers from other pathways such as the RAS/RAF/MAPK (Qiu et al 2001). This provides a canvas for complex signaling interactions of glucocorticoids with leptin, involving primarily non-genomic actions of these steroids. The most studied cross talk between glucocorticoids and JAK/STAT pathway reside in the protein - protein interactions between GR and STAT5 (Rogatsky and Ivashkiv 2006). GR enhance STAT5 mediated actions, whereas cytokine - STAT5 is inhibiting GR signaling. In contrast to other STATS, STAT3 is enhancing GR actions. Additionally, this molecule appears as key mediator of the direct effect of glucocorticoids on leptin‘s actions. Adrenalectomy enhances JAK/STAT signaling through activation of STAT3 and inhibition of SOCS-3 (Madiehe et al 2001). Further investigation showed that glucocorticoids inhibit the leptin-induced STAT3 phosporylation and JAK2 tyrosine phosphorylation in vitro and in vivo. Intracerebroventricular administration of glucocorticoids in rats, prior to leptin infusion results in increased food intake and a marked reduction of hypothalamic STAT3 phosphorylation (Ishida-Takahashi et al 2004). In the same study, a specific inhibitor for MEK, blocked the inhibitory effects of glucocorticoids on leptins‘ signalling in vitro, suggesting that their antagonism is exerted partly through interactions of GR signaling with kinases of the MAPK pathway. Because the observed inhibitory effects of glucocorticoids occurred rapidly, they probably belong to the non-genomic actions of glucocorticoids on leptin signaling.

Estrogens Gonadal steroids interfere with the complex metabolic regulations and the final outcome is often sexually dimorphic. Leptin signaling has a noteworthy interaction with estrogens. As in the case of glucocorticoids, STAT 3 plays a critical role on the cross talk of leptin and estrogen signaling. However, in contrast to glucocorticoids, estrogens share common physiological actions with leptin on food intake, body adiposity, energy expenditure, neuroplasticity and reproduction (Gao and Horvath 2008). In the ARC, estrogens mimic leptin‘s actions on NPY and POMC neurons by increasing excitability. These effects of estrogens on energy regulation do not require an intact ObR, as they are also observed in ob/ob and db/db mice (Grasa et al 2000), suggesting that estrogen – leptin signaling interplay bypasses ObRs and is exerted to downstream effectors of leptin pathway. STAT3 is the most suitable candidate for this interplay. In contrast to glucocorticoids, estrogens increase STAT3

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

10

George Soulis and Efthymia Kitraki

phosphorylation through distinct mechanisms, including either a direct association of ERs with STAT3, or indirect interactions with MAPK or PI3K components (Gao and Horvath 2008). The cross talk between estrogens and STAT3 is exerted at least in part through nongenomic actions of estrogen receptors and mostly through estrogen receptor alpha (ERa), the receptor that predominates in the ARC and mediates the antiobesity actions of estrogens (Roesch 2006).

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Norepinephrine Norepinephrine and epinephrine signalling is mediated by several a- and badrenoreceptor types coupled to G-proteins. G-proteins stimulate adenylate cyclase and phopholipase C to produce second messengers such as cyclic adenosine 5′-monophosphate (cAMP), inositol 1,4,5-triphospate (IP3), diacylglycerol (DAG) and calcium. These messengers subsequently activate protein kinases of different signal transduction pathways including protein kinases A, C and calcium/calmodulin kinases. Stimulated a1adrenoreceptors usually lead to the activation of IP3/DAG pathway, b-adrenoreceptors lead to the cAMP/PKA pathway, whereas a2-receptors block the cAMP pathway. NE acts via a1- and a2-adrenoceptors in the hypothalamus to modulate eating, while in the limbic system NE via b-receptors is involved in the development of LTP ( Joels and De Kloet 1989). The two subtypes of a-adrenergic receptors within the PVN exert antagonistic actions on eating in the rat: activation of a1-adrenoceptors suppresses eating whereas activation of a2-adrenoceptors promotes eating (Wellman et al 1993). Additionally, NE has a stimulatory role on HPA axis activation and glucocorticoid release, opposing leptin‘s effect. It has been suggested that apart from the direct effects of leptin on the adrenals, leptin-induced cessation of corticosteroid release may be mediated through a reduction of NE levels in the PVN. In support of this, a rodent study showed that both systemic and central administration of leptin decreases NE concentrations in the PVN and this decrease is accompanied by reduction of serum glucocorticoids (Clark et al 2008). This reduction of glucocorticoids was blocked by the α1- and α2-adrenergic agonists, whereas β-adrenergic agonists had no effect on the leptin-induced decrease in plasma glucocorticoids. In the limbic brain, sympathetic and neuroendocrine interactions over time synergise or contradict in the emotional and cognitive processing of a stressful event. For instance, NE via b-adrenoreceptors can either facilitate the appearance of LTP in the presence of glucocorticoids, or repress it, depending on the time domain of their interaction (Joels et al 2009). Glucocorticoids can activate cAMP/PKA pathway and concomitantly increase CREB phosphorylation in basolateral amygdala during learning when the training conditions also favour enhanced noradrenergic activation via b- and a1-receptors (Ferry et al 1999). Other studies have indicated a possible synergy of glucocorticoids with NE to mediate stress-related behavioural effects of glucocorticoids through the MAPK pathway (Revest et al 2005). NE via b-adrenoreceptors can also potentiate glucocorticoids‘ effects through the PI3K pathway (Schmidt et al 2005). However the exact mechanisms for the aforementioned stress hormones‘ interactions and most importantly for a possible interplay between NE and leptin signaling remain to be elucidated.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Interplay of Leptin with the Stress System Components

11

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

EFFECTS OF LEPTIN / STRESS HORMONES INTERACTIONS ON STRESS RESPONSE As previously mentioned, leptin‘s levels and function are modified by the stress hormones. Conversely, leptin interferes with the production of stress system mediators and may influence the outcome of stress responses. Increased leptin levels reduce glucocorticoids release from the adrenals (Spinedi and Gaillard 1998). In obese mice lacking the hormone (ob/ob mice), leptin administration also reduces glucocorticoids levels (Slieker et al 1996). Elevated leptin levels also exert an inhibitory effect on HPA axis response to stress (Heiman et al 1997; Giovambattista et al 2000). On the other hand, elevated leptin levels lead to the activation of SNS by promoting CRH release in the PVN (Yokotani et al 2001). There is evidence for the participation of brain NE in leptin-mediated changes on HPA axis responsiveness to stress. Reduced levels of leptin or leptin deficiency coincide with elevated NE levels (Proietto et al 2000). Food deprivation that reduces leptin levels augments plasma ACTH levels and NE release in the PVN of rats exposed to footshock stress, whereas intracerebroventricular leptin injection attenuates both stress responses (Kawakami et al 2008). Systemic administration of leptin in rats decreases both NE release from the PVN and plasma corticosterone levels, and this action is inhibited by a-adrenergic receptors‘ agonists (Clark et al 2008), implying a participation of these NE receptors in the involvement of leptin in stress response. In rats, metabolic disturbances due to unbalanced or caloric dense diets that alter leptin sensitivity can modify stress coping. Several studies have shown that prolonged fat intake often followed by weight gain, insulin and glucose alterations can enhance hypothalamic NE levels following stress (Pascoe et al 1991) and increase HPA axis activation in terms of corticosterone and ACTH release (Tannenbaum et al 1997; Kamara et al 1998). By using a short term fat diet protocol that caused homeostatic increases in leptin levels we detected a lower stress-induced increase in hypothalamic GR mRNA levels in fat-fed male rats (Kitraki et al 2004b). This result implies reduced responsiveness to stress and subsequently reduced effectiveness of these receptors to exert a negative feedback on HPA axis activation. A high fat diet combined with chronic stress can have additive effects on stress-induced impairment of synaptic plasticity. Rats with increased anxiety levels prefer high-fat, comfort food and in parallel have higher stress-induced dendritic retraction in their hippocampus compared to animals exposed to chronic stress alone (Baran et al 2005). Furthermore, the combination of chronic stress with a high fat and sugar diet can accelerate the appearance of obesity and the metabolic syndrome in mice, by stimulating the sympathetic system-mediated release of NPY directly into the adipose tissue (Kuo et al 2008). On the other hand, high fat diets have been shown to ameliorate anxiety impact on behaviour an important reason for the preferred consumption of such food at stress (van Dijk and Buwalda 2008). In animal studies high fat diets have been reported to reduce anxiety levels in experimental animals (Prasad and Prasad 1996; Buwalda et al 2001; Soulis et al 2007). SNS hypoactivation and reduced melanocortin signaling in the brain may confer to the anxiolytic diet effect (Chaki and Okubo 2007). Seeking for anxiety relief through palatable foods, can thus ultimately lead to a vicious cycle of increased neuroendocrine stress load, more comfort feeding and enhanced metabolic deterioration.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

12

George Soulis and Efthymia Kitraki

EFFECTS OF LEPTIN / STRESS HORMONES INTERACTIONS ON OTHER BRAIN FUNCTIONS The interplay of leptin with the stress hormones appears to extend in the whole range of leptin‘s multifaceted repertoire, including mood, synaptic plasticity and neuroprotection. Many of these features localize within the hippocampus, a semantic brain area for emotional and cognitive functions that is highly vulnerable to toxic and metabolic insults.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Emotionality Environmental stimuli that threaten homeostasis, such as unbalanced feeding, social defeat and stress at work, converge and are elaborated by the neuroendocrine stress response system. Unsuccessful coping will result to a state of permanent activation of the system. A wealth body of evidence suggests that elevated glucocorticoids and HPA axis dysfunction reside on the basis of both obesity and depression. A classical paradigm exemplifying this hypothesis is Cushing‘s syndrome, where hypercortisolemia, hypertension and overweight coincide with mood disorders (Bornstein et al 2006). Chronic stress is considered a predisposing factor for the onset of depression both in humans and in animal models (Akil 2005; Willner et al 2005). Elevated glucocorticoids increase excitability in the hippocampus that in turn interferes with neurotransmitter release, cognitive ability and plasticity. Synaptic terminals and dendritic arborisation are significantly affected by chronic stress, though mostly in a reversible way (Lucassen et al 2006). The same array of hippocampal dysfunction, including decreased neurogenesis, has been proposed to contribute to the emergence of depression (Krishnan and Nestler 2008). The reduced levels of glucocorticoid receptors in chronic stress do not allow efficient termination of the stress response that will shut down corticosteroid release, thus conferring to the stress – induced hippocampal dysfunction. Genetically modified mice to overexpress GR in the nervous system show better stress coping and reduced ‗depressive‘ behaviour following stress, supporting the role of GR in homeostatic feedback and its importance in depression (Ridder et al 2005). ObRb localization in the hippocampus, a site of importance for depression pathogenesis led researchers to examine a possible implication of leptin in the chronic stress - induced ‗depression‘ in rodents. Rats exposed to chronic stress have reduced leptin levels (Herman et al, 1995; Bhatnagar and Vining 2003), reduced glucocorticoid receptors‘ mRNA levels in the hippocampus (Kitraki et al 1999; Raone et al 2007; Chen et al 2008) and they often exhibit anhedonia, a core symptom of depressive illness in humans (Willner et al 2005). Lu et al (2006) showed that systemic or intrahippocampal leptin administration in rats exposed to chronic unpredictable stress, a well established paradigm of‗depression‘ in rodents, could reverse the depressive-like behaviour of these animals. This action of leptin was specific for the hippocampus, since diffusion of leptin into the hypothalamus affected metabolic but not emotional parameters. Leptin‘s anti-depressive profile was similar to anti-depressive drugs targeting the serotonin system that deteriorates in depression. Notably, chronic stress is among the factors that impair serotonergic function, triggering anxiety and depression (Leonard 2006).

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Interplay of Leptin with the Stress System Components

13

In humans, low leptin levels have been detected in some (Westling et al 2004) but not all cases of major depression studied (Deuschle et al 1999), while elevation of plasma leptin levels has been reported to coincide with improvement of the depressed phenotype (Esel et al 2005). Leptin administration to subjects with a genetic leptin deficiency also normalizes the metabolic as well as the neuroendocrine stress axis aberrations (Licinio et al 2004). The reciprocal interaction between circulating glucocorticoids and leptin that governs the metabolic equilibrium also characterizes emotional state and depression (Licinio et al 1997). Leptin is known to blunt stress response, in terms of corticosterone and ACTH release, and to block glucocorticoid production by the adrenals (Bornstein et al 1997). Thus, an intact leptin circuit can counterbalance the effects of glucocorticoids in mood disorders. Conversely, reduced leptin levels (in several chronic stress paradigms) or signalling (in the obese state, leptin resistance), may promote an exaggerated stress response similar to that often met in the depressed state, denoting a synergy of these two factors (obesity and chronic stress) in depression. Notably, other molecules downstream of glucocorticoid and leptin signalling such as CRH and brain derived neurotrophic factor (BDNF) are also implicated in depression. CRH levels and function deviate from normal in several brain areas of depressed patients and regulation of its levels and signalling is among the pharmacological interventions for the treatment of depression (Nemeroff et al 1988; De Kloet et al 2005). BDNF administration in the hippocampus mimics the behavioural profile achieved by leptin in rat models of depression (Hoshaw et al 2005). On the other hand, elevated glucocorticoids and chronic unpredictable stress reduce BDNF expression in the hippocampus (Smith et al 1995). Recent studies suggest an additional link between satiety signals and mood, controlled by SNS. This resides on the increase of BDNF gene expression in the hippocampus and of NE levels in the rat frontal cortex, upon stimulation of the vagus nerve (Follesa et al 2007). Stimulation of this nerve has been approved for the treatment of chronic, resistant, forms of depression (George et al 2007). This stimulation also improves memory function in both humans and animals, providing a means for the role of satiety factors in synaptic plasticity (Gomez-Pinilla 2008).

Synaptic Plasticity Both leptin and BNDF enhance synaptic plasticity in the hippocampus by several ways. Leptin potentiates activation of the NMDA receptors of glutamate by increasing long term potentiation, the cellular basis of learning and memory (Shanley et al 2001). Zucker rats and mice lacking leptin‘s receptor show impaired spatial learning (Li et al 2002). Diabetic patients and rodents exhibit learning deficits (Gispen and Biessels 2000). Leptin, as well as BDNF induce morphological changes in hippocampal dendrites (increased neurite outgrowth and branching) that are associated with synaptic remodelling and increased plasticity (O‘ Malley et al 2007). In contrast to leptin, elevated HPA axis activity and glucocorticoid levels are negatively correlated with neuroplasticity and cognitive performance. Elevated glucocorticoids reduce BDNF expression in the hippocampus (Smith et al 1995) that may additionally dampen the stress-induced elimination of plasticity. Chronic psychological stress reduces the dendritic arborisations of CA3 pyramidal neurons that in turn impair HPA axis negative feedback, leading to further glucocorticoid release and cognitive deficit (Conrad 2006). Glucocorticoids

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

14

George Soulis and Efthymia Kitraki

influence cognitive function, especially the hippocampus-dependent spatial learning and memory (Kim and Diamond 2002). The effect of glucocorticoids on spatial memory is Ushaped with low to moderate levels enhancing cognitive performance (Oitzl and de Kloet 1992). The two types of corticosteroid receptors in the hippocampus (GRs and MRs) mediate these effects intervening on different stages of memory processing. GRs acting is required during consolidation and recall of the information, whereas MRs are important for the adopted strategy to resolve the task. A balanced ratio of GR / MR activation is indispensable for an optimum learning and memory outcome.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Neuroprotection There is growing evidence that leptin exerts neuroprotective actions in the CNS. Many of the findings support leptin‘s potential therapeutic use in degenerative diseases, cerebral ischemia and epilepsy (Signore et al 2008). Leptin receptors in dopaminergic neurons of the substantia nigra support a role of leptin in the nigrostriatal pathway that is ablated in Parkinson‘s disease (Figlewicz et al 2003). In an animal model of the disease, leptin protects dopaminergic neurons from the neurotoxin 6-hydroxydopamine via a mitogen-activated protein kinase signalling pathway that may also implicate leptin-mediated BDNF induction (Weng Z et al 2007). Excitotoxicity induced by glutamate release is a major cause of neuronal damage, as a result of toxic agents acting in the brain, stroke/ischemia, or chronic stress. Glutamatergic excitation leads to excessive calcium release and to the formation of reactive oxygen species (ROS) that ultimately lead to apoptotic and necrotic cell death. In animal models of ischemic damage, as well as in neuronal cultures, leptin exerts a protective action against glutamatergic damage (Dicou et al 2001; Zhang and Chen 2008). Leptin acts as an anti-apoptotic agent through the activation of JAK2/STAT3, MEK/ERK and PI3-K/AKT signalling pathways. Downstream mediators include superoxide dismutase and Bcl-XL survival factors (Guo et al 2008). Epileptic seizures are often accompanied by neuronal cell death and hippocampal neurons are highly susceptible to seizure-induced excitotoxicity. Epileptic seizures induce the expression of BDNF in granule cells of the dentate gyrus and in mossy fibers. In the hippocampus BDNF exerts an anticonvulsive effect by inhibiting glutamate release following the epileptogenic insult (Reibel et al 2000). Leptin also exerts neuroprotective and -mostlyanticonvulsant actions in the hippocampus that require the activation of JAK2/STAT3 pathway (Shanley et al 2002). Mice with genetically ablated leptin gene are more prone to epileptic seizures (Erbayat-Altay et al 2006). Elimination of leptin‘s signalling, such that occurring in the obese state, is considered a risk factor for the appearance of epilepsy. Highly fat (ketogenic) diets that increase leptin levels have been used in the treatment of childhood intractable epilepsy (Kossoff et al 2009). However, consumption of diets enriched in saturated fat and refined sugar is in general harmful for brain function and physiology. Such diets promote obesity and increase lipid oxidation and consequently the levels of ROS and oxidative stress that endanger neuronal survival (Mattson 2007). Additionally, exposure of rats to high fat / high sucrose diet reduces synaptic plasticity and LTP in the hippocampus (Stranahan et al 2008) and impairs the performance of animals in hippocampal dependent spatial tasks (Molteni et al 2002). These effects are accompanied by a reduction of BNDF

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Interplay of Leptin with the Stress System Components

15

levels in this area, further stretching the favourable role of BDNF in hippocampal plasticity and cognitive function. In contrast to the protective actions of leptin, increased levels of glucocorticoids have been linked with several forms of neuronal damage. The main mechanism through which glucocorticoids affect neuronal integrity is the potentiation of glutamate-induced excitotoxicity (Sapolsky 2000). The glucocorticoid-induced ROS increase is mediated through GRs that increase the level of NADPH oxidase, (leading to ROS formation) and at the same time decrease the level of glutathione peroxidase (conferring detoxification) (You et al 2009). Other pathways, involving non-genomic actions of glucocorticoids on calcium increase have also been proposed and implicate the suppression of a pro-survival NR2A/ERK/MAPK signalling pathway (Xiao et al 2010). However, the role of glucocorticoids in the survival of hippocampal neurons appear biphasic as it has been shown to exert both protective and destructive actions. Recent data show that at low doses glucocorticoids have neuroprotective properties whereas at high doses enhance the epileptogenic toxicity of kainic acid (Du et al 2009). In these actions, an interaction of glucocorticoid receptors with members of the Bcl2 family, implicated in apoptosis, appears critical. At this point, it should be noted that the differential outcome of corticosteroid actions in neuronal fate may also attribute to the existence of the two distinct receptors for glucocorticoids in the limbic system: the low affinity GRs that are fully activated when hormone concentration is elevated and the high affinity MRs that are active even at low hormone levels. A previous study has shown that the two receptors exert opposing effects on hippocampal neurons‘ survival. GR activation promotes apoptosis of granule cells by enhancing the action of the pre-apoptotic molecules Bax and P53, whereas MR activation favours the action of anti-apoptotic mediators Bcl2 and Bcl-XL (Almeida et al 2000). While glucocorticoid excess and GRs overdrive are harmful for neurons, estrogens are considered important neuroprotective agents in neurodegenerative diseases, stroke, affective disorders, diabetes mellitus and cognitive function (De Nicola et al 2009). Estrogens exert their neuroprotective actions by activating the same pathways used by BDNF (ERK/MAPK, PI3K, cAMP/CREB) and up-regulate anti-apoptotic molecules like Bcl2, mimicking leptin‘s action (Scharfman and Maclusky 2005). Estradiol also potentiates memory formation by increasing NMDA receptor activity and LTP in the hippocampus (Liu et al 2008), as it has been also reported for leptin. Estrogens‘ neuroprotective role is greatly exemplified by their ability to enhance neurogenesis within the hippocampus (Isgor and Watson 2005). Importantly, neurogenesis enhancement by estrogens has also been reported in cases of deficient cell proliferation such as brain trauma, diabetes mellitus and aging (De Nicola et al 2009).

PERIFERAL EFFECTS OF LEPTIN / STRESS HORMONES INTERACTIONS The sympathetic nervous system plays an essential role in the regulation of metabolic and cardiovascular homeostasis. Aberrations from its normal function are linked to obesity. Low SNS activity has been suggested to be a risk factor for weight gain and the appearance of obesity, due to the reduction of energy expenditure (thermogenesis) (Bray et al 1989). On the other hand, SNS hyperactivation characterizes a number of metabolic and cardiovascular

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

16

George Soulis and Efthymia Kitraki

diseases that occur more frequently in obese individuals (Esler et al 2003). Whether the obesity-promoting SNS abnormality resides in the hypoactivation or the hyperactivation of the system is still a matter of debate and both mechanisms are probably contributing (Young and Macdonald 1992).

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Hypertension Obesity-related hypertension, a major contributor to cardiovascular damage, is related to increased sodium re-absorption that can be caused by kidney dysfunction, renin-angiotensin system activation or increased SNS activity (Da Silva et al 2009). Hyperleptinemia and central stimulation of the melanocortin pathway are among the factors leading to kidney SNS activation. Although weight gain, and thus increased leptin levels, can increase SNS activation even in non-obese subjects, this is mostly obvious in visceral obesity (Davy and Orr 2009). Furthermore, obesity may lead to SNS activation in a tissue-selective way: enhance SNS activation in kidney or skeletal muscle more than in the heart, where the increased cardiac tone owns to reduced parasympathetic activity. Interestingly, the increased leptin levels in obese subjects are able to activate the renal SNS, and thus contribute to hypertension, even in cases of reported resistance to the anorexic actions of the hormone. This is often referred to as ‗selective leptin resistance‘ (Correia and Haynes 2004) and may explain the extended contribution of leptin-SNS interaction in obesity hypertension. Evidence from animal studies and humans have shown that the stimulatory effect of leptin on renal SNS requires an intact POMC-melanocortin pathway and particularly MC4-R in the CNS. Pharmacological blockade of melanocortin receptors by intracerebral administration of a MC3/MC4R antagonist, completely inhibits kidney SNS activation (Haynes et al 1999). MC4R deficient mice are not hypertensive, although they develop obesity and have high levels of insulin and leptin (Tallam et al 2005). Obese humans lacking MC4R have also considerably lower blood pressure compared to control obese subjects (Greenfield et al 2009). The association between leptin / SNS activation and hypertension / cardiovascular disease is more evident in women than in men (Ma et al 2009) probably due to their greater total fat mass and their significantly higher leptin levels (Rosenbaum et al 1996). In nonobese women, the levels of circulating leptin comprise an independent predictor of sympathetic cardiovascular activity (Brydon et al 2008). However, peripheral leptin resistance, occurring after a certain percentage of fat accumulation (Matsumoto et al 2003) may explain the reduction of cardiac sympathetic responsiveness to leptin in otherwise healthy young women. Stress exposure is known to activate both SNS and HPA axis. An increased or prolonged sympathetic response to acute stress is a prediction for developing hypertension in normotensive subjects (Flaa et al 2008).

Adiposity Leptin – SNS interactions significantly affect adipogenesis and the maintenance of a balanced lipolysis to lipogenesis ratio. Recent evidence from experimental animals showing SNS outflow from brain to white adipose tissue (WAT) and vice versa suggest that lipid

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Interplay of Leptin with the Stress System Components

17

mobilization in the WAT occurs primarily through SNS innervations (Bartness et al 2010). The leptin / melanocortin system through MC4-R has been suggested to mediate the SNSmediated WAT lipolysis (Bartness and Song 2007). Leptin acting either centrally or peripherally selectively increases sympathetic outflow to white fat depots. Based on the above, it could be assumed that decreased SNS drive to WAT could promote increases in adiposity, leading to obesity. However, WAT samples from obese subjects have higher lipolytic activity (Fried et al 1993) and at the same time leptin levels are also abnormally increased, implying a state of leptin resistance. However, this leptin / SNS-mediated exaggerated WAT lipolysis will result in increased levels of free fatty acids, leading to dyslipidemia and insulin resistance. Additionally, the released free fatty acids can either feed forward the lipogenesis towards increased adipogenesis or, through a deranged betaoxidation, they can improperly accumulate in non-adipose tissues, such as liver, pancreas and heart, causing lipotoxicity (Penn et al 2006). Glucocorticoids exert dual effects on energy expenditure: within CNS, adrenal corticoids are anabolic, counteracting the actions of leptin and insulin, whereas in peripheral tissues they stimulate catabolic actions that are however overruled in cases of prolonged glucocorticoid excess, like in patients with Cushing‘s syndrome (Burt et al 2007). High glucocorticoid levels, mainly through food intake, lead to a positive energy balance and consequently to increased adiposity. In the periphery, glucocorticoids promote the differentiation of preadipocytes to mature adipocytes by facilitating centrally released NPY action in the abdominal fat, where glucocorticoids up-regulate the NPY receptor Y2 (Kuo et al 2007). Visceral adipocytes have higher lipolysis rate than the subcutaneous ones both under basal conditions and when hypertrophic (McCarthy 2001). Glucocorticoids enhance lipogenesis by stimulating lipoprotein lipase (LPL) activity selectively in visceral fat (Ottosson et al 1994). This enzyme hydrolyzes triglycerides to free fatty acids (and glycerol), thus enabling their uptake and storage by adipocytes. Under situations of heightened glucocorticoid secretion, such as those following stress, and of increased lipolysis, inability of the lipogenesis process to withdraw all free fatty acids released by LPL will lead to increased free fatty acids in the circulation (dyslipidemia, insulin resistance, atheromatosis) or / and lipotoxicity. The above mentioned dysfunctions are often met in the metabolic syndrome, highly associated with a stressful environment (Bjorntorp and Rosmond 2000). The actions of glucocorticoids in visceral fat are significantly potentiated by two more factors: the first is the selectively increased number of glucocorticoid receptors in this area, compared to other fat pads and the second is the locally increased activity of 11β-HSD-I (11β hydroxyl steroid dehydrogenase type I) in obese subjects (Bujalska et al 1999). This enzyme converts inactive cortisone to active cortisol/corticosterone and manipulation of its activity has recently become a target for potential treatment of obesity (Tomlinson et al 2004).

GENETIC AND ENVIRONMENTAL IMPACT ON LEPTIN – STRESS HORMONES INTERACTION Genetic and environmental factors such as polymorphisms, early life nutrition and stress, in combination with later life habits and experiences, influence individuals‘ predisposition to

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

18

George Soulis and Efthymia Kitraki

both obesity and stress-related disorders. The distinct combinations of these factors may further confer to the individual differences in response to dysfuctions.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Genetics Monogenic forms of obesity are infrequent in humans and involve genes for leptin, leptin receptor, melanocortin receptor 4 and POMC. In most cases however, obesity has a polygenic basis and several genes have been linked to its heritability in humans. Although a significant progress has been made in the field, a detailed description of obesity-promoting genes is out of the scope of this chapter and the reader is advised to refer to relevant recent reviews (Loos 2009; Hinney et al 2010). Over the last years a lot of research has been carried out to indentify genetic variants in genes contributing to increased body mass index (BMI) and obesity. In this setting, single nucleotide polymorphisms (SNPs) of different genes implicated in food control and energy expenditure have been examined for associations with specific features such as meal size, number of meals ingested, BMI or BMI change over time. Concerning polymorphisms in leptin or leptin receptor genes, there is so far weak association, if present, with response to diets or predisposition to obesity (Paracchini et al 2005). In a study among obese women, common haplotypes for leptin or its receptor have been associated with extreme snack eating behavior (De Krom et al 2007). In a community-based cohort study, including 9,960 individuals, SNPs rs1045895 and rs1137101 in leptin receptor were associated with enhanced BMI change over time. Notably the rs1045895 SNP is in an intron region and is not associated with mortality; however, it could be linked to other functional SNPs contributing to BMI gain (Gallicchio et al 2009). The lack of a clear association could be due to the complex nature of obesity, which involves a number of additional genes and environmental factors. Glucocorticoid receptors mediate most of glucocorticoids‘ metabolic actions. In contrast to leptin gene, several polymorphisms have been described for GR gene. Single nucleotide polymorphisms in GR gene have been mostly studied for associations to major depression and HPA axis dysfunction (Derijk et al 2008). Interestingly, some of the detected GR SNPs also relate to individual heterogeneity in metabolic responses, associating increased sensitivity to glucocorticoids with a higher risk for metabolic diseases. The exon 2 polymorphism, GR N363S, found in approximately 4% of the population, has been linked with increased sensitivity to glucocorticoids that is accompanied by exaggerated HPA axis response in males, but not females (Van Rossum and Lamberts 2004). This polymorphism has been also associated to a worse metabolic profile, correlated to increased body mass index and coronary artery disease (Di Blasio et al 2003). GR BclI site polymorphism, occurring in 37% of the population, confers increased corticosteroid sensitivity and worse cardiovascular and metabolic function, often accompanied with unipolar depression. The exon 2 GR polymorphism ER22/23EK, found in approximately 3% of the population, has been related to decreased glucocorticoid sensitivity and enhanced depression prevalence. However, in parallel, it provides carriers with a favourable metabolic profile, characterized by lower risk for diabetes type-2 and cardiovascular disease (Van Rossum and Lamberts 2004). Another GR polymorphism conferring a beneficial metabolic pattern is A3669G. This SNP, occurring to approximately 27.6% of the European population, is associated to decreased risk of central obesity in women and increased high-density lipoprotein in men (Syed et al 2006). Carriers

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Interplay of Leptin with the Stress System Components

19

however exhibit decreased glucocorticoid sensitivity, exaggerated HPA axis responses and a higher incidence of depression. The aforementioned findings provide a means for individual variability in metabolic and stress disorders, based on polymorphisms of a single gene and furthermore indicate that a certain genetic variant may confer benefits to a system and pitfalls to another. Future association studies on complex haplotypes consisting of obesity-linked GR polymorphisms in combination with obesity-linked SNPs from other relevant genes will help to better understand the genetic basis of susceptibility to metabolic diseases.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Environmental Factors Susceptibility to obesity, diabetes and the metabolic syndrome, as well as to distress can be also shaped through environmental manipulations during early development. During development, fluctuations in nutrients and hormones influence the formation and maturation of metabolic and neuroendocrine circuits in the new organism. In uterine growth, mother-derived signals cross the placenta to the fetus. Signals such as leptin and glucocorticoids convey information, among others, for the metabolic and the emotional status of the mother (diabetic, overfed, undernourished or stressed mother). The impact of nutrient availability during embryonic life in humans is U-shaped. Babies with both low and high birth weights have higher risk to develop diabetes in adulthood. This is supported by many studies including those on subjects born during the Dutch famine winter (Painter et al 2005) or subjects from mothers with gestational diabetes (Plagemann 2007). Leptin is involved in fetal growth. It increases proliferation of pancreatic island cells from fetal rats (Islam et al 2000) and importantly is required for normal brain development in rodents (Udagawa et al 2007). This imposes that fluctuation in leptin levels during pregnancy may influence the development of appetite regulation pathways and prescribe metabolic disturbances with later onset. Umbilical and circulating leptin levels are low in small for gestational age (SGA) babies and heightened in macrosomic offspring from diabetic mothers (Lea et al 2000). Nevertheless both categories are at risk to develop obesity later in life, though through different mechanisms. An accelerated catch-up growth in the case of SGA babies may disturb the prenatally-set central metabolic homeostasis, programmed to function at low nutrient availability, whereas in the case of overweight offspring, early hyperleptinemia promotes glucose deregulation and insulin resistance (Vickers 2007). Additionally, evidence from leptin deficient mice (ob/ob) suggest that leptin may function as a developmental signal for brain development. Ob/ob mice show defects in neuronal organization and altered dendritic orientation (Bereiter and Jeanrenaud 1980), while similar morphological alterations have been reported for db/db mice lacking leptin receptor (Garris 1989). The human fetus is hyporesponsive to stress. The embryo is protected by stress largely due to the action of the placental 11b-HSD-2 that under normal conditions metabolizes maternal cortisol to inert compounds. Reduced activity of this enzyme has been associated with reduced intrauterine growth of the fetus (Dy et al 2008). Fetuses exposed to stress through the mother are often born small for gestational age and in several cases they exhibit a disturbed HPA axis response later in life. As in the case of metabolic disturbances, the early

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

20

George Soulis and Efthymia Kitraki

life stress - induced disturbance depends on the gestational age at stress experience. Children exposed to gestational stress between 12 and 22 week exhibit a negative correlation between birth weight and saliva cortisol in response to a psychological stress (Wust et al 2005). Rats from undernourished mothers during pregnancy have high leptin levels in plasma, are prone to develop obesity and also exhibit increased leptin levels following SNS activation in adult life. Interestingly, leptin administration in the neonatal period prevents the programmed obesity in these animals (Vickers 2007). These data and similar findings in rodents support a programming action of leptin on central metabolic networks during postnatal brain development (Bouret and Simerly 2006). Furthermore, protein-restricted dams have reduced levels of 11b-HSD-2 due to low protein diet, whilst at the same time they have increased levels of circulating glucocorticoids, due to the life-threatening stress of food restriction (Vickers 2007). This combination could provide a mechanism of the interplay between leptin and glucocorticoids in programming the metabolic circuits during development. In rats, the human equivalent period for HPA axis development, including the so called stress hyporesponsive period, extends postnatally. After birth the HPA axis is immature and although it has been reported that maternal stress can increase CRH mRNA in utero (Van Bockstaele et al 2001), the axis reaches adult efficiency after the second postnatal week. During this postnatal period, two experimental manipulations show the importance of early life experiences in later life. Neonatal handling, a brief manipulation of neonatal rats during the stress hyporesponsive period, permanently modifies the stress response axis towards a better stress coping in adulthood. Handling - induced modifications include reduction of hypothalamic CRH and anxiety levels, reduction of leptin levels in males and increases of GR levels in the hippocampus (Francis et al 1996; Panagiotaropoulos et al 2004). In contrast to short term handling of rat neonates, longer periods of maternal separation (MS) ranging from 3 to 24 hours result in adult offspring with low stress coping efficiency, accompanied by reduced brain GR levels (Sutanto et al 1996). MS manipulation appears to affect both stress and metabolic systems. The maternally deprived pups show elevated basal corticosterone levels and a robust corticosterone and ACTH response to a mild stress during the stress hyporesponsive period (Levine 2001). At the same time, maternal separation for 3h daily from postnatal day 1-14 increases basal POMC levels in the arcuate hypothalamus and inhibits fasting –induced increase in NPY, in adult life (Kim et al 2005). In another study, 24 hours of maternal deprivation at postnatal days 5 or 14, decreased food intake of the deprived animals in adulthood (Penke et al 2001).

Epigenetics Early environmental manipulations, as these described above, may lead to epigenetic alterations in the respective systems that permanently modify gene expression. Changes in the methylation pattern and/or chromatin structure in the promoter of relevant genes are among the main mechanisms of epigenetic actions (Newnham et al 2009). In humans, the environmental impact on BMI has been nicely demonstrated in monozygotic twins, who do not differ epigenetically during the first years of their life, but as they grow up, they show remarkable differences in overall 5-methylcytosine DNA and histone acetylation patterns (Fraga et al 2005). Cytosine hypermethylation in gene promoters

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Interplay of Leptin with the Stress System Components

21

leads to cessation of gene transcription. Folate, an important vitamin in normal diets needed for nucleotide synthesis, also provides, through methionine synthesis, the methyl group in methylation reactions. Restricted diets, deficient in folate, have been observed to decrease genome-wide methylation both in humans and in animal models. Individuals who were prenatally exposed to famine during the Dutch Hunger Winter (1944-45) had, 6 decades later, reduced DNA methylation of the insulin-like growth factor 2 (IGF2) gene, compared with their unexposed same-sex siblings. Further research showed however that a certain polymorphism in IGF2 binding protein 2 gene (that is, the genetic background of the individual) was also an important risk factor for the severity of metabolic disturbances detected in the exposed individuals several decades later (Van Hoek et al 2009). Experiments in rodents, observing the methylation pattern of agouti gene, have suggested that maternal diet can have a significant effect on DNA methylation of the offspring (Waterland and Jirtle 2003). Reduction in the methylation of the adipogenic and lipogenic transcription factor peroxisome proliferator-activated receptor alpha (PPARa) has been shown to occur in the offspring of protein restricted pregnant rats (Lillycrop et al 2008). This hypomethylation leads to permanent transcriptional activation of liver genes participating in lipid metabolism. The consequences of this egigenetic alteration may promote insulin resistance and diabetes type 2, as PPARa knockout mice are protected from fat diet-induced insulin resistance (Guerre-Millo et al 2001). In the rat, early life adversity in the form of low maternal care can epigenetically modify GR gene expression by changing its methylation pattern in the hippocampus of the treated offspring (Weaver et al 2005). These findings have recently been translated to humans, where increased promoter methylation and decreased GR gene transcription were detected in the hippomampus of suicide victims with a history of childhood abuse (McGowan et al 2009). Leptin signaling during development is indispensable for both metabolic programming and neuronal growth (Forhead and Fowden 2009). The surge of leptin levels during the first two weeks of postnatal life in rodents may also contribute to HPA axis maturation over this period. Leptin levels in fetal circulation are prone to stress-induced changes. In sheep fetuses, cortisol infusion or maternal dexamethasone treatment increase plasma levels and adipose tissue mRNA for leptin (O‘Connor et al 2007) whereas in the rat, dexamethasone administration in the mother reduces leptin levels in fetal circulation (Smith and Waddell 2002). It is therefore possible that early life stressful experiences that increase glucocorticoid levels directly affect and modify leptin actions on the development of metabolic and neuroendocrine brain circuits.

CONCLUSIONS The interplay between leptin and stress hormones has significant implications in the establishment of a central metabolic disturbance (brain metabolic syndrome) that precedes the appearence of peripheral symptoms. Leptin levels are modified by stress hormones. Conversely, leptin enhances SNS activation, whereas it reduces HPA axis response to stress. Leptin antagonizes also the effects of glucocorticoids in the pathogenesis of depression, in synaptic plasticity and neuroprotection. The transctiption factor STAT3 of the canonical leptin pathway has a principal contribution in the cross talk of leptin with glucocorticoids, as

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

22

George Soulis and Efthymia Kitraki

well as with gonadal steoroids. In the periphery, visceral adipocytes are highly responsive to glucocorticoid-induced tissue growth and to SNS-controlled lipolysis. In cases of leptin or insulin resistance these processes aggravate central fat accumulation and dyslipidemia. In the kidney, exhibiting low leptin resistance compared to other tissues, leptin – SNS interaction is highly implicated in obesity hypertension. Genetic polymorphisms, such as those identified so far in the glucocorticoid receptor gene, may contribute to the factors increasing individual variability in metabolic and stress responses. Environmental manipulations during early development confer to the shaping of the circuits controlling the aforementioned responses and may further amplify the divergence of their interactions later in life.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

REFERENCES Akil H. Stressed and depressed. Nat. Med. 2005 Feb;11(2):116-8. Almeida OF, Condé GL, Crochemore C, Demeneix BA, Fischer D, Hassan AH, Meyer M, Holsboer F, Michaelidis TM. Subtle shifts in the ratio between pro- and antiapoptotic molecules FASEB J. 2000 Apr;14(5):779-90. Askari H, Liu J, Dagogo-Jack S. Hormonal regulation of human Int. J. Obes. Relat. Metab. Disord. 2000 Oct;24(10):1254-9 Baran SE, Campbell AM, Kleen JK, Foltz CH, Wright RL, Diamond DM, Conrad CD. Combination of high fat Neuroreport. 2005 Jan 19;16(1):39-43 Bartness TJ, Song CK. Thematic review series: adipocyte J. Lipid. Res. 2007 Aug;48(8):1655-72. Bartness TJ, Shrestha YB, Vaughan CH, Schwartz GJ, Song CK. Sensory and sympathetic nervous system Mol. Cell Endocrinol. 2010 Apr 29;318(1-2):34-43. Benoit SC, Thiele TE, Heinrichs SC, Rushing PA, Blake KA, Steeley RJ. Comparison of central administration of corticotropin Peptides. 2000 Mar;21(3):345-51 Bereiter DA, Jeanrenaud B. Altered dendritic orientation of hypothalamic neurons Brain Res. 1980 Nov 24;202(1):201-6. Bhatnagar S, Vining C Facilitation of hypothalamic-pituitary-adrenal responses to novel stress Horm. Behav. 2003 Jan;43(1):158-65. Bingham NC, Anderson KK, Reuter AL, Stallings NR, Parker KL Selective loss of leptin Endocrinology. 2008 May;149(5):2138-48 Björntorp P, Rosmond R. Obesity and cortisol Nutrition. 2000 Oct;16(10):924-36. Bornstein SR, Uhlmann K, Haidan A, Ehrhart-Bornstein M, Scherbaum WA. Evidence for a novel peripheral action of leptin Diabetes. 1997 Jul;46(7):1235-8. Bornstein SR, Schuppenies A, Wong ML, Licinio J. Approaching the shared biology of obesity Mol. Psychiatry. 2006 Oct;11(10):892-902. Boukouvalas G, Gerozissis K, Kitraki E. Fat feeding of rats during pubertal growth 2010, Cell Mol. Neurobiol. Jan;30(1):91-9. Bouret SG, Simerly RB. Developmental programming of hypothalamic feeding circuits. Clin. Genet. 2006 Oct;70(4):295-301. Bray GA, York DA, Fisler JS. Experimental obesity Vitam. Horm. 1989;45:1-125. Brydon L, O'Donnell K, Wright CE, Wawrzyniak AJ, Wardle J, Steptoe A. Circulating leptin Obesity (Silver Spring). 2008 Dec;16(12):2642-7.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Interplay of Leptin with the Stress System Components

23

Bujalska IJ, Kumar S, Hewison M, Stewart PM. Differentiation of adipose Endocrinology. 1999 Jul;140(7):3188-96. Burt MG, Gibney J, Ho KK. Protein metabolism Am. J. Physiol. Endocrinol. Metab. 2007 May; 292(5): E1426-32 Buttgereit F, Scheffold A. Rapid glucocorticoid effects on immune cells. Steroids. 2002 May;67(6):529-34. Buwalda B, Blom WA, Koolhaas JM, van Dijk G. Behavioral and physiological responses to stress Physiol. Behav. 2001 Jun;73(3):371-7. Chaki S, Okubo T. Melanocortin-4 receptor antagonists for the treatment Curr. Top Med. Chem. 2007;7(11):1145-51 Chandola T, Brunner E, Marmot M Chronic stress at work and the metabolic syndrome: prospective study. BMJ. 2006 Mar 4;332(7540):521-5. Chen JX, Tang YT, Yang JX. Changes of glucocorticoid receptor and levels of CRF mRNA, POMC mRNA in brain of chronic immobilization stress rats. Cell Mol. Neurobiol. 2008 Feb;28(2):237-44. Clark KA, Shin AC, Sirivelu MP, Mohankumar SM, Mohankumar PS. Systemic administration of leptin Brain Res. 2008 Feb 21;1195:89-95. Conrad CD. What is the functional significance of chronic stress Behav. Cogn. Neurosci. Rev. 2006 Mar;5(1):41-60. Correia ML, Haynes WG. Obesity-related hypertension Curr. Hypertens Rep. 2004 Jun;6(3):230-5 Cui H, Cai F, Belsham DD. Leptin signaling in neurotensin neuronsFASEB J. 2006 Dec;20(14):2654-6 Da Silva AA, do Carmo J, Dubinion J, Hall JE. The role of the sympathetic nervous system Curr. Hypertens Rep. 2009 Jun;11(3):206-11 Dallman MF, Strack AM, Akana SF, Bradbury MJ, Hanson ES, Scribner KA, Smith M. Feast Front Neuroendocrinol. 1993 Oct;14(4):303-47 Davy KP, Orr JS. Sympathetic nervous system Neurosci. Biobehav. Rev. 2009 Feb;33(2):11624 De Kloet ER, Joëls M, Holsboer F Stress and the brain Nat. Rev. Neurosci. 2005 Jun;6(6):463-75. De Kloet ER, Karst H, Joëls M. Corticosteroid hormones Front Neuroendocrinol. 2008 May;29(2):268-72 De Krom M, van der Schouw YT, Hendriks J, Ophoff RA, van Gils CH, Stolk RP, Grobbee DE, Adan R. Common genetic variations Diabetes. 2007 Jan;56(1):276-80. De Nicola AF, Pietranera L, Beauquis J, Ferrini MG, Saravia FE. Steroid protection Exp. Gerontol. 2009 Jan-Feb;44(1-2):34-40. Derijk RH, van Leeuwen N, Klok MD, Zitman FG. Corticosteroid receptor-gene variants: modulators of the stress Eur. J. Pharmacol. 2008 May 13;585(2-3):492-501 Deuschle M, Blum WF, Englaro P, Schweiger U, Weber B, Pflaum CD, Heuser I. Plasma leptin Horm. Metab. Res. 1996 Dec; 28(12): 714-7. Di Blasio AM, van Rossum EF, Maestrini S, Berselli ME, Tagliaferri M, Podestà F, Koper JW, Liuzzi A, Lamberts SW The relation between two polymorphisms Clin. Endocrinol. (Oxf). 2003 Jul;59(1):68-74 Dicou E, Attoub S, Gressens P. Neuroprotective effects of leptin Neuroreport. 2001 Dec 21;12(18):3947-51.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

24

George Soulis and Efthymia Kitraki

Drazen DL, Wortman MD, Schwartz MW, Clegg DJ, van Dijk G, Woods SC, Seeley RJ. Adrenalectomy alters Diabetes. 2003 Dec;52(12):2928-34. Du J, Wang Y, Hunter R, Wei Y, Blumenthal R, Falke C, Khairova R, Zhou R, Yuan P, Machado-Vieira R, McEwen BS, Manji HK. Dynamic regulation of mitochondrial function by glucocorticoids Proc. Natl. Acad. Sci. USA 2009 Mar 3;106(9):3543-8. Dy J, Guan H, Sampath-Kumar R, Richardson BS, Yang K. Placental 11beta-hydroxysteroid dehydrogenase type 2 is reduced in pregnancies complicated with idiopathic intrauterine growth Restriction: evidence that this is associated with an attenuated ratio of cortisone to cortisol in the umbilical artery. Placenta. 2008 Feb;29(2):193-200. Epel E, Lapidus R, McEwen B, Brownell K. Stress may add bite to appetite Psychoneuroendocrinology. 2001 Jan;26(1):37-49 Erbayat-Altay E, Yamada KA, Wong M, Thio LL. Increased severity of pentylenetetrazol induced seizures in leptin Neurosci. Lett. 2008 Mar 12;433(2):82-6. Esel E, Ozsoy S, Tutus A, Sofuoglu S, Kartalci S, Bayram F, Kokbudak Z, Kula M. Effects of antidepressant Prog. Neuropsychopharmacol. Biol. Psychiatry. 2005 May;29(4):565-70. Esler M, Lambert G, Brunner-La Rocca HP, Vaddadi G, Kaye D. Sympathetic nerve Acta Physiol. Scand. 2003 Mar;177(3):275-84. Fehm HL, Kern W, Peters A. The selfish brain Prog. Brain Res. 2006;153:129-40. Ferry B, Roozendaal B, McGaugh JL. Basolateral amygdala J. Neurosci. 1999 Jun 15;19(12):5119-23. Figlewicz DP, Evans SB, Murphy J, Hoen M, Baskin DG. Expression of receptors Brain Res. 2003 Feb 21;964(1):107-15. Figlewicz DP, Benoit SC. Insulin, leptin Am J Physiol Regul Integr Comp Physiol. 2009 Jan;296(1):R9-R19 Flaa A, Eide IK, Kjeldsen SE, Rostrup M. Sympathoadrenal stress Hypertension. 2008 Aug;52(2):336-41. Follesa P, Biggio F, Gorini G, Caria S, Talani G, Dazzi L, Puligheddu M, Marrosu F, Biggio G. Vagus nerve Brain Res. 2007 Nov 7;1179:28-34. Forhead AJ, Fowden AL. The hungry fetus J. Physiol. 2009 Mar 15;587(Pt 6):1145-52. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime Proc. Natl. Acad. Sci. USA 2005 Jul 26;102(30):10604-9. Francis D, Diorio J, LaPlante P, Weaver S, Seckl JR, Meaney MJ. The role of early environmental events in regulating neuroendocrine development. Moms, pups, stress Ann. N. Y. Acad. Sci. 1996 Sep 20;794:136-52 Fried SK, Leibel RL, Edens NK, Kral JG. Lipolysis in intraabdominal adipose Obes. Res. 1993 Nov;1(6):443-8 Frühbeck G. Intracellular signalling Biochem. J. 2006 Jan 1;393(Pt 1):7-20. Füzesi T, Wittmann G, Liposits Z, Lechan RM, Fekete C. Contribution of noradrenergic and adrenergic cell groups of the brainstem and agouti-related protein-synthesizing neurons of the arcuate nucleus to neuropeptide-y innervation of corticotropin-releasing hormone neurons in hypothalamic paraventricular nucleus of the rat. Endocrinology. 2007 Nov;148(11):5442-50.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Interplay of Leptin with the Stress System Components

25

Gallicchio L, Chang HH, Christo DK, Thuita L, Huang HY, Strickland P, Ruczinski I, Clipp S, Helzlsouer KJ. Single nucleotide polymorphisms BMC Med. Genet. 2009 Oct 9;10:103. Gao Q, Horvath TL. Cross-talk between estrogen Am. J. Physiol. Endocrinol. Metab. 2008 May;294(5):E817. Garris DR. Morphometric analysis of obesity Brain Res. 1989 Oct 30;501(1): 162-70. George MS, Nahas Z, Borckardt JJ, Anderson B, Burns C, Kose S, Short EB. Vagus nerve Expert Rev. Neurother. 2007 Jan;7(1):63-74. Giovambattista A, Chisari AN, Gaillard RC, Spinedi E. Food intake-induced leptin Neuroendocrinology. 2000 Dec;72(6):341-9. Gispen WH, Biessels GJ. Cognition and synaptic plasticity Trends Neurosci. 2000 Nov;23(11):542-9. Gómez F, Lahmame A, de Kloet ER, Armario A. Hypothalamic-pituitary-adrenal response Neuroendocrinology. 1996 Apr;63(4):327-37. Gómez-Pinilla F. Brain foods: the effects of nutrients Nat. Rev. Neurosci. 2008 Jul;9(7):56878. Grasa MM, Vilà R, Esteve M, Cabot C, Fernandez-López JA, Remesar X, Alemany M. Oleoyl-estrone lowers the body weight Horm. Metab. Res. 2000 Jun;32(6):246-50 Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron GS, Astruc B, Mayer JP, Brage S, See TC, Lomas DJ, O'Rahilly S, Farooqi IS. Modulation of blood N. Engl. J. Med. 2009 Jan 1;360(1):44-52 Guerre-Millo M, Rouault C, Poulain P, André J, Poitout V, Peters JM, Gonzalez FJ, Fruchart JC, Reach G, Staels B. PPAR-alpha-null Diabetes. 2001 Dec;50(12):2809-14. Guo Z, Jiang H, Xu X, Duan W, Mattson MP. Leptin-mediated cell survival J. Biol. Chem. 2008 Jan 18;283(3):1754-63. Haynes WG, Morgan DA, Djalali A, Sivitz WI, Mark AL. Interactions between the melanocortin system and leptin Hypertension. 1999 Jan;33(1 Pt 2):542-7 Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS. Leptin inhibition Endocrinology. 1997 Sep;138(9):3859-63 Herman JP, Adams D, Prewitt C. Regulatory changes in neuroendocrine stress Neuroendocrinology. 1995 Feb; 61(2): 180-90 Hinney A, Vogel CI, Hebebrand J. From monogenic to polygenic obesity Eur. Child Adolesc. Psychiatry. 2010 Mar;19(3):297-310. Hoshaw BA, Malberg JE, Lucki I. Central administration of IGF-I and BDNF leads to longlasting antidepressant Brain Res. 2005 Mar 10;1037(1-2):204-8 Isgor C, Watson SJ. Estrogen receptor alpha and beta mRNA expressions by proliferating and differentiating cells in the adult rat dentate gyrus and subventricular zone. Neuroscience. 2005;134(3):847-56. Ishida-Takahashi R, Uotani S, Abe T, Degawa-Yamauchi M, Fukushima T, Fujita N, Sakamaki H, Yamasaki H, Yamaguchi Y, Eguchi K. Rapid inhibition of leptin signaling by glucocorticoids in vitro and in vivo. J. Biol. Chem. 2004 May 7;279(19):19658-64. Islam MS, Sjöholm A, Emilsson V. Fetal pancreatic islets express functional leptin Int. J. Obes. Relat. Metab. Disord. 2000 Oct;24(10):1246-53 Joëls M, de Kloet ER. Effects of glucocorticoids and norepinephrine on the excitability in the hippocampus. Science. 1989 Sep 29;245(4925):1502-5.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

26

George Soulis and Efthymia Kitraki

Joëls M, Karst H, DeRijk R, de Kloet ER. The coming out of the brain Trends Neurosci. 2008 Jan;31(1):1-7 Joëls M, Krugers HJ, Lucassen PJ, Karst H Corticosteroid effects on cellular physiology Brain Res. 2009 Oct 13;1293:91-100 Kamara K, Eskay R, Castonguay T. High-fat Physiol. Behav. 1998 Apr;64(1):1-6. Karandrea D, Kittas C, Kitraki E. Contribution of sex Neuroendocrinology. 2000 Jun;71(6):343-53. Karandrea D, Kittas C, Kitraki E. Forced swimming differentially affects male and female brain Neuroendocrinology. 2002 Apr;75(4):217-26. Kawakami A, Okada N, Rokkaku K, Honda K, Ishibashi S, Onaka T. Leptin inhibits and ghrelin augments hypothalamic noradrenaline release after stress Stress. 2008;11(5):3639. Kelesidis T, Kelesidis I, Chou S, Mantzoros CS. Narrative review: the role of leptin Ann. Intern. Med. 2010 Jan 19;152(2):93-100. Kim HJ, Lee JH, Choi SH, Lee YS, Jahng JW. Fasting-induced increases of arcuate NPY mRNA Neuropeptides. 2005 Dec;39(6):587-94 Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost memories. Nat. Rev. Neurosci. 2002 Jun;3(6):453-62. Kitraki E, Karandrea D, Kittas C. Long-lasting effects of stress Neuroendocrinology. 1999 May;69(5):331-8. Kitraki E, Kremmyda O, Youlatos D, Alexis MN, Kittas C. Gender-dependent alterations in corticosteroid receptor status and spatial performance following 21 days of restraint stress 2004a, Neuroscience.;125(1):47-55 Kitraki E, Soulis G, Gerozissis K Impaired neuroendocrine response 2004b Neuroendocrinology. ;79(6):338-45 Kossoff EH, Zupec-Kania BA, Amark PE, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R, Buchhalter JR, Caraballo RH, Helen Cross J, Dahlin MG, Donner EJ, Klepper J, Jehle RS, Kim HD, Christiana Liu YM, Nation J, Nordli DR Jr, Pfeifer HH, Rho JM, Stafstrom CE, Thiele EA, Turner Z, Wirrell EC, Wheless JW, Veggiotti P, Vining EP; Charlie Foundation, Practice Committee of the Child Neurology Society; Practice Committee of the Child Neurology Society; International Ketogenic Diet Study Group. Optimal clinical management Epilepsia. 2009 Feb;50(2):304-17. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008 Oct 16;455(7215):894-902 Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, Lee EW, Burnett MS, Fricke ST, Kvetnansky R, Herzog H, Zukowska Z. Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat. Med. 2007 Jul;13(7):803-11. Kuo LE, Czarnecka M, Kitlinska JB, Tilan JU, Kvetnanský R, Zukowska Z. Chronic stress Ann. N. Y. Acad. Sci. 2008 Dec;1148:232-7. La Fleur SE, Akana SF, Manalo SL, Dallman MF. Interaction between corticosterone and insulin Endocrinology. 2004 May;145(5):2174-85. Laferrère B, Fried SK, Hough K, Campbell SA, Thornton J, Pi-Sunyer FX. Synergistic effects of feeding and dexamethasone on serum leptin levels. J. Clin. Endocrinol. Metab. 1998 Oct;83(10):3742-5 Landsberg L. Feast Cell Mol. Neurobiol. 2006 Jul-Aug;26(4-6):497-508

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Interplay of Leptin with the Stress System Components

27

Larsen PJ, Mau SE. Effect of acute stress. Peptides. 1994;15(5):783-90. Lea RG, Howe D, Hannah LT, Bonneau O, Hunter L, Hoggard N. Placental leptin Mol. Hum. Reprod. 2000 Aug;6(8):763-9. Leal-Cerro A, Considine RV, Peino R, Venegas E, Astorga R, Casanueva FF, Dieguez C. Serum immunoreactive leptin Horm. Metab. Res. 1996 Dec;28(12):711-3. Leonard BE. HPA and immune axes in stress Neuroimmunomodulation. 2006;13(5-6):26876. Levin BE, Routh VH, Kang L, Sanders NM, Dunn-Meynell AA. Neuronal glucosensing: what do we know after 50 years? Diabetes. 2004 Oct;53(10):2521-8 Levine S. Primary social relations Physiol. Behav. 2001 Jun;73(3):255-60. Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. Impairment of long-term potentiation and spatial memory Neuroscience. 2002;113(3):607-15. Licinio J, Mantzoros C, Negrão AB, Cizza G, Wong ML, Bongiorno PB, Chrousos GP, Karp B, Allen C, Flier JS, Gold PW. Human leptin Nat. Med. 1997 May;3(5):575-9. Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML. Phenotypic effects of leptin Proc. Natl. Acad. Sci. USA 2004 Mar 30;101(13):4531-6. Lillycrop KA, Phillips ES, Torrens C, Hanson MA, Jackson AA, Burdge GC. Feeding pregnant rats a protein-restricted diet Br. J. Nutr. 2008 Aug;100(2):278-82 Liu F, Day M, Muñiz LC, Bitran D, Arias R, Revilla-Sanchez R, Grauer S, Zhang G, Kelley C, Pulito V, Sung A, Mervis RF, Navarra R, Hirst WD, Reinhart PH, Marquis KL, Moss SJ, Pangalos MN, Brandon NJ. Activation of estrogen Nat. Neurosci. 2008 Mar;11(3): 334-43 Loos RJ. Recent progress in the genetics Br. J. Clin. Pharmacol. 2009 Dec;68(6):811-29. Lu XY, Kim CS, Frazer A, Zhang W. Leptin: a potential novel antidepressant Proc. Natl. Acad. Sci. USA 2006 Jan 31;103(5):1593-8. Lucassen PJ, Heine VM, Muller MB, van der Beek EM, Wiegant VM, De Kloet ER, Joels M, Fuchs E, Swaab DF, Czeh B. Stress, depression CNS Neurol. Disord. Drug Targets. 2006 Oct;5(5):531-46. Ma D, Feitosa MF, Wilk JB, Laramie JM, Yu K, Leiendecker-Foster C, Myers RH, Province MA, Borecki IB. Leptin is associated with blood pressure and hypertension in women from the National Heart, Lung, and Blood Institute Family Heart Study. Hypertension. 2009 Mar;53(3):473-9. Madiehe AM, Lin L, White C, Braymer HD, Bray GA, York DA. Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2001 Dec;281(6):R2048-58. Makimura H, Mizuno TM, Roberts J, Silverstein J, Beasley J, Mobbs CV. Adrenalectomy reverses obese phenotype and restores hypothalamic melanocortin tone in leptin-deficient ob/ob mice. Diabetes. 2000 Nov;49(11):1917-23. Makimura H, Mizuno TM, Isoda F, Beasley J, Silverstein JH, Mobbs CV. Role of glucocorticoids BMC Physiol. 2003 Jul 9;3:5. Matsumoto T, Miyatsuji A, Miyawaki T, Yanagimoto Y, Moritani T. Potential association between endogenous Am. J. Hum. Biol. 2003 Jan-Feb;15(1):8-15. Mattson MP. Calcium and neurodegeneration. Aging Cell. 2007 Jun;6(3):337-50. McCarty MF. Modulation of adipocyte Med. Hypotheses. 2001 Aug;57(2):192-200.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

28

George Soulis and Efthymia Kitraki

McEwen BS, Wingfield JC. The concept of allostasis in biology and biomedicine. Horm. Behav. 2003 Jan;43(1):2-15. McGowan PO, Sasaki A, D'Alessio AC, Dymov S, Labonté B, Szyf M, Turecki G, Meaney MJ. Epigenetic regulation of the glucocorticoid receptor Nat. Neurosci. 2009 Mar;12(3):342-8. Molteni R, Barnard RJ, Ying Z, Roberts CK, Gómez-Pinilla F. A high-fat Neuroscience. 2002;112(4):803-14 Morrison CD. Leptin signaling in brain Biochim. Biophys. Acta. 2009 May;1792(5):401-8. Nemeroff CB, Owens MJ, Bissette G, Andorn AC, Stanley M. Reduced corticotropin Arch Gen. Psychiatry. 1988 Jun;45(6):577-9. Newnham JP, Pennell CE, Lye SJ, Rampono J, Challis JR. Early life origins of obesity Obstet Gynecol. Clin. North Am. 2009 Jun;36(2):227-44, xii. Nieuwenhuizen AG, Rutters F. The hypothalamic-pituitary-adrenal-axis in the regulation of energy Physiol Behav. 2008 May 23;94(2):169-77. Nutr. Metab. Cardiovasc. Dis. 2008 Feb;18(2):158-68 O'Connor DM, Blache D, Hoggard N, Brookes E, Wooding FB, Fowden AL, Forhead AJ.Developmental control of plasma leptin Endocrinology. 2007 Aug;148(8):3750-7. Oitzl MS, de Kloet ER. Selective corticosteroid antagonists modulate specific aspects of spatial orientation learning Behav. Neurosci. 1992 Feb;106(1):62-71 O'Malley D, MacDonald N, Mizielinska S, Connolly CN, Irving AJ, Harvey J. Leptin promotes rapid dynamic changes in hippocampal dendritic morphology Mol. Cell Neurosci. 2007 Aug;35(4):559-72. Ottosson M, Vikman-Adolfsson K, Enerbäck S, Olivecrona G, Björntorp P. The effects of cortisol J. Clin. Endocrinol. Metab. 1994 Sep;79(3):820-5. Painter RC, Roseboom TJ, Bleker OP. Prenatal exposure Reprod. Toxicol. 2005 SepOct;20(3):345-52. Panagiotaropoulos T, Pondiki S, Papaioannou A, Alikaridis F, Stamatakis A, Gerozissis K, Stylianopoulou F. Neonatal handling and gender modulate brain Neuroendocrinology. 2004;80(3):181-91 Paracchini V, Pedotti P, Taioli E Genetics of leptin Am. J. Epidemiol. 2005 Jul 15;162(2):101-14. Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B, Zhang CY, Xu C, Vianna CR, Balthasar N, Lee CE, Elmquist JK, Cowley MA, Lowell BB. Glucose sensing Nature. 2007 Sep 13;449 (7159): 228-32 Pascoe WS, Smythe GA, Storlien LH. Enhanced responses to stress Brain Res. 1991 Jun 7;550(2):192-6. Penke Z, Felszeghy K, Fernette B, Sage, Nyakas C, Burlet A. Postnatal maternal deprivation produces long-lasting modifications of the stress response, feeding and stress-related behaviour in the rat. Eur. J. Neurosci. 2001 Aug;14(4):747-55. Penn DM, Jordan, Kelso EW, Davenport JE, Harris RB. Effects of central or peripheral leptin administration on norepinephrine turnover in defined fat depots. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2006 Dec;291(6):R1613-21 Plagemann A. A matter J. Matern. Fetal. Neonatal Med. 2008 Mar;21(3):143-8 Prasad A, Prasad C. Short-term consumption Physiol. Behav. 1996 Sep;60(3):1039-42 Proietto J, Fam BC, Ainslie DA, Thorburn AW. Novel anti-obesity Expert Opin. Investig. Drugs. 2000 Jun;9(6):1317-26

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Interplay of Leptin with the Stress System Components

29

Pruessner JC, Champagne F, Meaney MJ, Dagher A. Dopamine release in response J. Neurosci. 2004 Mar 17;24(11):2825-31. Qiu J, Wang P, Jing Q, Zhang W, Li X, Zhong Y, Sun G, Pei G, Chen Y. Rapid activation of ERK1/2 mitogen Biochem. Biophys. Res. Commun. 2001 Oct 5;287(4):1017-24. Raone A, Cassanelli A, Scheggi S, Rauggi R, Danielli B, De Montis MG. Hypothalamuspituitary-adrenal modifications Neuroscience. 2007 Jun 8;146(4):1734-42. Rayner DV, Trayhurn P. Regulation of leptin production: sympathetic nervous system interactions. J. Mol. Med. 2001;79(1):8-20. Reibel S, Larmet Y, Lê BT, Carnahan J, Marescaux C, Depaulis A. Brain-derived neurotrophic factor delays hippocampal kindling in the rat. Neuroscience. 2000;100(4): 777-88 Revest JM, Di Blasi F, Kitchener P, Rougé-Pont F, Desmedt A, Turiault M, Tronche F, Piazza PV. The MAPK pathway and Egr-1 mediate stress Nat. Neurosci. 2005 May;8(5):664-72. Ridder S, Chourbaji S, Hellweg R, Urani A, Zacher C, Schmid W, Zink M, Hörtnagl H, Flor H, Henn FA, Schütz G, Gass P. Mice with genetically altered glucocorticoid receptor J. Neurosci. 2005 Jun 29;25(26):6243-50. Ritter S, Dinh TT, Li AJ. Hindbrain catecholamine neurons Physiol. Behav. 2006 Nov 30;89(4):490-500. Roesch DM. Effects of selective estrogen Physiol. Behav. 2006 Jan 30;87(1):39-44. Rogatsky I, Ivashkiv LB. Glucocorticoid modulation of cytokine signaling. Tissue Antigens. 2006 Jul;68(1):1-12. Rosenbaum M, Nicolson M, Hirsch J, Heymsfield SB, Gallagher D, Chu F, Leibel RL. Effects of gender, body composition J. Clin. Endocrinol. Metab. 1996 Sep;81(9):3424-7. Rougé-Pont F, Deroche V, Le Moal M, Piazza PV. Individual differences in stress Eur. J. Neurosci. 1998 Dec;10(12):3903-7 Sánchez-Lasheras C, Könner AC, Brüning JC. Integrative neurobiology of energy homeostasis, neurocircuits, signals and mediators. Front Neuroendocrinol. 2010 Jan; 31(1): 4-15. Sapolsky RM The possibility of neurotoxicity Biol. Psychiatry. 2000 Oct 15;48(8):755-65. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids Endocr. Rev. 2000 Feb;21(1):55-89. Scharfman HE, Maclusky NJ. Similarities between actions of estrogen Trends Neurosci. 2005 Feb;28(2):79-85. Schmidt P, Holsboer F, Spengler D. Beta(2)-adrenergic receptors potentiate glucocorticoid receptor transactivation via G protein beta gamma-subunits and the phosphoinositide 3kinase pathway Mol. Endocrinol. 2001 Apr;15(4):553-64. Shanley LJ, Irving AJ, Harvey J. Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity. Neurosci. 2001 Dec 15;21(24):RC186. Shanley LJ, O'Malley D, Irving AJ, Ashford ML, Harvey J. Leptin inhibits epileptiform-like activity in rat hippocampal neurones via PI 3-kinase-driven activation of BK channels. J. Physiol. 2002 Dec 15;545(Pt 3):933-44. Signore AP, Zhang F, Weng Z, Gao Y, Chen J. Leptin neuroprotection J. Neurochem. 2008 Sep;106(5):1977-90.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

30

George Soulis and Efthymia Kitraki

Slieker LJ, Sloop KW, Surface PL, Kriauciunas A, LaQuier F, Manetta J, Bue-Valleskey J, Stephens TW. Regulation of expression of ob mRNA J. Biol. Chem. 1996 Mar 8;271(10):5301-4. Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids J. Neurosci. 1995 Mar;15(3 Pt 1):1768-77. Smith JT, Waddell BJ. Leptin receptor expression in the rat placenta Biol. Reprod. 2002 Oct;67(4):1204-10. Smoak KA, Cidlowski JA. Mechanisms of glucocorticoid receptor signaling during inflammation. Mech. Ageing Dev. 2004 Oct-Nov;125(10-11):697-706. Soulis G, Papalexi E, Kittas C, Kitraki E. Early impact of a fat Behav. Neurosci. 2007 Jun;121(3):483-90 Spinedi E, Gaillard RC. A regulatory loop between the hypothalamo-pituitary-adrenal (HPA) axis and circulating leptin Endocrinology. 1998 Sep;139(9):4016-20 Stranahan AM, Norman ED, Lee K, Cutler RG, Telljohann RS, Egan JM, Mattson MP. Dietinduced insulin Hippocampus. 2008;18(11):1085-8. Sutanto W, Rosenfeld P, de Kloet ER, Levine S. Long-term effects of neonatal maternal deprivation Brain Res. Dev. Brain Res. 1996 Apr 30;92(2):156-63. Syed AA, Irving JA, Redfern CP, Hall AG, Unwin NC, White M, Bhopal RS, Weaver JU. Association of glucocorticoid receptor Obesity (Silver Spring). 2006 May;14(5):759-64. Tallam LS, Stec DE, Willis MA, da Silva AA, Hall JE. Melanocortin-4 receptor-deficient mice Hypertension. 2005 Aug;46(2):326-32. Tannenbaum BM, Brindley DN, Tannenbaum GS, Dallman MF, McArthur MD, Meaney MJ. High-fat Am. J. Physiol. 1997 Dec;273(6 Pt 1):E1168-77. Tataranni PA, Larson DE, Snitker S, Young JB, Flatt JP, Ravussin E Effects of glucocorticoids Am. J. Physiol. 1996 Aug;271(2 Pt 1):E317-25. Tempel DL, Leibowitz SF. PVN steroid implants Brain Res. Bull. 1989 Dec;23(6):553-60. Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr. Rev. 2004 Oct;25(5):831-66. Udagawa J, Hatta T, Hashimoto R, Otani H. Roles of leptin Congenit. Anom. (Kyoto). 2007 Sep;47(3):77-83. Valassi E, Scacchi M, Cavagnini F. Neuroendocrine control of food Nutr. Metab. Cardiovasc. Dis. 2008 Feb;18(2):158-68. Van Bockstaele EJ, Bajic D, Proudfit H, Valentino RJ. Topographic architecture of stress Physiol. Behav. 2001 Jun;73(3):273-83. Van Dijk G, Buwalda B. Neurobiology of the metabolic syndrome: an allostatic perspective Eur. J. Pharmacol. 2008 May 6;585(1):137-46. Van Hoek M, Langendonk JG, de Rooij SR, Sijbrands EJ, Roseboom TJ. Genetic variant in the IGF2BP2 gene may interact with fetal malnutrition to affect glucose metabolism. Diabetes. 2009 Jun;58(6):1440-4. Van Rossum EF, Lamberts SW. Polymorphisms in the glucocorticoid receptor Recent Prog. Horm. Res. 2004;59:333-57. Vickers MH. Developmental programming Curr. Opin. Endocrinol. Diabetes Obes. 2007 Feb;14(1):17-22. Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation Mol. Cell Biol. 2003 Aug;23(15):5293-300.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Interplay of Leptin with the Stress System Components

31

Weaver IC, Champagne FA, Brown SE, Dymov S, Sharma S, Meaney MJ, Szyf M. Reversal of maternal programming J. Neurosci. 2005 Nov 23;25(47):11045-54. Wellman PJ, Davies BT, Morien A, McMahon L. Modulation of feeding by hypothalamic paraventricular nucleus Life Sci. 1993; 53(9):669-79. Weng Z, Signore AP, Gao Y, Wang S, Zhang F, Hastings T, Yin XM, Chen J. Leptin protects against 6-hydroxydopamine-induced dopaminergic J. Biol. Chem. 2007 Nov 23;282(47):34479-91. Westling S, Ahrén B, Träskman-Bendz L, Westrin A. Low CSF J. Affect. Disord. 2004 Jul;81(1):41-8. Willner P. Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology. 2005;52(2):90-110. Wüst S, Entringer S, Federenko IS, Schlotz W, Hellhammer DH. Birth weight is associated with salivary cortisol Psychoneuroendocrinology. 2005 Jul;30(6):591-8. Xiao L, Feng C, Chen Y. Glucocorticoid rapidly enhances NMDA-evoked neurotoxicity by attenuating the NR2A-containing NMDA receptor-mediated ERK1/2 activation. Mol. Endocrinol. 2010 Mar;24(3):497-510. Yokotani K, Murakami Y, Okada S, Hirata M Role of brain Eur. J. Pharmacol. 2001 May 11;419(2-3):183-9. You JM, Yun SJ, Nam KN, Kang C, Won R, Lee EH. Mechanism of glucocorticoid-induced oxidative stress Can. J. Physiol. Pharmacol. 2009 Jun;87(6):440-7. Young JB, Macdonald IA. Sympathoadrenal activity in human Int. J. Obes. Relat. Metab. Disord. 1992 Dec;16(12):959-67 Zakrzewska KE, Cusin I, Sainsbury A, Rohner-Jeanrenaud F, Jeanrenaud B. Glucocorticoids as counterregulatory hormones Diabetes. 1997 Apr;46(4):717-9 Zakrzewska KE, Cusin I, Stricker-Krongrad A, Boss O, Ricquier D, Jeanrenaud B, RohnerJeanrenaud F. Induction of obesity Diabetes. 1999 Feb;48(2):365-70. Zellner DA, Loaiza S, Gonzalez Z, Pita J, Morales J, Pecora D, Wolf A. Food selection changes under stress Physiol. Behav. 2006 Apr 15;87(4):789-93. Zhang F, Chen J. Leptin protects hippocampal CA1 neuronsJ. Neurochem. 2008 Oct;107(2):578-87.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

In: Leptin: Hormonal Functions, Dysfunctions and Clinical Uses ISBN: 978-1-61122-891-5 Editors: Rose M. Hemling and Arthur T. Belkin ©2011 Nova Science Publishers, Inc.

Chapter 2

THE EFFECT OF DRUGS ON LEPTIN METABOLISM Irem Fatma Uludag Izmir Tepecik Educational and Research Hospital, Neurology Clinic, Istanbul, Turkey

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ABSTRACT The continuing epidemics of obesity worldwidegave rise to the studies investigating the drugs used for the treatment of obesity as well as the drugs inducing weight gain as an metabolic adverse effect and the invention of the leptin, one of the more important molecules in the pathogenesis of obesity, introduced a new direction for these studies.This chapter focused on the results of previous studies providing information about the effects on serum leptin levels of some drugs.

ANTIEPILEPTIC DRUGS Epilepsy is generally a lifelong disorder and therefore theside effects of antiepileptic medications are particularly important. Obesity is one of these side effects and the mechanisms, including leptin related pathways, underlying weight gain during antiepileptic treatment are widely investigated. Valproic acid is a first-line and widely used antiepileptic agent, with a very broad spectrum of activity. It is also increasingly used for other indications, such as bipolar psychiatric disorder and migraine prophylaxis [1, 2, 3]. Weight gain is one of the major adverse effects observed during valproic acid treatment. It‘s demonstrated by Verrotti et al. that valproic acid induced weight gain is associated with increased serum leptin levels [4].In vitro studies support a direct effect of the valproic acid on adipocytes [5]. It‘s hypothetised that valproic acidproduce a state of leptin resistance [6, 7]. In contrast, Greco et al. and GSM: +905304690368, Fax: +902324570055. E mail: [email protected].

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

34

Irem Fatma Uludag

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Lagace et al. suggested that high leptin levels in patients taking VPA could be the result of obesity due to increased production of leptin by the adipose tissue [8, 9].Pylvänen et al. found similar leptin levels in obese patients taking valproic acid and obese control subjects [10] and Lagace et al. reported that valproic acid paradoxically inhibits adipogenesis in vitro [9]. Carbamazepine is also a first line antiepileptic drug like valproic acid which may induce weight gain. In the study of Çaksen et al. carbamazepine was not thought to have a significant effect on serum leptin levels in epileptic children [11]. Uludag et al. found that patients under carbamazepine treatment were not different from controls according to leptin and [12]. Hamed et al. also demonstrated that carbamazepine treatment does not change serum leptin levels significantly [13]. Topiramate is a new antiepileptic drug which originally have been developed as an oral antidiabetic agent. Weight loss is a very frequent adverse effect in patients treated with topiramate. Some studies investigated the potential association between topiramate induced weight loss and serum leptin levels.In rats, serum levels in the topiramate group were remarkably lower than those of the control group [14]. Husum et al. found that single injections of topiramate reduce leptin in only obese rats and not in depressed rats which have lower body mass index [15]. In children, Li et al. suggested that there was no significant difference in leptin before and after the topiramate treatment [16]. Kim et al. observed increased serum levels of leptin in valproic acid treated patients compared to topiramate treated patients [17]. Lamotrigine is a structurally and pharmacologically novel antiepileptic drug which is also used in bipolar disorder. Lamotrigine has shown weight-loss properties in some obese populations, including patients with bipolar disorder [18].Leptin levels were not different in patients with binge eating disorder taking lamotrigine and placebo [19].

ANTIDEPRESSANT DRUGS Since weight and appetite are frequently altered in depression, leptin has been investigated in patients with depression in recent years. The results of the studies concerning serum leptin levels in patients with depression were inconsistent: unaltered [20], increased [21], decreased [22] or increased only in women [23] leptin levels have been reported. The assessment of the effect of the antidepressant therapy on leptin levels have also been difficult when the impact of the disease itself is not clear. The tricyclic antidepressant amitriptyline and its major active metabolite nortriptyline are known to induce weight gain. Paroxetine is a selective serotonine reuptake inhibitor antidepressant which typically does not affect body weight.Hinze-Selch et al. investigated the serum leptin levels in patients taking amitriptyline, nortriptyline, paroxetine and in psychiatric patients without medication [24]. They found out that drug-free treatment and treatment with paroxetine did not have any effect on weight or plasma levels of leptin [24]. However although the patients treated with amitriptyline/nortripyline had a significant weight gain over time, the tricyclic antidepressants did not affect plasma levels of leptin [24]. They concluded that the weight gain induced by psychotropic agents is not necessarily accompanied by an increase in circulating levels of leptin [24].

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

The Effect of Drugs on Leptin Metabolism

35

Citalopram is a well-tolerated selective serotonin reuptake inhibitor with highly selective serotonin reuptake inhibition. Citalopram has essentially no affinity for cholinergic or noradrenergic receptors and has relatively modest effects on food intake and weight changes compared with others in the selective serotonin reuptake inhibitor class. Citalopram therapy did not change leptin levels in depressive women in the study of Kauffman et al [25].Escitalopram is the S-stereoisomer of citalopram and is characterized by high selectivity of serotonin reuptake inhibition. No changes in serum leptin levels were observed with high doses of escitalopram in patients with binge-eating disorder in a placebo controlled trial [26]. Noradrenergic and specific serotoninergic antidepressant mirtazapine may prompt increases of appetite and weight. Kraus et al. reported a significant weight gain and only a slight rise in leptin levels with mirtazapine [27]. In this study venlafaxine induced a significant weight loss whereas plasma levels of leptin did not change significantly [27]. Increases of morning leptin levels concomitant with weight gain were found in depressed patients treated with mirtazapine by Kraus et al. and Schmid et al [28, 29]. These effects were not observed by amitriptyline in previous studies despite significant weight gain [24]. Significant increase in leptin concentrations with mirtazapine is reported in depressive women by Laimer et al [30]. In contrast to these reports indicating an enhancing effect for mirtazapine on leptin levels, Zeman et al suggested that depressive disorder itself may be at least in part, responsible for the elevated leptin levels in depressive patients since they have not found any differences in leptin levels between the drug free depressive women and depressive women treated either with escitaloprame alone or in the combination with mirtazapine [31]. Fluoxetine is a commonly used selective serotonin reuptake inhibitor antidepressant drug. Fluoxetine causes weight loss and it may be suggested as an adjunctive drug in the treatment of obesity. In rats chronic fluoxetine treatment induced a reduction in the consumption of a type of food rich in simple carbohydrates and in serum leptin concentrations [32]. In African women with depression serum leptin levels were found to be lower in the group treated with fluoxetine than the group treated with the tricyclic antidepressant imipramine [33]. Esel et al. reported that leptin levels are elevated in depressive women and different antidepressant drugs (amitriptyline, venlafaxine, paroxetine, fluoxetine) has additional increasing effect on leptin levels, rather than a normalizing effect [34]. Since the sympathetic nervous system has an inhibitor activity on leptin secretion [35] and the serotonergic system has an enhancing effect on leptin [36], the explanations for the more elevated leptin values with the improvement from depression may be the inhibition of increased sympathetic nervous system activity or the increase in serotonergic activity by antidepressant drugs. Another possible axplanation is the increase in appetite with improvement from depression.

ANTIPSYCHOTIC DRUGS Antipsychotic (or neuroleptic) drugs are tranquilizing psychiatric medications primarily used to manage psychosis particularly in schizophrenia and bipolar disorder. They tend to block receptors in the brain's dopamine pathways. Atypical antipsychotics (second generation antipsychotics) have fewer adverse effects and greater relative effectiveness as compared to existing antipsychotics an they are largely used for the management of patients with a variety

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

36

Irem Fatma Uludag

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

of psychotic disorders and severe behavioral disturbances. Weight gain is one of the potentially serious metabolic adverse effects of the atypical antipsychotics [37]. Among the drug-induced effects on leptin levels, the literature on atypical antipsychotic related obesity and leptin is relatively well developed (reviewed by Jin et al.) [38]. Many investigators examined possible correlations between changes in serum leptin levels and antipsychotic-associated metabolic changes. The first reports focused on clozapine and olanzapine demonstrated significant increase in leptin levels [39, 40]. Numerous prospective trials of clozapine-treated patients [39-44] and olanzapine-treated patients [40, 45-49] confirmed the association between use of these medications and increased serum leptin levels. Baptista et al. suggested that the impact of olanzapine in serum leptin levels is limited to a small group and patients [50 . confirmed that the previously reported abnormal correlation between serum leptin levels and the body mass index is not that gross after prolonged treatment with olanzapine or clozapine [51]. Adjunctive therapies with amantadine [52], nizatidine [53] and topiramate [54] improved leptin levels in patients taking olanzapine. For atypical antipsychotics with less metabolic adverse effects such as quetiapine [55] and risperidone [56-59], the increases in serum leptin levels were not marked. To separate diagnosis and treatment effects, Arranz et al. compared leptin levels of drugnaive schizophrenia patients, drug-free schizophrenia patients, and controls [60]. Drug-naive schizophrenia subjects did not differ from controls in this study [60]. Treatment of drug-naive patients with antipsychotics is found to be associated with an increase in plasma leptin, demonstrating also that the elevations are related to the drug treatment and not the disease process [61, 62]. The mechanism underlying the effects of the antipsychotic drugs on body weight is thought to be a drug induced leptin resistance: an attenuation of the normal hormonal control mechanisms whereby elevations in blood leptin provide an anorexigenic signal via the hypothalamus, and consequent disinhibition of food intake [63].

HYPOLIPIDAEMIC DRUGS Plasma leptin concentration is a measure of total body fat mass. Therefore, weight loss in patients treated with hypolipidaemic drugs may lead to a decrease in leptin concentrations. However, in treatment with some hypolipidaemic drugs, the decrease in leptin levels may be more pronounced than the reduction in serum lipids. Fibrates are a group of antidyslipidemic drugs that exert their effects through peroxisome proliferator-activated receptor α (PPARα) activation which, in turn, leads to increased transcription of rate-limiting enzymes that are involved in microsomal and peroxysomal β oxidation in fatty acid catabolism [64-65]. Fenofibratehas been shown to decrease serum leptin levels in hypertriglyceridemic type 2 diabetic patients by Damci et al [66]. During this study the body mass index of the patients remained unchanged and the authors attributed the change on serum leptin levels to the better glycemic control with fenofibrate treatment, to the decrease in triglyceride levels and to the direct effect of fenofibrate on adipose tissue [66].However in a randomized double-blind placebo controlled study leptin levels remained unchanged after fenofibrate treatment in insulin resistant non diabetic metabolic syndome subjects [67]. Jeong et al. demonstrated later in mice that fenofibrate treatment decreases

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

The Effect of Drugs on Leptin Metabolism

37

adipocyte size and lower adipose leptin [68]. In the study of Krysiak et al. fenofibric acid which is the biologically active form of fenofibrate, decreased leptin secretion in cultures of omental fat and subcutaneous tissue of mixed dyslipidemic patients but did not alter leptin release in cultures of omental fat and subcutaneous tissue of normolipidemic subjects [69]. The effect of fenofibric acid was stronger in visceral than subcutaneous fat [69]. Another PPARα agonist, bezofibrate, reduced leptin levels in dyslipidemic type 2 diabetic patients [70]. Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors) are another major group of lipid lowering agents.The effect of statins on leptin levels is still contradictory. In the study of Krysiak et al. combined administration of atorvastatin decreased leptin release in cultures of omental fat and subcutaneous tissue of mixed dyslipidemic patients while atorvastatin alone exhibited no effect [69]. In patients with normal lipid profile, no significant effect was produced in cultures of omental fat and subcutaneous tissue with atorvastatin administrated alone or in combination with fenofibric acid [69]. Atorvastatin did not affect plasma leptin levels in hyperlipidemic type 2 diabetic patientsbut atorvastatin has also been found to reduce leptin in patients with type 2 diabetes [71, 72].Pravastatin did not change leptin levels in healthy volunteers [73].Simvastatin, or the combination of simvastatin and ezetimibehad any effect on serum leptin in healthy men but simvastatin reduced leptin levels independently of its lipid lowering action in patients with coronary heart disease [74, 75]. Ezetimibe is a potent cholesterol-absorption inhibitor. To our knowledge, only two study in healthy participants and one experimental study have evaluated the effect of ezetimibe on leptin levels [74, 76]. Ezetimibe did not alter leptin concentration in these studies [74, 76, 77]. Resveratrol (3,5,4‘-trihydroxystilbene) is a diphenol synthesized by some species of spermatophytes that may evoke advantageous effects as a lipid decreasing compound [78-80]. Baur et al. found out that resveratrol administered orally decreases blood leptin concentrations in mice with hyperleptinaemia [81]. Szkudelska et al. demonstrated that resveratrol directly restricts leptin secretion from isolated rat adipocytes and showed that this effect of resveratrol is probably due to metabolic disturbances in fat cells resulting in a profound depletion of ATP [82]. Rimonabant is the first endocannabinoid receptor antagonist lipid-lowering medication but the use of rimonabant is suspended because of its psychiatric side effects [83-86]. Rimonabant has been shown to decrease leptin in both experimental and human studies [8788]. In the Rimonabant In Obesity (RIO)-Lipids study, treatment with rimonabant was associated with a significant reduction of 27% in leptin levels [88]. In the study of Florentin et al. treatment for 3 months with rimonabant, both as monotherapy and in combination with fenofibrate or ezetimibe, resulted in a significant reduction in plasma leptin concentration in overweight/obese patients with dyslipidemia [89]. In this study the addition of fenofibrate or ezetimibe did not enhance the rimonabant-induced leptin reduction but improved the effects of rimonabant for the same degree of weight loss [89].

ANTIHYPERTANSIVE DRUGS Angiotensin II, the active product of the renin-angiotensin system, regulates cardivascular function and electrolyte metabolism [90]. Angiotensin II is also produced by local

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

38

Irem Fatma Uludag

reninangiotensinsystems in many organs including adipose tissue and modulates the productionof adipokines [90]. Previous studies demonstrated that exogenous angiotensin II increased leptin gene expression and secretion from cultured and human adipocytes [91], suggesting a link between angiotensin II and leptin in the control of adipocyte function but chronic infusion of pressor doses of angiotensin II to rats reduced adipose tissue mass and the circulating leptin concentration [92].Cassis et al. suggested that under normal conditions endogenously produced angiotensin II directly stimulates leptin release from adipocytesbut with pathophysiologies associated with elevated systemic angiotensin II, the predominant effect is reductions in leptin through angiotensin II-induced sympathetic stimulation [93]. In turn, blockade of the renin-angiotensinsystem with inhibitors of angiotensin II formation or angiotensin II receptor blockers may influence leptin levels. Telmisartan is an angiotensin II receptor blocker with agonistic properties on PPARγ which is the enzyme controlling and repressing the expression of the leptin ob gene [94, 95]. Telmisartan has been shown in diet-induced obese mice to prevent or improve the increase in adipocyte size and plasma leptin concentration with an angiotensin receptor independent mechanism of action related to PPARγ [96].Aubert et al. demonstrated also in mice that the leptin decreasing effect of telmisartan is due to its anorexigenic properties independent from the angiotensin receptor blockage [97]. In hypertensive obese patients, telmisartan showed a reduction of blood pressure and leptin levels when weight is unchanged while olmesartan did not decrease leptin [98]. Another antihypertensive drug, enalaprilwhich is an angiotensin converting enzyme inhibitor was able to reduce significantly leptin levels in normotensive adult rats by enhancing the mRNA expression of the lipolytic genes PPARγ [99].

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ANTIOBESITY DRUGS Metformin is a widely used oral glucose-lowering agent that improves insulin sensitivity in peripheral target organs like skeletal muscle, fat tissue, and liver [100]. In addition, metformin has long been suggested clinically to reduce food intake in diabetic and nondiabetic patients [101-103]. Aubert et al. demonstrated in rats that the hypothalamic leptin receptor gene is modulated after metformin treatment and suggested that the anorectic effects of the drug are potentially mediated via an increase in the central sensitivity to leptin [104]. In this study the weight loss achieved by metformin was correlated with pretreatment plasma leptin levels [104]. Sibutramine hydrochloride monohydrate is one of the molecules licensed for use as antiobesity drug; sibutramine is a norepinephrine and serotonin reuptake inhibitor approved for the long-term management of obesity [105]. Sibutramine, added to the previously taken antidiabetic therapy, gave a decrease of leptin compared with baseline in the study of Derosa et al [106]. The decrease in leptin was faster with sibutramine plus L-carnitine than sibutramine alone [106]. Sari et al. also demonstrated a decrease in serum leptin levels in obese women taking sibutramine and sibutramine plus metformin however combination of sibutramine with metformin did not result in any further effects on leptin levels when compared to sibutramine alone [107].

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

The Effect of Drugs on Leptin Metabolism

39

Since the observation that cannabinoid-1 receptor antagonist rimonabant (see Hipolipidaemic Drugs) reduces food intake, cannabinoid-1 receptor antagonists have been used extensively in preclinical studies and in clinical settings to define the role of the endocannabinoid system in appetite behaviors [108].A potent and highly selective cannabinoid-1 receptor antagonist, PF-95453 has been shown to reduce leptin levels in obese monkeys by Wagner et al [109]. Rutecarpine, an indolopyridoquinazolinone alkaloid, is a major component of the fruit of Evodia rutaecarpa[110, 111]. Evodia rutaecarpa has been used as a traditional antiinflammatory herbal medicine [110, 111]. Dietary supplementation with evodiamine, another alkaloid of the fruit of Evodia rutaecarpa, has been shown to ameliorate diet-induced obesity, partially by inhibiting adipocyte differentiation [100]. Kim et al. showed in mice that rutecarpine reduces food intake and bodyweight gain by improving orexigenic sensitivity through the inhibition of neuropeptide Y and agouti-related protein expression [112].

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ANTIOXIDANTS Obesity has been reported to be associated with oxidative stress in humans and mice [113-115]. In addition, adiponectin and leptin levels have been reported to be associated with oxidative stres levels, although the cause-and-effect relationship between adipocytokines and oxidative stress remains unclear [116]. Shen et al. assessed leptin levels in obese rats treated with the antioxidant vitamin E and found out that administration of vitamin E decreases leptin expression [117]. Serum leptin levels were correlated with the presence of urinary 8-epiprostaglandin-F2α, a systemic oxidative stres marker [117]. Shen et al. hypothesized with this study that obesity can produce oxidative stres through leptin and that can play an important role in the treatment of obesity-related diseases [117]. Vitamin C, another antioxidant vitamin, caused a dramatic concentration-dependent fall in leptin secretion on epididymal primary rat adipocytes [118]. Flavonoids are a large heterogeneous group of plant polyphenols which are ingested continuously in small amounts [119]. Quercetin is one of the most abundant flavonoids in edible plants[119]. Quercetin has high anti-oxidative potential,which is well established under in vitro conditions [120]. In cell culture studies quercetin enhanced lipolysis and inhibited adipocyte differentiation [121, 122]. However despite these anti-oxidant and lipid lowering properties, in rats plasma leptin concentrations were not different between subjects fed with low-fat diet, high-fat diet and high-fat diet supplemented with quercetin[123].

ANTIRHEUMATIC DRUGS Rheumatoid arthritis is characterized by the dysregulation of immune-endocrine balance in favor of pro-inflammatory cytokines and hormones. Adjuvant-induced arthritis in rats is the model of human rheumatoid arthritis. In experimental series the developed stage of adjuvant-induced arthritis was related to anorexia and low leptin levels [124, 125]. Methotrexate is the most commonly prescribed disease-modifying antirheumatic drug to treat rheumatoid arthritis. In adjuvant-induced arthritis methotrexate treatment improved anorexia

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

40

Irem Fatma Uludag

related leptin reduction in a dose dependent manner [124]. Bokarewa et al. also showed that patients treated with methotrexate had higher levels of leptin than those treated with other disease-modifying antirheumatic drugs like sulfasalazine and cyclosporin [126]. In the past few years, use of tumor necrosis factor (TNF) inhibitors has been introduced and established as a useful treatment in rheumatoid arthritis [127-129]. Popa et al. and Harle et al. reported no change of serum levels of leptin after treatment of rheumatic arthritis patients with anti-TNF agent adalimumab [130, 131]. Another TNF inhibitor, infliximab did not change leptin levels in patients with rheumatoid arthritis in a long term study [132].

STEROID DRUGS Leptin concentrations increase during inflammation and infection, suggesting that it could act as a cytokine per se and additionally stimulate the production of other cytokines [133]. In the study of Cimmino et al. leptin concentration was increased during glucocorticoid treatment in patients of polimyalgia rheumatica which is a disease characterized by systemic inflammation [134]. The authors hypothesized that this finding was a direct effect exerted by glucorticoids [134]. Leptin is also found to be increased by dexamethasone, a potent synthetic member of the glucocorticoid class in normal individuals [135] and in obese women [136]. In addition, a correlation has been demonstrated between endogenous glucocorticoids used at physiological range and leptin concentrations [137].

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

THYROID HORMONES Thyroid hormones have important effects on energy balance, since they influence both energy intake and expenditure. Previous studies have shown that alterations in thyroid status may lead to changes in serum leptin both in humans and rodents. Serum leptin concentrations are increased in hypothyroid rats [138]. In normal rats, triiodothyronine (T3) wasable to inhibit leptin release in visceral white adipose tissue but this effect was not consistent in subcutaneous white adipose tissue highlighting the fact that the regulation of hormonal production by white adipose tissue depends on the type of depot and its anatomical location [139].

SEX HORMONES It has been suggested that leptin is involved in some functions during pregnancy, particularly in the placenta, where it was found to be expressed.Gambino et al. found out that in human placental cells 17-beta-estradiol (E2) which is the major estrogen in humans enhances leptin secretion [140].

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

The Effect of Drugs on Leptin Metabolism

41

MIGRAINE PREVENTIVE DRUGS Amitriptyline (a tricyclic antidepressant), flunarizine (a calcium channel blocker) and cyproheptadine (an antihistaminic and antiserotonergic) have been the widely used prophylactic agents in patients with migraine. Berilgen et al. demonstrated an increase in leptin levels in patients taking both amitriptyline and flunarizine [141]. They argued that both drugs might cause leptin resistance, possibly by different mechanisms, and thereby lead to increased serum leptin levels [141].High leptin levels were also reported in children treated with flunarizine and cyproheptadine [142].

MELATONIN Melatonin is secreted by the pineal gland into the circulation almost entirely at night [143]. This nocturnal secretion mediates entrainment of endogenous circadian rhythms [143]. Pineal melatonin secretion decline with aging [144, 145]. Adiposity, especially visceral adiposity, increases with advancing age as do plasma leptin levels [146].Rasmussen et al. have shown that supplementation of melatonin in middle-aged male rats mimics some youthful energy regulatory responses, decreasing body weight, intraabdominal adiposity, and plasma leptin concentrations [147, 148].

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ORGANOTIN COMPOUNDS Organotins, such as tributyltin (TBT), have been used as antifouling agents in paints for marine shipping and for a variety of other uses. Human exposure to nonpoint sources of organotins may occur through contaminated dietary sources (seafood and shellfish) [149, 150]. With an average seafood consumption of 0.067-0.163 kg/day, the potential daily intake of TBT calculated is high [149, 150].Baillie-Hamilton postulates a role for chemical toxins in the etiology of obesity and it has been shown that chronic lifetime exposure to organotins could result in obesity and obesity-related disorders [151].Zuo et al. observed that chronic and repeat exposure to low doses of TBT could result in obesity accompanied with hyperleptinemia in male mice [152]. The doses of TBT used in this study were in accord with the butyltin intake estimated for humans [152].

REFERENCES [1] [2] [3]

Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs. 2002;16(10):695–714. Klapper J. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia. 1997;17:103–108. Haddad PM, Das A, Ashfaq M, Wieck A. A review of valproate in psychiatric practice. Expert Opin. Drug Metab. Toxicol. 2009;5(5):539-51.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

42 [4]

[5]

[6]

[7]

[8]

[9]

[10] [11]

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

[12] [13]

[14]

[15]

[16] [17] [18]

Irem Fatma Uludag

Verrotti A, Basciani F, Morresi S, de Martino M, Morgese G, Chiarelli F. Serum leptin changes in epileptic patients who gain wegiht after therapy with valproic acid. Neurology. 1999;53(1):230-2. Luef GJ, Lechleitner M, Bauer G, Trinka E, Hengster P. Valproic acid modulates islet cell insulin secretion: a possible mechanism of weight gain in epilepsy patients. Epilepsy Res. 2003;55:53-58. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF. Serum immunoreactiveleptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 1996; 334(5): 292-5. Kolaczynski JM, Ohannesian J, Considine RV, Marco CC, Caro JF. Response of leptin to short term and prolonged overfeeding in humans. J. Clin. Endocrinol. Metab. 1996; 81:4162–4165. Greco R, Latini G, Chiarelli F, Iannetti P, Verrotti A. Leptin, ghrelin, and adiponectin in epileptic patients treated with valproic acid. Neurology. 2005;65(11):1808-9. Lagace DC, McLeod RS, Nachtigal MW. Valproic acid inhibits leptin secretion and reduces leptin messenger ribonucleic acid levels in adipocytes. Endocrinology. 2004; 145(12):5493-5503. Pylvänen V, Knip M, Pakarinen A, Kotila M, Turkka J, Isojärvi JI. Serum insulin and leptin levels in valproate-associated obesity. Epilepsia. 2002;43:514-517. Caksen H, Deda G, Berberoğlu M, İçağasıoğlu D, Turan EB. Serum leptin levels in children receiving long-term carbamazepine. Acta Paediatr Taiwan.2003;44 (2):82—83. Uludag IF, Kulu U, Sener U, Kose S, Zorlu Y. The effect of carbamazepine treatment on serum leptin levels. Epilepsy Res. 2009;86(1):48-53. Hamed SA, Fida NM, Hamed EA. States of serum leptin and insulin in children with epilepsy: risk predictors of weight gain. Eur. J. Paediatr. Neurol. 2009;13(3):261-8. Li J, Li D, Huang SP. Effects of topiramate and valproate acid on serum insulin and leptin levels in young and adult rat. Zhongguo Dang Dai Er Ke Za Zhi. 2007;9(3):229-32. Husum H, Van Kammen D, Termeer E, Bolwig G, Mathe´ A. Topiramate normalizes hippocampal NPY-LI in flinders sensitive line ‘depressed‘ rats and upregulates NPY, galanin, and CRH-LI in the hypothalamus: implications for mood-stabilizing and weight loss-inducing effects. Neuropsychopharmacology. 2003; 28: 1292–9. Li HF, Zou Y, Xia ZZ, Gao F, Feng JH, Yang CW. Effects of topiramate on weight and metabolism in children with epilepsy. Acta Paediatr. 2009;98(9):1521-5. Kim JY, Lee HW. Metabolic and hormonal disturbances in women with epilepsy on antiepileptic drug monotherapy. Epilepsia. 2007;48(7):1366-70. Bowden CL, Calabrese JR, Ketter TA, Sachs GS, White RL, Thompson TR. Impact of lamotrigine and lithium on weight in obese and nonobese patients with bipolar I disorder. Am J Psychiatry. 2006;163:1199–1201.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

The Effect of Drugs on Leptin Metabolism

43

[19] Guerdjikova AI, McElroy SL, Welge JA, Nelson E, Keck PE, Hudson JI.Lamotrigine in the treatment of binge-eating disorder with obesity: a randomized, placebo-controlled monotherapy trial. Int. Clin. Psychopharmacol. 2009;24(3):1508. [20] Deuschle M, Blum WF, Englaro P, Schweiger U, Weber B, Pflaum CD, Heuser I. Plasma leptin in depressed patients and healthy controls. Horm. Metab. Res. 1996;28: 714–717. [21] Antonijevic IA, Murck H, Frieboes RM, Horn R, Brabant G, Steiger A. Elevated nocturnal profiles of serum leptin in patients with depression. J. Psychiatr. Res. 1998; 32: 403–410. [22] Kraus T, Haack M, Schuld A, Hinze-Selch D, Pollmacher T. Low leptin levels but normal body mass indices in patients with depression or schizophrenia. Neuroendocrinology 2001;73:243–247. [23] Rubin RT, Rhodes ME, Czambel RK. Sexual diergism of baseline plasma leptin and leptin suppression by arginine vasopressin in major depressives and matched controls. Psychiatry Res. 2002;113:255–268. [24] Hinze-Selch D, Schuld A, Kraus T, Kühn M, Uhr M, Haack M, Pollmächer T.Effects of antidepressants on weight and on the plasma levels of leptin, TNFalpha and soluble TNF receptors: A longitudinal study in patients treated with amitriptyline or paroxetine. Neuropsychopharmacology. 2000;23(1):13-9. [25] Kauffman RP, Castracane VD, White DL, Baldock SD, Owens R.Impact of the selective serotonin reuptake inhibitor citalopram on insulin sensitivity, leptin and basal cortisol secretion in depressed and non-depressed euglycemic women of reproductive age. Gynecol. Endocrinol. 2005;21(3):129-37. [26] Guerdjikova AI, McElroy SL, Kotwal R, Welge JA, Nelson E, Lake K, Alessio DD, Keck PE Jr, Hudson JI. High-dose escitalopram in the treatment of bingeeating disorder with obesity: a placebo-controlled monotherapy trial. Hum. Psychopharmacol. 2008;23(1):1-11. [27] Kraus T, Haack M, Schuld A, Hinze-Selch D, Koethe D, Pollmacher T. Body weight, tumor necrosis factor system, and leptin production during treatment with mirtazapine or venlafaxine. Pharma- copsychiatry 2002;35:220–225. [28] Kraus T, Haack M, Schuld A, Hinze-Selch D, Kuhn M, Uhr M, Pollmächer T. Body weight and leptin plasma levels during treatment with antipsychotic drugs. Am. J. Psychiatry 1999:156:312–314. [29] Schmid DA, Wichniak A, Uhr M, Ising M, Brunner H, Held K, Weikel JC, Sonntag A, Steiger A.Changes of sleep architecture, spectral composition of sleep EEG, the nocturnal secretion of cortisol, ACTH, GH, prolactin, melatonin, ghrelin, and leptin, and the DEX-CRH test in depressed patients during treatment with mirtazapine. Neuropsychopharmacology 2006;31(4):832-44. [30] Laimer M, Kramer-Reinstadler K, Rauchenzauner M, Lechner-Schoner T, Strauss R, Engl J, Deisenhammer EA, Hinterhuber H, Patsch JR, Ebenbichler CF. Effect of mirtazapine treatment on body composition and metabolism. J. Clin. Psychiatry 2006; 67(3):421-4.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

44

Irem Fatma Uludag

[31] Zeman M, Jirak R, Jachymova M, Vecka M, Tvrzicka E, Zak A. Leptin, adiponectin, leptin to adiponectin ratio and insulin resistance in depressive women. Neuro Endocrinol. Lett. 2009;30(3):387-95. [32] Gamaro GD, Prediger ME, Lopes J, Bassani MG, Dalmaz C.Fluoxetine alters feeding behavior and leptin levels in chronically-stressed rats. Pharmacol. Biochem. Behav. 2008; 90(3):312-7. [33] Moosa MY, Panz VR, Jeenah FY, Joffe BI.African women with depression: the effect of imipramine and fluoxetine on body mass index and leptin secretion. J. Clin. Psychopharmacol. 2003;23(6):549-52. [34] Esel E, Ozsoy S, Tutus A, Sofuoglu S, Kartalci S, Bayram F, Kokbudak Z, Kula M. Effects of antidepressant treatment and of gender on serum leptin levels in patients with major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 2005;29(4):565-70. [35] Rayner DV, Trayhurn P. Regulation of leptin production: sympathetic nervous system interactions. J. Mol. Med. 2001;79:8–20. [36] Yamada J, Sugimoto Y, Ujikawa M. The serotonin precursor 5-hydroxytryptophan elevates serum leptin levels in mice. Eur. J. Pharmacol. 1999;383:49–51. [37] Newcomer J. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J. Clin. Psychiatry 2007;68 (Suppl 1):20–27. [38] Jin H, Meyer JM, Mudaliar S, Jeste DV. Impact of atypical antipsychotic therapy on leptin, ghrelin, and adiponectin. Schizophr. Res. 2008;100(1–3):70−85. [39] Bromel T, Blum WF, Ziegler A, Schulz E, Bender M, Fleischhaker C, Remschmidt H, Krieg JC, Hebebrand J. Serum leptin levels increase rapidly after initiation of clozapine therapy. Molecular Psychiatry 1998;3:76–80. [40] Kraus T, Haack M, Schuld A, Hinze-Selch D, Kuhn M, Uhr M, Pollmacher T. Body weight and leptin plasma levels during treatment with antipsychotic drugs. American Journal of Psychiatry 1999;156:312–4. [41] Monteleone P, Fabrazzo M, Tortorella A, La Pia S, Maj M. Pronounced early increase in circulating leptin predicts a lower weight gain during clozapine treatment. Journal of Clinical Psychopharmacology 2002;22:424–6. [42] Kivircik BB, Alptekin K, Caliskan S, Comlekci A, Oruk G, Tumuklu M, Kurklu K, Arkar H, Turk A, Caliskan M, Yesil S. Effect of clozapine on serum leptin, insulin levels, and body weight and composition in patients with schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2003;27:795–9. [43] Sporn AL, Bobb AJ, Gogtay N, Stevens H, Greenstein DK, Clasen LS, Tossell JW, Nugent T, Gochman PA, Sharp WS, Mattai A, Lenane MC, Yanovski JA, Rapoport JL. Hormonal correlates of clozapine- induced weight gain in psychotic children: an exploratory study. Journal of the American Academy of Child and Adolescent Psychiatry 2005;44:925–33. [44] Theisen FM, Gebhardt S, Bromel T, Otto B, Heldwein W, Heinzel-Gutenbrunner M, Krieg JC, Remschmidt H, Tschop M, Hebebrand J. A prospective study of serum ghrelin levels in patients treated with clozapine. Journal of Neural Transmission 2005;112:1411–6.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

The Effect of Drugs on Leptin Metabolism

45

[45] Eder U, Mangweth B, Ebenbichler C, Weiss E, Hofer A, Hummer M, Kemmler G, Lechleitner M, Fleischhacker WW. Association of olanzapine-induced weight gain with an increase in body fat. American Journal of Psychiatry 2001;158:1719–22. [46] Graham KA, Perkins DO, Edwards LJ, Barrier RC Jr, Lieberman JA, Harp JB. Effect of olanzapine on body composition and energy expenditure in adults with first-episode psychosis.[see comment]. American Journal of Psychiatry 2005;162:118–23. [47] Ebenbichler C, Laimer M, Kranebitter M, Lechleitner M, Patsch JR, Baumgartner S, Edlinger M, Hofer A, Hummer M, Rettenbacher MA, Fleischhacker WW. The soluble leptin receptor in olanzapine-induced weight gain: results from a prospective study. Schizophrenia Research 2005;75:143–6. [48] Murashita M, Kusumi I, Inoue T, Takahashi Y, Hosoda H, Kangawa K, Koyama T. Olanzapine increases plasma ghrelin level in patients with schizophrenia. Psychoneuroendocrinology 2005;30:106–10. [49] Hosojima H, Togo T, Odawara T, Hasegawa K, Miura S, Kato Y, Kanai A, Kase A, Uchikado H, Hirayasu Y. Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia. Journal of Psychopharmacology 2006;20:75–9. [50] Baptista T, Dávila A, El Fakih Y, Uzcátegui E, Rangel NN, Olivares Y, Galeazzi T, Vargas D, Peña R, Marquina D, Villarroel V, Teneud L, Beaulieu S. Similar frequency of abnormal correlation between serum leptin levels and BMI before and after olanzapine treatment in schizophrenia. Int. Clin. Psychopharmacol. 2007;22(4):205-11. [51] Peña R, Marquina D, Serrano A, Elfakih Y, de Baptista EA, Carrizo E, Fernández V, Valery L, Teneud L, Baptista T.Frequency of abnormal correlation between leptin and the body mass index during first and second generation antipsychotic drug treatment. Schizophr. Res. 2008;106(2-3):315-9. [52] Graham KA, Gu H, Lieberman JA, Harp JB, Perkins DO. Double-blind, placebocontrolled investigation of amantadine for weight loss in subjects who gained weight with olanzapine. American Journal of Psychiatry 2005;162:1744–6. [53] Atmaca M, Kuloglu M, Tezcan E, Ustundag B. Nizatidine treatment and its relationship with leptin levels in patients with olanzapine-induced weight gain. Human Psychopharmacology 2003b;18:457–61. [54] Narula PK, Rehan HS, Unni KE, Gupta N.Topiramate for prevention of olanzapine associated weight gain and metabolic dysfunction in schizophrenia: a double-blind, placebo-controlled trial. Schizophr. Res. 2010;118(1-3):218-23. [55] Atmaca M, Kuloglu M, Tezcan E, Ustundag B. Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics. Journal of Clinical Psychiatry 2003;64:598–604. [56] Maayan LA, Vakhrusheva J.Risperidone associated weight, leptin, and anthropometric changes in children and adolescents with psychotic disorders in early treatment. Hum. Psychopharmacol. 2010;25(2):133-8.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

46

Irem Fatma Uludag

[57] Fitzgerald PB, Scaffidi A, Morris MJ, de Castella AR, Kulkarni J. The relationship of changes in leptin, neuropeptide Y and reproductive hormones to antipsychotic induced weight gain. Human Psychopharmacology 2003;18:551–7. [58] McIntyre RS, Mancini DA, Basile VS, Srinivasan J, Kennedy SH. Antipsychoticinduced weight gain: bipolar disorder and leptin. Journal of Clinical Psychopharmacology 2003;23:323–7. [59] Martin A, Scahill L, Anderson GM, Aman M, Arnold LE, McCracken J, McDougle CJ, Tierney E, Chuang S, Vitiello B. Weight and leptin changes among risperidonetreated youths with autism: 6- month prospective data. American Journal of Psychiatry 2004; 161:1125–7. [60] Arranz B, Rosel P, Ramirez N, Duenas R, Fernandez P, Sanchez JM, Navarro MA, San L. Insulin resistance and increased leptin concentrations in noncompliant schizophrenia patients but not in antipsychotic-naive first-episode schizophrenia patients. Journal of Clinical Psychiatry 2004;65:1335– 42. [61] Zhang ZJ, Yao ZJ, Liu W, Fang Q, Reynolds GP. Effects of antipsychotics on fat deposition and changes in leptin and insulin levels. magnetic resonance imaging study of previously untreated people with schizophrenia. Br. J. Psychiatry 2004;184:58−62. [62] Perez-Iglesias R, Vazquez-Barquero JL, Amado JA, Berja A, Garcia-Unzueta MT, Pelayo-Teran JM, Carrasco-Martin E, Mata I, Crespo-Facorro B. Effect of antipsychotics on peptides involved in energy balance in drug-naive psychotic patients after 1 year of treatment. J. Clin. Psychopharmacol. 2008;28(3):289−295. [63] Reynolds GP, Kirk SL.Metabolic side effects of antipsychotic drug treatment-pharmacological mechanisms. Pharmacol. Ther. 2010;125(1):169-79. [64] The Bezafibrate Infarction Prevention (BIP) Study Group, Behar S, Brunner D, Kaplinsky E, Mandelzweig L, Benderly M. Secondaryprevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. The bezafibrate infarctionprevention (BIP) study. Circulation 2000;102:21-7. [65] Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001; 357(9260): 905-10. [66] Damci T, Tatliagac S, Osar Z, Ilkova H.Fenofibrate treatment is associated with better glycemic control and lower serum leptin and insulin levels in type 2 diabetic patients with hypertriglyceridemia. Eur. J. Intern. Med. 2003;14(6):357-360. [67] Belfort R, Berria R, Cornell J, Cusi K. Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome. J. Clin. Endocrinol. Metab. 2010;95(2):829-36. [68] Jeong S, Yoon M.Fenofibrate inhibits adipocyte hypertrophy and insulin resistance by activating adipose PPARalpha in high fat diet-induced obese mice. Exp. Mol. Med. 2009;41(6):397-405. [69] Krysiak R, Labuzek K, Okopień B. Effect of atorvastatin and fenofibric acid on adipokine release from visceral and subcutaneous adipose tissue of patients with mixed dyslipidemia and normolipidemic subjects. Pharmacol. Rep. 2009;61(6):1134-45.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

The Effect of Drugs on Leptin Metabolism

47

[70] Ogawa S, Takeuchi K, Sugimura K, Fukuda M, Lee R, Ito S, Sato T.Bezafibrate reduces blood glucose in type 2 diabetes mellitus. Metabolism. 2000 Mar;49(3):331-4. [71] Chu CH, Lee JK, Lam HC, Lu CC, Sun CC, Wang MC, Chuang MJ, Wei MC.Atorvastatin does not affect insulin sensitivity and the adiponectin or leptin levels in hyperlipidemic Type 2 diabetes. J. Endocrinol. Invest 2008;31(1):42-7. [72] Von Eynatten M, Schneider JG, Hadziselimovic S, Hamann A, Bierhaus A, Nawroth PP, Dugi KA.Adipocytokines as a novel target for the anti-inflammatory effect of atorvastatin in patients with type 2 diabetes. Diabetes Care 2005;28(3):754-5. [73] Gannagé-Yared MH, Azar RR, Amm-Azar M, Khalifé S, Germanos-Haddad M, Neemtallah R, Halaby G.Pravastatin does not affect insulin sensitivity and adipocytokines levels in healthy nondiabetic patients. Metabolism 2005;54(7):94751. [74] Gouni-Berthold I, Berthold HK, Chamberland JP, Krone W, Mantzoros CS.Shortterm treatment with ezetimibe, simvastatin or their combination does not alter circulating adiponectin, resistin or leptin levels in healthy men. Clin. Endocrinol. (Oxf) 2008; 68(4): 536-41. [75] Sun YM, Li J, Luan Y, Wang LF.Effect of statin therapy on leptin levels in patients with coronary heart disease. Peptides 2010;31(6):1205-7. [76] Van Heek M, Austin TM, Farley C, Cook JA, Tetzloff GG, Davis HR.Ezetimibe, a potent cholesterol absorption inhibitor, normalizes combined dyslipidemia in obese hyperinsulinemic hamsters. Diabetes 2001;50(6):1330-5. [77] Gupta M, Szmitko PE, Tsigoulis M, Braga MF, Kajil M, Herjikaka S, Quan A, Teoh H, Verma S.Effects of Ezetimibe Add-On to Statin Therapy on Adipokine Production in Patients with Metabolic Syndrome and Stable Vascular Disease. Cardiovasc. Pharmacol. 2010. [Epub ahead of print] [78] Nonomura S, Kanagawa H, Makimoto A. Chemical constituents ofpolygonaceous plants. Studies on the components of Ko-jo-kon.(Polygonum cuspidatum-SIEB et ZUCC). Yakugaku Zasshi 1963;83:988–90. [79] Arichi H, Kimura Y, Okuda H, Baba K, Kozawa M, Arichi S. Effects of stilbene components of the roots of Polygonum cuspidatum Sieb. et Zucc. on lipid metabolism. Chem. Pharm. Bull. 1982;30:1766–70. [80] Miura D, Miura Y, Yagasaki K. Hypolipidemic action of dietary resveratrol, a phytoalexin in grapes and red wine, in hepatoma-bearing rats. Life Sci. 2003;73:1393–400. [81] Baur JA, Pearson KJ, Price NL, Jamieson NL, Lerin C, Kalra A et al. Resveratrol improves health and survival of mice on high-calorie diet. Nature 2006;444:337– 42. [82] Szkudelska K, Nogowski L, Szkudelski T.The inhibitory effect of resveratrol on leptin secretion from rat adipocytes. Eur. J. Clin. Invest. 2009;39(10):899-905. [83] Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr. Rev. 2006;27(1):73-100.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

48

Irem Fatma Uludag

[84] Van Gaal L, Pi-Sunyer X, Despres JP, McCarthy C, Scheen A. Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: pooled 1-year data from the Rimonabant in Obesity (RIO) program. Diabetes Care. 2008;31(suppl 2):S229-S240. [85] Kakafika AI, Mikhailidis DP, Karagiannis A, Athyros VG. The role of endocannabinoid system blockade in the treatment of the metabolic syndrome. J. Clin. Pharmacol. 2007;47(5):642-662. [86] Press Release. The European Medicines Agency recommends suspension of the marketing authorisation of Acomplia. http://www.emea.europa.eu/. Accessed September 14, 2009. [87] Cota D, Sandoval DA, Olivieri M, Prodi E, D‘Alessio DA, Woods SC, Seeley RJ, Obici S. Food intake-independent effects of CB1 antagonism on glucose and lipid metabolism. Obesity (Silver Spring). 2009;17(8):1641-1645. [88] Despres JP, Golay A, Sjostrom L. and the Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N. Engl. J. Med. 2005;353(20):2121-2134. [89] Florentin M, Liberopoulos EN, Tellis CC, Derdemezis CS, Elisaf M, Tselepis A.Effects of rimonabant, as monotherapy and in combination with fenofibrate or ezetimibe, on plasma adipokine levels: a pilot study. Angiology 2010;61(4):365-71. [90] Engeli S, Schling P, Gorzelniak K, Boschmann M, Janke J, Ailhaud G, Teboul M, Massiera F, Sharma AM. The adipose-tissue renin-angiotensin-aldosteronesystem: role in the metabolic syndrome? Int. J. Biochem. CellBiol. 2003; 35: 807-25. [91] Kim S, Whelan J, Claycombe K, Reath BD, Moustaid-Moussa N. Angiotensin II increases leptin secretion by 3T3–L1 and human adipocytes via a prostaglandinindependent mechanism. J. Nutr. 2002;132:1135–1140. [92] Cassis LA, Marshall DE, Fettinger MJ, Rosenbluth B, Lodder RA. Mechanisms contributing to angiotensin II regulation of body weight. Am. J. Physiol. 1998;274: E867–E876. [93] Cassis LA, English VL, Bharadwaj K, Boustany CM. Differential effects of local versus systemic angiotensin II in the regulation of leptin release from adipocytes. Endocrinology 2004;145: 169-74. [94] Benson C, Perdhadsingh HA, Ho CI. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma modulating activity. Hypertension 2004;43:993-1002. [95] Hollenberg AN, Susulic VS, Madura JP, Zhang B, Moller DE. Tontonoz P et al. Functional antagonism between CCAAT/ enhancer binding protein-alpha and peroxisome proliferatorsactivated receptor-gamma on the leptin promoter. J. Biol. Chem. 1997; 272: 5283-90. [96] Rong X, Li Y, Ebihara K, Zhao M, Naowaboot J, Kusakabe T, Kuwahara K, Murray M, Nakao K. Angiotensin II type 1 receptor-independent beneficial effects of telmisartan on dietary-induced obesity, insulin resistance and fatty liver in mice. Diabetologia. 2010. [Epub ahead of print]

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

The Effect of Drugs on Leptin Metabolism

49

[97] Aubert G, Burnier M, Dulloo A, Perregaux C, Mazzolai L, Pralong F, Zanchi A.Neuroendocrine characterization and anorexigenic effects of telmisartan in dietand glitazone-induced weight gain. Metabolism 2010;59(1):25-32. [98] De Luis DA, Conde R, González-Sagrado M, Aller R, Izaola O, Dueñas A, Pérez Castrillón JL, Romero E. Effects of telmisartan vs olmesartan on metabolic parameters, insulin and adipocytokines in hypertensive obese patients. Nutr. Hosp. 2010;25(2):275-9. [99] Santos EL, de Picoli Souza K, da Silva ED, Batista EC, Martins PJ, D'Almeida V, Pesquero JB. Long term treatment with ACE inhibitor enalapril decreases body weight gain and increases life span in rats. Biochem. Pharmacol. 2009;78(8):951-8. [100] Wang T, Wang Y, Kontani Y, Kobayashi Y, Sato Y, Mori N, Yamashita H. Evodiamine improves diet-induced obesity in a uncoupling protein-1-independent manner: involvement of antiadipogenic mechanism and extracellularly regulated kinase/mitogen-activated protein kinase signaling. Endocrinology 2008;149:358– 366. [101] Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann. Intern. Med. 2002; 137:25-33. [102] Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 2006;355:2427-43. [103] Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N. Engl. J. Med. 1995;333:550-4. [104] Aubert G, Mansuy V, Voirol MJ, Pellerin L, Pralong FP.The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression. Metabolism. 2010 [Epub ahead of print]. [105] Padwal RS, Majumdar SR. Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet 2007;369:71-7. [106] Derosa G, Maffioli P, Salvadeo SA, Ferrari I, Gravina A, Mereu R, D'Angelo A, Palumbo I, Randazzo S, Cicero AF.Metabolism. Effects of combination of sibutramine and L-carnitine compared with sibutramine monotherapy on inflammatory parameters in diabetic patients. 2010. [Epub ahead of print] [107] Sari R, Eray E, Ozdem S, Akbas H, Coban E.Comparison of the effects of sibutramine versus sibutramine plus metformin in obese women. Clin. Exp. Med. 2009 [Epub ahead of print]. [108] Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Néliat G, Caput D, Ferrara P, Soubrié P, Brelière JC, Le Fur G. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994; 350:240–244. [109] Wagner JD, Zhang L, Kavanagh K, Ward GM, Chin J, Hadcock J, Auerbach B, Harwood HJ.A Selective Cannabinoid-1 Receptor Antagonist, PF-95453, Reduces Body Weight and Body Fat to a Greater Extent than Pair-Fed Controls in Obese Monkeys. J. Pharmacol. Exp. Ther. 2010 [Epub ahead of print].

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

50

Irem Fatma Uludag

[110] Ahn H, Nam JW, Seo EK, Mar W. Induction of NAD(P)H: quinone reductase by rutaecarpine isolated from the fruits of Evodia rutaecarpa in the murine hepatic Hepa-1c1c7 cell line. Planta Med. 2008;74:1387–1390. [111] Woo HG, Lee CH, Noh MS, Lee JJ, Jung JS, Baik EJ, Moon CH, Lee SH. Rutaecarpine, a quinazolinocarboline alkaloid, inhibits prostaglandin production in RAW264.7 macrophages. Planta Med. 2001;67:505–509. [112] Kim SJ, Lee SJ, Lee S, Chae S, Han MD, Mar W, Nam KW. Rutecarpine ameliorates bodyweight gain through the inhibition of orexigenic neuropeptides NPY and AgRP in mice. Biochem. Biophys. Res. Commun. 2009;389(3):437-42. [113] Keaney JF Jr, Larson MG, Vasan RS, Wilson PW, Lipinska I, Corey D, Massaro JM, Sutherland P, Vita JA, Benjamin EJ. Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham study. Arterioscler. Thromb Vasc. Biol. 2003;23:434–9. [114] Vincent HK, Powers SK, Stewart DJ, Shanely RA, Demirel H, Naito H. Obesity is associated with increased myocardial oxidative stress. Int. J. Obes. 1999;23:67–74. [115] Soltys K, Dikdan G, Koneru B. Oxidative stress in fatty livers of obese Zucker rats: rapid amelioration and improved tolerance to warm ischemia with tocopherol. Hepatology 2001;34:13–8. [116] Nakanishi S, Yamane K, Kamei N, Nojima H, Okubo M, Kohno N. A protective effect of adiponectin against oxidative stress in Japanese Americans: the association between adiponectin or leptin and urinary isoprostane. Metab. Clin. Exp. 2005;54:194–9. [117] Shen XH, Tang QY, Huang J, Cai W.Vitamin E regulates adipocytokine expression in a rat model of dietary-induced obesity. Exp. Biol. Med. (Maywood). 2010;235(1):47-51. [118] Garcia-Diaz DF, Campion J, Milagro FI, Boque N, Moreno-Aliaga MJ, Martinez JA.Vitamin C inhibits leptin secretion and some glucose/lipid metabolic pathways in primary rat adipocytes. J. Mol. Endocrinol. 2010;45(1):33-43. [119] Hertog MGL, Hollman PCH, Katan MB. Content of potentially anticarcinogenic flavonoids of 28 vegetables and 9 fruits commonly consumed in the Netherlands. J. Agric. Food Chem. 1992;40:2379–2383. [120] Soobrattee MA, Neergheen VS, Luximon-Ramma A, Aruoma OI, Bahorun T. Phenolics as potential antioxidant therapeutic agents: mechanism and actions. Mutat. Res. 2005;579:200–213. [121] Kuppusamy UR, Das NP. Effects of flavonoids on cyclic-AMP phospho-diesterase and lipid mobilization in rat adipocytes. Biochem. Pharmacol1. 992;44:1307–1315. [122] Chien PJ, Chen, YC, Lu SC, Sheu F. Dietary flavonoids suppress adipogenesis in 3T3-L1 preadipocytes. J. Food Drug Anal. 2005;13:168–175. [123] Wein S, Behm N, Petersen RK, Kristiansen K, Wolffram S.Quercetin enhances adiponectin secretion by a PPAR-gamma independent mechanism. Eur. J. Pharm. Sci. 2010; 41(1):16-22. [124] Jurcovicova J, Svik K, Scsukova S, Bauerova K, Rovensky J, Stancikova M.Methotrexate treatment ameliorated testicular suppression and anorexia related

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

The Effect of Drugs on Leptin Metabolism

51

leptin reduction in rats with adjuvant arthritis. Rheumatol. Int. 2009;29(10):118791. [125] Stofkova A, Skurlova M, Tybitanclova K, Veselsky L, Zelezna B, Jurcovicova J. Relationship among nitric oxide, leptin, ACTH, corticosterone, and IL-1, in the early and late phases of adjuvant arthritis in male Long Evans rats. Life Sci. 2006;79:2486–2491. [126] Bokarewa M, Bokarew D, Hultgren O, Tarkowski A. Leptin consumption in the inflamed joints of patients with rheumatoid arthritis. Ann. Rheum. Dis. 2003;62:952–956. [127] Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, Weaver AL, Keystone EC, Furst DE, Mease PJ, Ruderman EM, Horwitz DA, Arkfeld DG, Garrison L, Burge DJ, Blosch CM, Lange ML, McDonnell ND, Weinblatt ME. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann. Intern. Med. 1999;130:478–486. [128] Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, Antoni C, Leeb B, Elliott MJ, Woody JN, Schaible TF, Feldmann M. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998; 41: 1552–1563. [129] Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, Teoh LA, Fischkoff SA, Chartash EK. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The armada trial. Arthritis Rheum. 2003;48:35–45. [130] Harle P, Sarzi-Puttini P, Cutolo M, Straub RH. No change of serum levels of leptin and adiponectin during anti-tumour necrosis factor antibody treatment with adalimumab in patients with rheumatoid arthritis. Ann. Rheum. Dis. 2006;65:970– 971. [131] Popa C, Netea MG, Radstake TR, van Riel PL, Barrera P, van der Meer JW. Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis. Ann. Rheum. Dis. 2005;64:1195–1198. [132] Derdemezis CS, Filippatos TD, Voulgari PV, Tselepis AD, Drosos AA, Kiortsis DN.Effects of a 6-month infliximab treatment on plasma levels of leptin and adiponectin in patients with rheumatoid arthritis. Fundam. Clin. Pharmacol. 2009; 23(5): 595-600. [133] Otero M, Lago R, Gomez R, Dieguez C, Lago F, Gomez-Reino J, Gualillo O Towards a proinflammatory and immunomodulatory emerging role of leptin. Rheumatology 2006; 45: 944–950. [134] Cimmino MA, Andraghetti G, Briatore L, Salani B, Parodi M, Cutolo M, Cordera R. Changes in adiponectin and leptin concentrations during glucocorticoid treatment: a pilot study in patients with polymyalgia rheumatica. Ann. N. Y. Acad. Sci. 2010; 1193(1): 160-3.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

52

Irem Fatma Uludag

[135] Miell JP, Englaro P, Blum. WF. Dexamethasone induces an acute and sustained rise in circulating leptin levels in normal human subjects. Horm. Metab. Res. 1996;28:704–707. [136] Putignano B, Brunani A, Dubini A, Bertolini M, Pasquali R, Cavagnini F; "Study Group on Obesity" of the Italian Society of Endocrinology. Effect of small doses of dexamethasone on plasma leptin levels in normal and obese subjects: a dose response study. J. Endocrinol. Invest. 2003;26:111–116. [137] Elimam A, Knutsson U, Brönnegård M, Stierna P, Albertsson-Wikland K, Marcus C. Variations in glucocorticoid levels within the physiological range affect plasma leptin levels. Eur. J. Endocrinol. 1998;139:615–620. [138] Iossa S, Lionetti L, Mollixa MP, Crescenzo R, Barletta A, Liverini G. Fat balance and serum leptin concen- trations in normal, hypothyroid, and hyperthyroid rats. Int. J. Obes. Relat. Metab. Disord. 2001; 25: 417–425. [139] Cabanelas A, Cordeiro A, Santos Almeida NA, Monteiro de Paula GS, Coelho VM, Ortiga-Carvalho TM, Pazos-Moura CC. Effect of triiodothyronine on adiponectin expression and leptin release by white adipose tissue of normal rats. Horm. Metab. Res. 2010; 42(4):254-60. [140] Gambino YP, Maymó JL, Pérez-Pérez A, Dueñas JL, Sánchez-Margalet V, Calvo JC, Varone CL.17 Beta-estradiol enhances leptin expression in human placental cells through genomic and nongenomic actions. Biol. Reprod. 2010;83(1):42-51. [141] Berilgen MS, Bulut S, Gonen M, Tekatas A, Dag E, Mungen B. Comparison of the effects of amitriptyline and flunarizine on weight gain and serum leptin, C peptide and insulin levels when used as migraine preventive treatment. Cephalalgia 2005;25:1048-53. [142] Hirfanoglu T, Serdaroglu A, Gulbahar O, Cansu A.Prophylactic drugs and cytokine and leptin levels in children with migraine. Pediatr Neurol. 2009;41(4):281-7. [143] Cagnacci A. Melatoninin relation to physiology in adult humans. Pineal Res. 1996;21: 200 –213. [144] Reiter R. The ageing pineal gland and its physiological consequences. BioEssays 1992;14:169–175. [145] Pang SF, Tsang CW, Hong GX, Vip PC, Tang PL, Brown GM. Fluctuation of blood melatonin concentrations with age: result of changes in pineal melatonin secretion, body growth and aging. J. Pineal Res. 1990;8:179–192. [146] Bjorntorp P. Neuroendocrine ageing. J. Intern. Med. 1995;238:401–404. [147] Rasmussen DD, Boldt BM, Wilkinson CW, Yellon SM, Matsumoto AM. Daily melatonin administration at middle age suppresses male rat visceral fat, plasma leptin, and plasma insulin to youthful levels. Endocrinology 1999;140:1009 –1012. [148] Wolden-Hanson T, Mitton DR, McCants RL, Yellon SM, Wilkinson CW, Matsumoto AM, Rasmussen DD. Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat. Endocrinology 2000;141(2):487-97. [149] Belfroid AC, Purperhart M, Ariese F. Organotin levels in seafood. Mar. Pollut Bull. 2000; 40(3):226–232.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

The Effect of Drugs on Leptin Metabolism

53

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

[150] Lee CC, Wang T, Hsieh CY, Tien CJ. Organotin contamination in fishes with different living patterns and its implications for human health risk in Taiwan. Environ. Pollut. 2005; 137:198–208. [151] Baillie-Hamilton PF. Chemical toxins: A hypothesis to explain the global obesity epidemic. J. Altern. Complem. Med. 2002;8:185–192. [152] Zuo Z, Chen S, Wu T, Zhang J, Su Y, Chen Y, Wang C.Tributyltin causes obesity and hepatic steatosis in male mice. Environ. Toxicol. 2009 [Epub ahead of print].

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

In: Leptin: Hormonal Functions, Dysfunctions and Clinical Uses ISBN: 978-1-61122-891-5 Editors: Rose M. Hemling and Arthur T. Belkin ©2011 Nova Science Publishers, Inc.

Chapter 3

LEPTIN: A NOVEL THERAPEUTIC TARGET IN THE FIGHT AGAINST NEURO-DEGENERATION? G. H. Doherty School of Biology, University of St. Andrews, Fife, UK

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ABSTRACT Neurodegenerative diseases present one of the greatest ongoing challenges to modern medicine with a paucity of therapies available and a lack of understanding as to why many patients develop these disorders. Given that neurodegeneration largely affects the elderly and that the world is seeing a marked demographic shift towards an ageing population, the need to better understand and treat these conditions is becoming ever more urgent. Recent research has implicated low levels of the anti-obesity hormone leptin in the development of neurodegeneration and has suggested that exogenous leptin may offer protection from the loss of neurons associated with this process. At the moment our understanding of leptin‘s potential in this field is very much in its infancy, thus it seems timely to bring the emerging evidence together. Therefore, this chapter considers the data revealing that leptin deficiency can play a key role in degenerative changes in the central nervous system and investigates the potential of leptin as a novel therapeutic reagent in the fight against neurodegenerative diseases.

INTRODUCTION Medical advances and changing lifestyles have led to a continuing global demographic shift towards an ageing population. In 2001 the United Kingdom population census revealed, for the first time, a greater number of over 65s living in the UK than under 16s (Franco et al., School of Biology, University of St. Andrews, Bute Building, West Burn Lane, St Andrews, Fife, KY16 9TS. Tel. + 44 1334 463611. e-mail: [email protected].

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

56

G. H. Doherty

2007). It is unfortunate that although a healthy old age is universally desired, it is not universally attained with the incidence of ill-health more prevalent in the over 65s than in younger age groups (Cutler and Mattson, 2006). Neurodegenerative disorders are characterised by a loss of both neuronal populations and changes in the physiological functions of the neurons that remain. The Alzheimer‘s Society (UK) estimate that there are currently 750 000 people living with dementia in the UK alone, and data released by the Parkinson‘s Disease Society (UK) estimates that there are 120 000 living with Parkinson‘s. Given that the greatest risk factor for the development of neurodegenerative conditions is ageing, it is not surprising that it has been forecast that Western Societies will see a 100% increase in Alzheimer‘s cases between 2001 and 2040, with a 300% increase forecast for emerging economics such as India and China (Ferri et al., 2005). Since these neurodegenerative diseases remain ultimately incurable, it is clear that the human population is facing an increasing socio-economic burden in caring for individuals afflicted by such disorders. Therefore, the search for measures to prevent and cure these conditions promises to be a fundamental research focus for many years to come. It is within this climate that a number of research papers have emerged over recent years revealing potential roles for the circulating hormone leptin in the etiology of neurodegenerative disorders, and as a potential therapeutic target for their treatment. Specifically, leptin has been shown to both protect neurons from cell death (Doherty et al., 2008) and to enhance neurophysiology (Shanley et al., 2001). More details of such findings will be discussed later in this chapter. It is such data that has led to researchers posing the question of whether leptin has therapeutic potential beyond its current use as an anti-obesity drug. Leptin has a number of advantages as a therapeutic reagent: it is a naturally occurring biological molecule and is therefore likely to be generally well tolerated by patients; data suggests, as we will see, that leptin can act against neurodegeneration at a number of levels; and finally, given that leptin is already licensed for human use, this implies that the translation time from a positive research outcome to clinical application would be far lower than for a novel compound.

THE ANTI-OBESITY HORMONE LEPTIN The circulating hormone leptin was revealed 15 years ago to be the product of the ob gene, itself cloned in 1994 (Zhang et al., 1994; Halaas et al., 1995; Pelleymounter et al., 1995). The ob gene encodes a 45kb RNA that was initially believed to be expressed exclusively in adipose tissue (Zhang et al., 1994). It is now well established that ob mRNA is also expressed in the placenta and stomach, and, crucially for this chapter, in a number of brain regions including the hypothalamus (Hoggard et al., 1997; Mix et al., 2000; Morash et al., 1999). The translated polypeptide hormone leptin was named from the Greek ―leptos‖ meaning thin. Following cloning of the ob gene and identification of leptin as the gene product, it was quickly shown that leptin functions to regulate body weight (Halaas et al., 1995; Pelleymounter et al., 1995). Thus leptin signalling reduces food intake giving an inverse relationship between plasma leptin levels and appetite. This in turn means that, in an ideal situation, as accretion of adipose tissue occurs due to increased food intake, leptin levels will rise. Due to this rise in leptin levels, appetite will be reduced and body weight maintained

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Leptin

57

within a narrow band (Maffei et al, 1995). In periods of prolonged fasting, leptin levels markedly decrease stimulating appetite whereas periods of overfeeding result in a substantial rise in leptin levels signalling that satiety has been reached and thus reducing appetite (Flier, 1997; Kolaczynski et al., 1996a; Kolaczynski et al., 1996b). Circulating leptin exists as a 16kDa protein (Halaas et al., 1995) for which the receptor, Ob-R, was identified in 1995 (Tartaglia et al., 1995). Ob-R belongs to the family of Class I cytokine receptors and is widely expressed throughout the body (Tartaglia et al., 1995). Ob-R mRNA is alternatively spliced to give a number of Ob isoforms of which the longest, Ob-Rb, is critical for leptin signalling (Fei et al., 1997). All Ob-R isoforms (Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, Ob-Re and Ob-Rf) possess the extracellular leptin binding domain but it is only Ob-Rb that contains the full-length intracellular domain that permits downstream signalling following leptin binding (Bjørbaek et al., 1998; Elmquist et al., 1998; Fei et al., 1997; Friedman and Halaas, 1998; Mercer et al,. 1996; Wang et al, 1996). As mentioned above, the primary physiological role identified for leptin is the regulation of body weight via control of food intake. This effect is predominantly mediated via leptin‘s actions on the arcuate nucleus of the hypothalamus (Schwartz et al., 1996; Bingham et al., 2008; Dhillon et al,. 2006). The hypothalamus plays a number of roles within the body, the most important of which, perhaps, is the linking of the body‘s two major control systems – the nervous system and the endocrine system via its close anatomical and functional links with the pituitary gland. Within the hypothalamus, the arcuate nucleus contains leptinresponsive neurons that project centrally to other regions of the hypothalamus to control appetite. Leptin also has a number of effects in the periphery. These include the direct inhibition of insulin expression in, and release from, pancreatic -cells in vitro (Emilsson et al., 1997; Kulkarni et al., 1997). Interestingly these findings are in contrast to the other data that reveals that leptin has insulin-enhancing actions (Rossetti et al., 1997; Shi et al., 1998; Kamohara et al., 1997). This finding links leptin to metabolic control and diabetes, and so more recently leptin has been trialed and shown to be a successful therapy for Type I diabetes mellitus exhibiting some advantages over traditional insulin treatments (Wang et al., 2010). Leptin also prevents lipogenesis in adipocytes in vitro. This is the metabolic process whereby simple sugars convert to fatty acids; and triacylglycerols are synthesised via the reaction of fatty acids with glycerol. The same study revealed that leptin stimulates fatty acid oxidation and thus a unique form of lipolysis (the breakdown of triglycerides into free fatty acids) (Wang et al., 1999). Leptin-induced lipolysis leads to the intracellular oxidation of the free fatty acids whereas in lipolysis triggered by other stimuli, the free fatty acids are exported to the liver for oxidation to ketoacids. Therefore, these data go some way to explaining one of the interesting features of leptin-driven fat loss – a decrease in body fat without a corresponding increase in free fatty acids or ketones. Furthermore, leptin is involved in the activation of the immune response, with reports of direct regulation of the B and T cell responses (Busso et al., 2002) and regulation of both hematopoiesis and lymphopoiesis (Howard et al., 1999; Bennett et al., 1996) having been reported. In addition to its long-established role in the regulation of food intake, leptin has been shown to have a number of other roles in the central nervous system as will be discussed. For instance, leptin can modulate both long term potentiation and long term depression in the hippocampus (Shanley et al., 2001; Li et al., 2002; Durakoglugil et al., 2005). Long term

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

58

G. H. Doherty

potentiation and long term depression represent the cellular basis of memory formation. Therefore it is not surprising that leptin aids memory retention in rodents in vivo (Farr et al., 2006).

SIGNALLING VIA THE OB RECEPTOR

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

The physiological actions of leptin are mediated via its binding to the transmembrane ObR receptor of which, although there are multiple splice variants, only the full length Ob-Rb isoform has signalling competence (Fei et al., 1997). Downstream of Ob –Rb activation, a number of signalling pathways can be triggered (Figure 1) but a crucial first step is the activation of Janus Kinase-2 (JAK2) that is associated with Ob-R. The leptin receptor per se has no intrinsic enzymatic activity thus JAK2 auto-phosphorylation is a necessary first step in initiating intracellular signal transduction cascades (Tartaglia et al., 1997; Kloek et al., 2002). Once JAK2 has been phosphorylated and activated, it phosphorylates distinct tyrosine residues located within the intracellular domain of Ob-Rb: Tyr985: Tyr1077 and Tyr1138 (Gong et al., 2007). Each tyrosine site, upon phosphorylation, triggers a unique downstream signalling event (Figure 1).

Figure 1. Signalling downstream of leptin binding to Ob-Rb.

Thus phosphoyrlation of Tyr985 recruits SH2-containing tyrosine phosphatase-2 (SHP-2), the first step in an ERK signalling event (Gong et al., 2007; Banks et al., 2000; Bjørbaek et Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Leptin

59

al., 2001). Phosphorylation of Tyr1077 promotes the recruitment and activation of STAT5 (Gong et al, 2007; Hekerman et al., 2005). Finally, it is known that phosphorylation of ObRb at Tyr1138 recruits and activates another of the STAT transcription factors, STAT-3 (Banks et al., 2000; Hekerman et al., 2005). This same site is also proposed to activate STAT5 although to a lesser extent than Tyr1077 (Gong et al., 2007; Hekerman et al., 2005). Thus evidence has begun to accumulate revealing how some of the signalling streams are initiated following Ob-Rb activation. However in addition to ERK, STAT3 and STAT5, leptin is known to activate a number of other signal transduction cascades downstream of its binding to Ob-Rb including mammalian target of rapamycin (mTOR), phosphatidyl inositol kinase-3 (P1-3K) and inhibition of AMP-dependent protein kinase (AMPK) (Figure 1) (Cota et al., 2006; Minokoshi et al., 2004; Niswender et al., 2001; Plum et al., 2006; Xu et al., 2005). The enzymatic events upstream of the activation of these pathways at the level of Ob-Rb phosphorylation currently remain to be elucidated. Binding of leptin to the full length OB-Rb receptor triggers a multitude of pathways leading to activation of, for example, ERK, PI-3 kinase, MTOR or AMPK activity depending upon cell type and circumstance. Gene expression can also be modulated via activity of the STAT family of transcription factors.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

LEPTIN RESISTANCE AND INSENSITIVITY It is clear that adequate levels of circulating leptin, together with an appropriate response to the hormone, are important for both weight control and a host of other physiological and homeostatic processes. Thus if an individual has a reduced ability to synthesise or respond to leptin, there are likely to be a number of consequences. In rodent models, mutation of the ob gene as observed in ob/ob C57/BL6 mice leads to obesity recognisable by around four weeks of age. These mice also exhibit a diabetes-like syndrome of hyperglycemia, glucose intolerance, elevated plasma insulin, subfertility, impaired wound healing, and an increase in hormone production from both pituitary and adrenal glands (Garris and Garris, 2004). C57/BL6 db/db mice and Zucker fa/fa rats have loss of function mutations in the Ob-R receptor and are obese with db/db mice visibly obese by around 4 weeks of age and exhibiting a range of symptoms similar to that observed in the ob/ob mice including metabolic changes and delayed wound healing (Garris and Garris, 2004). It has been established that obesity in humans can, in a small number of cases, be caused by failure to respond adequately to leptin signalling (Farooqi et al., 2001; Montague et al., 1997; Strobel et al., 1998). There are a number of mechanisms by which leptin resistance can arise (Figure 2). A multitude of factors can contribute to the failure of individuals to respond adequately to the effects of leptin. BBB = blood-brain barrier. In order to respond to leptin, the hormone has to be firstly available at the site of action. Thus it has been determined that in obese subjects there is a reduction in the transport of leptin from the peripheral circulation, across the blood-brain barrier, and into the brain (Caro et al., 1996; El-Haschimi et al., 2000; Schwartz et al., 1996). It is known that Ob-Ra, a truncated form of Ob-R that possesses the leptin binding domain but that lacks the intracellular signalling domain, mediates leptin‘s transport across the blood-brain barrier (Hileman et al., 2000; Hileman et al., 2002; Kastin et al., 1999). This process can be

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

60

G. H. Doherty

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

inhibited by a soluble form of Ob-R, Ob-Re (Tu et al., 2008). This implies that tight regulation of the levels of the Ob-R splice variants at the blood-brain barrier may be necessary for optimal leptin transport across it. However, it is important to note that at least one other mechanism of leptin transport to target neurons within the central nervous system has been identified. Thus a subpopulation of circuate nucleus neurons that have been shown to express Ob-R, project to the median eminence (Faouzi. et al., 2007), which is part of the hypothalamus that is essentially devoid of the blood-brain barrier. Since the median eminence lacks tight junctions therefore allowing the entry of circulating hormones such as leptin (Saunders et al., 1999), these neurons can receive leptin via their connection to this region (Faouzi et al., 2007). Hence, the decrease in transport of leptin across the blood-brain barrier warrants further study to determine the importance of this in light of other possible mechanisms of leptin entry into the central nervous system.

Figure 2. Causes of leptin resistance or insensitivity.

Once leptin has reached the site of its action, the target cells must contain and express the correct apparatus to respond to it. Therefore the target cells must express adequate Ob-Rb in order to bind and respond to leptin. It is known that only a minor proportion of a cell‘s Ob-Rb is located at the plasma membrane with the rest held in the Golgi and in small vesicles (Belouzard et al., 2004; Seo et al., 2009). This implies that correct intracellular trafficking of Ob-Rb is necessary to put in place the machinery to respond to leptin. Whether defects in this pathway contribute to leptin resistance in human subjects remains to be proven but could certainly prove an interesting line of investigation.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Leptin

61

As mentioned earlier in this chapter, once leptin binds to Ob-Rb, a number of signal transduction pathways can be activated. Ob-Rb signalling is subject to modulation by both positive and negative regulators thereof. Thus SH2B1 functions to enhance cellular sensitivity to leptin (Li et al., 2007). In contrast, suppressor of cytokine signalling 3 (SOCS-3) and protein tyrosine phosphatase 1B (PTP1B) inhibit leptin signalling (Bjørback et al., 1999; Kaszubska et al., 2002; Zabolotny et al., 2002). It is interesting to note that expression of SOCS-3 is known to increase with age (Peralta et al., 2002), a finding that may go some way to explaining why leptin resistance increases with age (Scarpace et al., 2000).

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

LEPTIN AND NEURODEGENERATION A number of neurobiological functions have been attributed to leptin that suggest that it has a potential role to play in the pathogenesis of neurodegenerative conditions. Around 10 years ago it was determined that leptin was able to inhibit apoptosis in the periphery (Lord et al., 1998) and in cell lines (Russo et al., 2004). Thereafter leptin was found to be able to prevent cell death in a variety of neuronal types, and an endogenous role for leptin in promoting neuronal survival is revealed through the discovery that leptin deficient mice have reduced brain weight (Ahima et al., 1999). Thus leptin can inhibit NMDA-mediated excitotoxicity in murine cortical neurons in vitro and can accordingly reduce cortical lesions when systemically administered to mice given excitotoxic doses of ibotenate in vivo (Dicou et al., 2001). Leptin‘s neuroprotective function is not limited to the neurons of the central nervous system and it has been demonstrated that primary cultures of murine peripheral cranial sensory neurons can be protected from growth factor withdrawal-induced apoptosis by leptin administration (Doherty et al., 2008). Following on from such findings a number of groups have tested whether leptin can be neuroprotective in models of neurodegeneration. Thus leptin protects against damage caused by oxygen-glucose deprivation or mouse middle cerebral artery occlusion (Zhang et al., 2007). Both of these models are used to mimic the neurodegeneration caused by stroke and therefore imply that leptin could reduce neuronal damage following such an event. Similarly leptin is neuroprotective in murine models of Parkinson‘s Disease. 6-hydroxydopamine is a selective neurotoxin for dopaminergic neurons and is often used both in vivo and in vitro to destroy the dopaminergic neurons that are specifically lost in Parkinson‘s Disease. Leptin can protect dopaminergic cell lines from 6-hydroxydopamine (Weng et al., 2007) and also protects primary cultures of murine midbrain dopaminergic neurons from apoptosis induced by either 6-hydroxydopamine or TNF- (Doherty et al., 2008). The latter finding is perhaps of particular importance given the emerging research emphasis in the role of neuroinflammation in Parkinson‘s Disease. Another disorder that is associated with neuronal death is epilepsy with seizures known to lead to localised loss of neurons. The region of the brain that is most susceptible to seizure activity is the hippocampus and leptin has been shown to protect hippocampal neurons from cell death (Guo et al., 2008). Of course preventing neuronal death per se may not be sufficient in order to alleviate the symptoms associated with neurological disorders. It is also imperative that the surviving neurons exhibit normal neurophysiology. Intriguingly, with regards to epilepsy, leptin has been shown to have anticonvulsive properties in addition to it

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

62

G. H. Doherty

neuroprotective functions. As such, through the activation of large conductance calciumactivated potassium channels, leptin inhibits the firing of hippocampal neurons, the aberrant firing of which is associated with epileptic seizures (Shanley et al., 2002). Leptin deficiency or the failure to respond to this hormone may be crucial in the development of epilepsy in certain individual as it is known that leptin deficient mice have a higher occurrence of seizures and that this can be prevented by exogenous leptin administration (Erbayat-Altay et al., 2008). It has also been postulated that one of the mechanisms by which a ketogenic diet is useful in preventing epileptic seizures is due to the increase in leptin levels triggered by such regimes (Kinzig et al., 2005; Thio et al., 2006). Thus endogenous leptin may have an important role to play in epilepsy with reduced levels capable, in model systems at least, of increasing the susceptibility to have seizures, and elevated levels, as produced in response to a ketogenic diet, temporally associated with decreased seizure frequency. A unique feature of neurons as compared to other cell types is the presence of processes – the dendrites and axons by which neurons communicate with each other and receive and send information to the periphery. Therefore it is interesting to note that leptin can promote the outgrowth of processes from cerebellar Purkinje neurons in culture, and increases the number of branch points and the complexity of the neurite arbor (Oldreive et al., 2008). It has also been established that leptin deficient mice have disrupted hypothalamic projection pathways and that exogenous leptin can enhance the ability of hypothalamic neurons to project axons (Bouret et al., 2004). In addition, leptin rapidly enhances the motility and density of dendritic filopodia extended by hippocampal neurons (O’Malley et al., 2007). These findings imply that leptin can modulate the neuronal arbor at both a macro and a micro level, encouraging the extension of processes to potentially replace lost or damaged connections and also increasing synaptic density. Synaptic plasticity is the ability of a connection between to neurons to change in strength and is widely investigated as the cellular basis of memory formation. It has been discovered that leptin can modulate hippocampal synaptic plasticity through its ability to enhance NMDA receptor function (Shanley et al., 2001; Oomura et al., 2006), and through activation of large conductance calcium-activated potassium channels (Shanley et al., 2002). As mentioned above, leptin can remodel dendritic processes emanating from hippocampal neurons thus triggering activity-dependent changes in synaptic strength further influencing synaptic plasticity (O’Malley et al., 2007). Given the wealth of in vitro data demonstrating that leptin can modulate LTP and LTD, it is perhaps unsurprising that leptin has been shown to be involved in learning and memory in vivo. Rodents that have deficiencies in the Ob receptor exhibit memory impairment linking leptin to this function (Li et al., 2002). The above data gleaned in the laboratory strongly suggests that leptin could play a key role in neurodegenerative conditions both as a therapeutic reagent and perhaps, via deficiencies in either leptin, its transport or its receptor signaling, in the pathogenesis of these disorders. The Framingham cohort is a unqiue data set that has, since 1948, followed individuals over many years, testing blood samples and keeping detailed health and lifestyle records. Data from the Framingham cohort identified that decreased circulating plasma leptin levels are associated with increased incidence of dementia and Alzheimer‘s Disease (Lieb et al., 2009). However, a cross-sectional study of vascular dementia patients versus nondemented age-matched controls did not identify any differences in plasma leptin concentrations between these two groups (Ban et al., 2009), and polymorphism of the Ob-R gene that alters leptin binding capacity is not associated with an increased risk of developing

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Leptin

63

late onset Alzheimer‘s Disease (Utsunomiya et al., 2010). In spite of the observations from the cross-sectional data, the link between low levels of leptin and the prevalence of dementia observed in the Framingham study remains interesting for two reasons. The first is the large size of the study, which adds weight to the data. The second is that low levels of leptin may be important in the development of Alzheimer‘s at any given stage of the disease process and the development of Alzheimer‘s occurs over many decades. Thus the levels that are seen in late-stage symptomatic individuals may not be representative of the levels that these patients had earlier on in the pathology of the disease.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

LEPTIN’S POTENTIAL AS A THERAPY FOR NEURODEGENERATION Leptin has been shown to exert a positive influence on both neuronal survival and physiology and therefore has begun to be touted as a potential therapy for a variety of neurological conditions. In order to become a functional medicine, we need to ask several questions of leptin. Firstly, can the in vitro research translate to an effective medicine for human use? Secondly, how can we deliver leptin precisely and accurately to the regions of the brain that are specifically affected in each of these degenerative conditions? And finally, what are the side effects of leptin administration? In contrast to many novel therapies being suggested for the treatment of neurodegeneration, leptin has the distinct advantage of already being licensed for human use. Thus it is known that the drug can be safely administered to human patients and this markedly reduces the time-frame from the laboratory discoveries that reveal that a compound could be useful for treating a disorder, through clinical trials and finally onwards towards the treatment of patients. To date leptin has been tested and used in the treatment of a number of conditions including obesity and lipodystrophy. Thus leptin administration to leptin-deficient, morbidly obese adults results in highly significant weight loss with accordant increases observed in physical activity. Furthermore, a number of changes in endocrinology and metabolism are observed including resolution of Type II diabetes mellitus and hypogonadism (Licinio et al., 2004). The condition lipodystrophy can be further subdivided according to the gene mutations carried by patients but is always characterised by the loss of adipose tissue in conjunction with a range of metabolic aberrations including decreased circulating levels of leptin. Evidence from rodent models of the disorder suggested that administration of exogenous leptin could ameliorate some of the symptoms associated with lipodystrophy (Shimomura et al., 1999; Gavrilova et al., 2000; Ebihara et al., 2001). Therefore human trials have begun using leptin to treat lipodystrophy patients and success in alleviating a number of metabolic symptoms has been reported (Chong et al., 2010). Thus empirical observations in rodent models suggesting a potential therapeutic role for leptin have resulted, for lipodystrophy and obesity at least, in observed health improvements for patients. Leptin is not an easy drug to administer or to take, and the current treatment for obesity, for instance, involves giving subcutaneous injections of the drug.. In addition, to date, these injections have been given to patients to treat peripheral and hypothalamic symptoms, that is to deal with metabolic aberrations and to modulate behaviours and endocrine pathways at the

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

64

G. H. Doherty

level of the hypothalamus. It remains to be seen whether subcutaneous administration of leptin can significantly influence the neurons in other areas of the central nervous system such as the hippocampus and cortex that are affected in Alzheimer‘s Disease or the dopaminergic neurons of the substantia nigra that are one of the major sites of neuronal loss in Parkinson‘s Disease. Another method of leptin delivery that has therefore been tested is intranasal administration, which in rodents successfully raises brain leptin levels, particularly in the hypothalamus (Schulz et al., 2004; Fliedner et al., 2006). Finally, leptin can be delivered by a single injection directly into the afflicted brain region. Thus non-replicative, nonimmunogenic and non-pathogenic recombinant adeno-associated virus encoding the ob gene has been used as a form of central gene therapy to provide a stable supply of leptin in a given brain region. This technique has been proven to provide long-term suppression of weight gain in pre-pubertal rats (Beretta et al., 2002), to inhibit fat deposition for the rest of the rodent life span following gene transfer (Boghossian et al., 2005) and to block high fat diet induced weight gain (Dube et al., 2002).

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

CONCLUSION Since its identification as a satiety signal in the mid-nineties, leptin has generated a large amount of research interest such that by August 2010 over 18 000 research articles relating to this hormone had been published. It is well established that leptin is a polypeptide hormone that signals via the Ob-R receptor and a plethora of papers have detailed the downstream signalling pathways that this receptor-ligand interaction mediates at the biochemical level. More recently interest has begun to spread out from leptin‘s role as an appetite-suppressing signal to look more generally at leptin‘s effects on neurophysiology and neuronal viability. Within this research environment it is clear that leptin is a potent neuroprotective agent and that it has beneficial effects on neurophysiology that suggest, for instance, that it could act as a cognitive enhancer. Furthermore, given that there is emerging evidence that reduced circulating leptin levels are a risk factor for the development of neurodegeneration it is not surprising that this hormone is being thoroughly researched as a possible therapeutic for such disorders. Leptin is an attractive therapeutic target for a number of reasons from its current licence for human use as an anti-obesity drug, which would markedly speed up the drug discovery pipeline, to its beneficial effects on the nervous system at multiple levels from neuronal survival to synaptic plasticity. Furthermore, as a naturally-occurring compound, leptin is well tolerated with few known side effects in a therapeutic setting. However, problems relating to drug delivery remain with much important work still to be carried out to uncover an effective method of leptin delivery into regions of the central nervous system that are affected by neurodegeneration. On this front, central gene therapy is proving very promising, providing long lasting results in rodent models, implying that if this technique could be safely and effectively applied to humans, a one-off treatment could be sufficient for most patients. It is clear that much more work needs to be done before we can truly determine whether leptin can benefit sufferers from neurodegenerative conditions. In particular it will be important to determine when patients who might benefit from leptin therapy should be treated. As an anti-apoptotic agent leptin can protect against neuronal death. However, given

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Leptin

65

that almost 80% of the neurons of the substantia nigra pars compacta have already died before Parkinson‘s Disease patients become symptomatic, this anti-apoptotic role on its own might confer little benefit to these patients. However, used in conjunction with neurorestorative techniques such as fetal grafting or stem cell therapies, it is reasonable to postulate that leptin could play a role in protecting grafted tissue within the host environment particularly until the graft becomes well established. In other neurodegenerative conditions such as Alzheimer‘s Disease leptin might play a very different role. Here the anti-apoptotic effects of leptin could perhaps be harnessed to prevent further neuronal death whilst the beneficial effects of the leptin on synaptic plasticity could help patients retain and form new memories. In the case of stroke, neuronal death continues for a few days following the attack and here prompt leptin administration could be a possible method of inhibiting neuronal death that occurs subsequent to the initial infarct. It is unlikely that leptin will prove to be a magic bullet that will cure all or indeed any neurodegenerative conditions. However, the range of beneficial effects of this hormone on the nervous system and the on-going research into methods of delivering this drug to the nervous system imply that leptin could benefit patients in a number of ways. It is not inconceivable to consider a world where neurodegeneration can be stopped in its tracks and that patients with these disorders would not continue to deteriorate but could maintain the status quo. This may not return the full quality or quantity of life that these individuals had before being affected but it would offer a better quality of life than further deterioration. If we consider a realistic short-term research target of turning neurodegenerative conditions into something that patients can live with and continue to have quality of life, then leptin looks a very promising drug in achieving this aim.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ACKNOWLEDGMENTS The author would like to thank Dr Frank Gunn-Moore for proof-reading of this manuscript, and Rosemary Middleton for assistance in preparation of the manuscript. Dr Doherty holds an Alzheimer‘s Society personal research fellowship (grant number 93) with support from the Henry Smith Charity. Alzheimer's Society is a charity (registration no. 296645) and a company registered in England and Wales (registration no. 2115499). The University of St Andrews is a charity registered in Scotland (registration no. SC013532).

REFERENCES Ahima, RS; Bjorbaek, C; Osei, S; Flier, JS. Regulation of neuronal and glial proteins Endocrinology, 1999, 140(6), 2755-62. Ban, Y; Watanabe, T; Suguro, T; Matsuyama, TA; Iso, Y; Sakai ,T; Sato, R; Idei, T; Nakano, Y; Ota, H; Miyazaki, A; Kato, N; Hirano, T, Ban, Y; Kobayashi, Y. Increased plasma urotensin-II and carotid atherosclerosis J. Atheroscler. Thromb., 2009, 16(3), 179-87. Banks, AS; Davis, SM; Bates, SH; Myers MG Jr. Activation of downstream signals J. Biol. Chem., 2000, 275(19), 14563-72.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

66

G. H. Doherty

Belouzard, S; Delcroix, D; Rouillé, Y. Low levels of expression of leptin J. Biol. Chem., 2004, 279(27), 28499-508. Bennett, BD; Solar, GP; Yuan, JQ; Mathias, J; Thomas, GR; Matthews, W. A role for leptin Curr. Biol., 1996, 6(9), 1170-80. Beretta, E; Dube, MG; Kalra, PS; Kalra, SP. Long-term suppression Pediatr. Res., 2002, 52(2), 189-98. Bingham, NC; Anderson, KK; Reuter, AL; Stallings, NR; Parker, KL. Selective loss of leptin Endocrinology, 2008, 149(5),2138-48. Bjørbaek, C; Buchholz, RM; Davis, SM; Bates, SH; Pierroz, DD; Gu, H; Neel, BG; Myers, MG Jr; Flier, JS. Divergent roles of SHP-2 in ERK activation by leptin J. Biol. Chem., 2001 Feb 16, 276(7), 4747-55. Bjørbaek, C; El-Haschimi, K; Frantz, JD; Flier, JS. The role of SOCS-3 in leptin J. Biol. Chem., 1999, 274(42), 30059-65. Bjørbaek, C; Elmquist, JK; Michl, P; Ahima, RS; van Bueren, A; McCall, AL; Flier JS. Expression of leptin Endocrinology, 1998, 139(8), 3485-91. Boghossian, S; Ueno, N; Dube, MG; Kalra, P; Kalra, S. Leptin gene transfer Peptides, 2005, 26(8), 1512-9. Bouret, SG; Draper, SJ; Simerly, RB. Trophic action of leptin Science., 2004,304(5667), 10810. Busso, N; So, A; Chobaz-Péclat, V; Morard, C; Martinez-Soria, E; Talabot-Ayer, D; Gabay, C. Leptin signaling deficiency J. Immunol., 2002, 168(2), 875-82. Caro, JF; Kolaczynski, JW; Nyce, MR; Ohannesian, JP; Opentanova, I; Goldman, WH; Lynn, RB; Zhang, PL; Sinha, MK; Considine RV. Decreased cerebrospinal-fluid Lancet, 1996, 348(9021), 159-61. Chong, AY; Lupsa, BC; Cochran, EK; Gorden, P. Efficacy of leptin Diabetologia, 2010, 53(1), 27-35. Cota, D; Proulx, K; Smith, KA; Kozma, SC; Thomas, G; Woods, SC; Seeley, RJ. Hypothalamic mTOR signaling regulates food Science, 2006, 312(5775), 927-30. Cutler, RG; Mattson, MP. The adversities of aging. Ageing Res. Rev., 2006, 5(3), 221-38. Dhillon, H; Zigman, JM; Ye, C; Lee, CE; McGovern, RA; Tang, V; Kenny, CD; Christiansen, LM; White, RD; Edelstein, EA; Coppari, R; Balthasar, N; Cowley, MA; Chua, S Jr; Elmquist, JK; Lowell, BB. Leptin directly activates SF1 neurons Neuron, 2006, 49(2), 191-203. Dicou, E; Attoub, S; Gressens, P. Neuroprotective effects of leptin Neuroreport, 2001,12(18), 3947-51. Doherty, GH; Oldreive, C; Harvey J. Neuroprotective actions of leptin Neuroscience, 2008, 154(4), 1297-307. Dube, MG; Beretta, E; Dhillon, H; Ueno, N; Kalra, PS; Kalra, SP. Central leptin Diabetes.,2002, 51(6), 1729-36. Durakoglugil, M; Irving, AJ; Harvey, J. Leptin induces a novel form of NMDA receptordependent long-term depression J. Neurochem., 2005, 95(2), 396-405. Ebihara, K; Ogawa, Y; Masuzaki, H; Shintani, M; Miyanaga, F; Aizawa-Abe, M; Hayashi, T; Hosoda, K; Inoue, G; Yoshimasa, Y; Gavrilova, O; Reitman, ML; Nakao, K. Transgenic overexpression of leptin Diabetes., 2001, 50(6), 1440-8. El-Haschimi, K; Pierroz, DD; Hileman, SM; Bjørbaek, C; Flier JS. Two defects J. Clin. Invest., 2000, 105(12), 1827-32.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Leptin

67

Elmquist, JK; Bjørbaek, C; Ahima, RS; Flier, JS; Saper CB. Distributions of leptin J. Comp. Neurol, 1998, 395(4),535-47. Emilsson, V; Liu, YL; Cawthorne, MA; Morton, NM; Davenport, M. Expression of the functional leptin Diabetes, 1997, 46(2), 313-6. Erbayat-Altay, E; Yamada, KA; Wong, M; Thio, LL. Increased severity of pentylenetetrazol induced seizures in leptin Neurosci. Lett., 2008, 433(2), 82-6. Faouzi, M; Leshan, R; Björnholm, M; Hennessey, T; Jones, J; Münzberg, H. Differential accessibility Endocrinology, 2007, 148(11), 5414-23. Farooqi, IS; Keogh, JM; Kamath, S; Jones, S; Gibson, WT; Trussell, R; Jebb, SA; Lip, GY; O'Rahilly, S. Partial leptin Nature, 2001, 414(6859), 34-5. Farr, SA; Banks, WA; Morley, JE. Effects of leptin Peptides, 2006, 27(6), 1420-5. Fei, H; Okano, HJ; Li, C; Lee, GH; Zhao, C; Darnell, R; Friedman, JM. Anatomic localization Proc. Natl. Acad. Sci. USA, 1997, 94(13),7001-5. Ferri, CP; Prince, M; Brayne, C; Brodaty, H; Fratiglioni, L; Ganguli, M; Hall, K; Hasegawa, K; Hendrie, H; Huang, Y; Jorm, A; Mathers, C; Menezes, PR; Rimmer, E; Scazufca, M. Global prevalence of dementia Lancet, 2005, 366(9503), 2112-7. Fliedner, S; Schulz, C; Lehnert H. Brain uptake of intranasally applied radioiodinated leptin Endocrinology, 2006 , 147(5), 2088-94. Flier, JS. Leptin expression and action, new experimental paradigms. Proc. Natl. Acad. Sci. USA, 1997, 94(9), 4242-5. Franco, OH; Kirkwood, TB; Powell, JR; Catt, M; Goodwin, J; Ordovas, JM, van der Ouderaa, F. Ten commandments for the future of ageing research in the UK BMC Geriatr., 2007, 7, 10. Friedman, JM; Halaas, JL. Leptin and the regulation of body weight Nature, 1998, 395(6704), 763-70. Garris, DR; Garris, BL. Cytochemical analysis of pancreatic islet hypercytolipidemia following diabetes Pathobiology, 2004, 71(5), 231-40. Gavrilova, O;, Marcus-Samuels, B; Leon, LR;, Vinson, C; Reitman, ML. Leptin and diabetes Nature, 2000, 403(6772), 850 Gong, Y; Ishida-Takahashi, R; Villanueva, EC; Fingar, DC; Münzberg, H; Myers, MG Jr. The long form of the leptin J. Biol. Chem., 2007, 282(42), 31019-27. Guo, Z; Jiang, H; Xu, X; Duan, W; Mattson, MP. Leptin-mediated cell survival J. Biol. Chem., 2008, 283(3), 1754-63. Halaas, JL; Gajiwala, KS; Maffei, M; Cohen, SL; Chait, BT; Rabinowitz, D; Lallone, RL; Burley, SK; Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene Science, 1995, 269(5223), 543-6. Hekerman, P; Zeidler, J; Bamberg-Lemper, S; Knobelspies, H; Lavens, D; Tavernier, J; Joost, HG; Becker, W. Pleiotropy of leptin FEBS J, 2005, 272(1), 109-19. Hileman, SM; Pierroz, DD; Masuzaki ,H; Bjørbaek, C; El-Haschimi , K; Banks, WA; Flier, JS. Characterizaton of short isoforms of the leptin Endocrinology, 2002, 143(3), 775-83. Hileman, SM; Tornøe, J; Flier, JS; Bjørbaek, C. Transcellular transport Endocrinology, 2000, 141(6), 1955-61. Hoggard, N; Mercer, JG; Rayner, DV; Moar, K; Trayhurn, P; Williams, LM. Localization of leptin Biochem. Biophys. Res. Commun., 1997, 232(2), 383-7. Howard, JK; Lord, GM; Matarese, G; Vendetti, S; Ghatei, MA; Ritter, MA; Lechler, RI; Bloom, SR. Leptin protects mice J. Clin. Invest., 1999, 104(8), 1051-9.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

68

G. H. Doherty

Kamohara, S; Burcelin, R; Halaas, JL; Friedman, JM; Charron, MJ. Acute stimulation of glucose Nature, 1997, 389(6649), 374-7. Kastin, AJ; Pan, W; Maness, LM; Koletsky, RJ; Ernsberger, P. Decreased transport Peptides, 1999, 20(12), 1449-53. Kaszubska, W; Falls, HD; Schaefer, VG; Haasch, D; Frost, L; Hessler, P; Kroeger, PE; White. DW; Jirousek, MR; Trevillyan, JM. Protein tyrosine Mol. Cell Endocrinol., 2002, 195(1-2), 109-18. Kinzig, KP; Scott, KA; Hyun, J; Bi, S; Moran, TH. Altered hypothalamic signaling and responses to food Obes. Res., 2005, 13(10), 1672-82. Kloek, C; Haq, AK; Dunn, SL; Lavery, HJ; Banks, AS; Myers, MG Jr. Regulation of Jak kinases by intracellular leptin J. Biol. Chem., 2002, 277(44), 41547-55. Kolaczynski, JW; Considine, RV; Ohannesian, J; Marco, C; Opentanova, I; Nyce, MR; Myint, M; Caro, JF. Responses of leptin Diabetes, 1996a, 45(11), 1511-5. Kolaczynski, JW; Ohannesian, JP; Considine, RV; Marco, CC; Caro, JF. Response of leptin to short-term and prolonged overfeeding in humans. J. Clin. Endocrinol. Metab., 1996b 81(11), 4162-5. Kulkarni, RN; Wang, ZL; Wang, RM; Hurley, JD; Smith, DM; Ghatei, MA; Withers, DJ; Gardiner, JV; Bailey, CJ; Bloom, SR. Leptin rapidly suppresses insulin J. Clin. Invest., 1997, 100(11), 2729-36. Li, XL; Aou, S; Oomura, Y; Hori, N; Fukunaga, K; Hori, T. Impairment of long-term potentiation and spatial memory Neuroscience, 2002, 113(3), 607-15. Li, Z; Zhou ,Y; Carter-Su, C; Myers ,MG Jr; Rui, L. SH2B1 enhances leptin Mol. Endocrinol., 2007, 21(9), 2270-81. Licinio, J; Caglayan, S; Ozata, M; Yildiz ,BO; de Miranda, PB; O'Kirwan, F; Whitby, R; Liang, L; Cohen, P; Bhasin, S; Krauss, RM; Veldhuis, JD; Wagner, AJ; DePaoli, AM; McCann, SM; Wong, ML. Phenotypic effects of leptin Proc. Natl. Acad. Sci. USA., 2004, 101(13), 4531-6. Lieb, W; Beiser, AS; Vasan, RS; Tan, ZS; Au, R; Harris, TB; Roubenoff, R; Auerbach, S; DeCarli ,C; Wolf, PA; Seshadri,S. Association of plasma leptin JAMA., 2009, 302(23), 2565-72. Lord, GM; Matarese, G; Howard, JK; Baker, RJ; Bloom, SR; Lechler, RI. Leptin modulates the T-cell immune response Nature, 1998, 394(6696), 897-901. Maffei, M; Halaas, J; Ravussin, E; Pratley, RE; Lee, GH; Zhang, Y; Fei, H; Kim, S; Lallone, R; Ranganathan, S. Leptin levels in human Nat. Med., 1995, 1(11), 1155-61. Mercer, JG; Hoggard, N; Williams, LM; Lawrence, CB; Hannah, LT; Trayhurn, P. Localization of leptin FEBS Lett., 1996, 387(2-3), 113-6. Minokoshi, Y; Alquier, T; Furukawa, N; Kim, YB; Lee, A; Xue, B; Mu, J; Foufelle, F; Ferré, P; Birnbaum, MJ; Stuck, BJ; Kahn, BB. AMP-kinase regulates food Nature, 2004, 428(6982), 569-74. Mix, H; Widjaja, A; Jandl, O; Cornberg, M; Kaul, A; Göke, M; Beil, W; Kuske, M; Brabant, G; Manns, MP; Wagner S. Expression of leptin Gut, 2000, 47(4), 481-6. Montague, CT; Farooqi, IS; Whitehead, JP; Soos, MA; Rau, H; Wareham, NJ; Sewter, CP; Digby, JE; Mohammed, SN; Hurst, JA; Cheetham, CH; Earley , AR; Barnett, AH; Prins, JB; O'Rahilly, S. Congenital leptin Nature, 1997 , 387(6636), 903-8. Morash, B; Li, A; Murphy, PR; Wilkinson, M; Ur, E. Leptin gene expression Endocrinology,. 1999, 140(12), 5995-8.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Leptin

69

Niswender, KD; Morton, GJ; Stearns, WH; Rhodes, CJ; Myers, MG Jr; Schwartz ,MW. Intracellular signalling Nature, 2001, 413(6858), 794-5 Oldreive, CE; Harvey, J,;Doherty GH. Neurotrophic effects of leptin Neurosci. Lett., 2008, 438(1), 17-21. O'Malley, D; MacDonald, N; Mizielinska, S; Connolly, CN; Irving, AJ; Harvey, J. Leptin promotes rapid dynamic changes in hippocampal dendritic morphology Mol. Cell Neurosci., 2007, 35(4), 559-72. Oomura, Y; Hori, N; Shiraishi, T; Fukunaga, K; Takeda, H; Tsuji, M; Matsumiya, T; Ishibashi, M; Aou, S; Li, XL; Kohno, D; Uramura, K; Sougawa, H; Yada, T; Wayner, MJ; Sasaki, K. Leptin facilitates learning Peptides, 2006, 27(11), 2738-49. Pelleymounter, MA; Cullen, MJ; Baker, MB; Hecht, R; Winters, D; Boone, T; Collins, F. Effects of the obese gene Science, 1995, 269(5223), 540-3. Peralta, S; Carrascosa ,JM; Gallardo, N; Ros, M; Arribas C. Ageing increases SOCS-3 expression in rat hypothalamus Biochem. Biophys. Res. Commun., 2002 , 296(2), 425-8. Plum, L; Ma, X; Hampel, B; Balthasar, N; Coppari, R; Münzberg, H; Shanabrough, M; Burdakov, D; Rother, E; Janoschek, R; Alber, J; Belgardt, BF; Koch, L; Seibler, J; Schwenk ,F; Fekete, C; Suzuki, A; Mak, TW; Krone, W; Horvath, TL; Ashcroft, FM; Brüning ,JC. Enhanced PIP3 signaling in POMC neurons J. Clin. Invest., 2006, 116(7), 1886-901 Rossetti, L; Massillon, D; Barzilai, N; Vuguin, P; Chen, W; Hawkins, M; Wu, J; Wang, J. Short term effects of leptin J. Biol. Chem., 1997, 272(44), 27758-63. Russo, VC; Metaxas, S; Kobayashi, K; Harris, M; Werther, GA. Antiapoptotic effects of leptin Endocrinology, 2004, 145(9), 4103-12. Saunders, NR; Habgood, MD; Dziegielewska KM. Barrier mechanisms in the brain Clin. Exp. Pharmacol. Physiol., 1999, 26(1), 11-9. Scarpace, PJ; Matheny, M; Moore, RL; Tümer, N. Impaired leptin Diabetes, 2000, 49(3), 431-5,. Schulz, C; Paulus, K; Lehnert, H. Central nervous and metabolic effects of intranasally applied leptin Endocrinology, 2004, 145(6), 2696-701. Schwartz, MW; Seeley, RJ; Campfield, LA; Burn, P; Baskin, DG. Identification of targets of leptin J. Clin. Invest., 1996, 98(5), 1101-6. Seo, S; Guo, DF; Bugge, K; Morgan, DA; Rahmouni, K; Sheffield, VC. Requirement of Bardet-Biedl syndrome Hum. Mol. Genet., 2009, 18(7), 1323-31. Shanley, LJ; Irving, AJ; Harvey, J. Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity J. Neurosci., 2001, 21(24), RC186. Shanley, LJ; O'Malley, D; Irving AJ; Ashford, ML; Harvey, J. Leptin inhibits epileptiformlike activity in rat hippocampal neurones via PI 3-kinase-driven activation of BK channels. J. Physiol., 2002, 545(Pt 3), 933-44. Shi, ZQ; Nelson, A; Whitcomb, L; Wang, J; Cohen, AM. Intracerebroventricular administration of leptin Metabolism, 1998, 47(10), 1274-80. Shimomura, I; Hammer, RE; Ikemoto, S; Brown, MS; Goldstein, JL. Leptin reverses insulin Nature, 1999, 401(6748), 73-6. Strobel, A; Issad, T; Camoin, L; Ozata, M; Strosberg AD. A leptin Nat. Genet., 1998 , 18(3), 213-5. Tartaglia, LA; Dembski, M; Weng, X; Deng, N; Culpepper, J; Devos, R; Richards, GJ; Campfield, LA; Clark, FT; Deeds, J; Muir, C; Sanker, S; Moriarty, A; Moore, KJ;

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

70

G. H. Doherty

Smutko, JS; Mays, GG; Wool, EA; Monroe, CA; Tepper, RI. Identification and expression cloning Cell, 1995, 83(7), 1263-71. Thio, LL; Erbayat-Altay, E; Rensing, N; Yamada, KA. Leptin contributes to slower weight gain Pediatr. Res., 2006, 60(4), 413-7. Tu, H; Kastin, AJ; Hsuchou, H; Pan, W. Soluble receptor inhibits leptin J. Cell Physiol., 2008, 214(2), 301-5. Utsunomiya, K; Shinkai, T; Sakata, S; Hwang, R; Yamada, K; Chen, HI; Fukunaka, Y; Ohmori, O; Nakamura, J. Lack of association between the leptin Alzheimer Dis. Assoc. Disord., 2010, 24(1), 101-3. Wang, MY; Chen, L; Clark, GO; Lee, Y; Stevens, RD; Ilkayeva, OR; Wenner, BR; Bain, JR; Charron, MJ; Newgard, CB; Unger RH. Leptin therapy Proc. Natl. Acad. Sci. USA., 2010, 107(11), 4813-9. Wang, MY; Lee, Y; Unger, RH. Novel form of lipolysis J. Biol. Chem., 1999, 274(25), 17541-4. Wang, MY; Zhou, YT; Newgard, CB; Unger RH. A novel leptin FEBS Lett., 1996, 392(2), 87-90. Weng, Z; Signore, AP; Gao, Y; Wang, S; Zhang, F; Hastings, T; Yin, XM; Chen, J. Leptin protects against 6-hydroxydopamine-induced dopaminergic J. Biol. Chem., 2007, 282(47), 34479-91. Xu, AW; Kaelin, CB; Takeda, K; Akira, S; Schwartz, MW; Barsh, GS. PI3K J. Clin. Invest., 2005, 115(4), 951-8. Zabolotny, JM; Bence-Hanulec, KK; Stricker-Krongrad, A; Haj, F; Wang, Y; Minokoshi, Y; Kim, YB; Elmquist, JK; Tartaglia, LA; Kahn, BB; Neel, BG. PTP1B regulates leptin Dev. Cell., 2002, 2(4), 489-95. Zhang, F; Wang, S; Signore, AP; Chen, J. Neuroprotective effects of leptin Stroke, 2007, 38(8), 2329-36. Zhang, Y; Proenca, R; Maffei, M; Barone, M; Leopold, L; Friedman, JM. Positional cloning Nature, 1994, 372(6505), 425-32.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

In: Leptin: Hormonal Functions, Dysfunctions and Clinical Uses ISBN: 978-1-61122-891-5 Editors: Rose M. Hemling and Arthur T. Belkin ©2011 Nova Science Publishers, Inc.

Chapter 4

ROLE OF LEPTIN IN THE ACTIVATION OF THE IMMUNE SYSTEM Patricia Fernández-Riejos, Souad Najib, José Santos-Alvarez, Consuelo Martín-Romero, Antonio Pérez-Pérez, Carmen González-Yanes and Víctor Sánchez-Margalet Department of Clinical Biochemistry, Virgen Macarena University Hospital, University of Seville, Spain

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ABSTRACT Adipose tissue is an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that may be present in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Leptin is one of the most important hormones secreted by the adipocyte, with a variety of physiological roles related with the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. The adipocytederived hormone leptin has been shown to regulate the immune response, innate and adaptative response, both in normal as well as in pathological conditions. The role of leptin in regulating immune response has been assessed in vitro as well as in clinical studies. It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility. On the other hand, leptin can promote autoreactivity. As a pro-inflammatory adipokine, it can induce T helper 1 cells and may contribute to the development and progression of autoimmune responses. A number of studies have implicated a role of leptin in the pathogenesis of several autoimmune diseases, including type 1 diabetes, inflammatory bowel disease, and possibly rheumatoid arthritis. This aspect is also of interest in relation to the well-known gender bias in susceptibility to autoimmunity. Autoimmune diseases are frequently more prevalentin

To whom correspondence should be addressed: Víctor Sánchez-Margalet, Dpt. Clinical Biochemistry, Virgen Macarena University Hospital, Av. Dr. Fedriani 3, Seville 41071.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

72

Patricia Fernández-Riejos, Souad Najib, José Santos-Alvarez et al. females, and females are relatively hyperleptinemic. The modulation of circulating leptin levels has a pivotal role on some inflammatory and autoimmune conditions.

Keyword: Leptin; immune response; inflammation; cellular immunology; immune tolerance; autoimmunity

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

1. INTRODUCTION White adipose tissue plays a very important role in the energetic balance of mammals. This tissue is specialized in storing lipids and supplying fuel to the whole body whenever it is necessary. In order to face energetic requirements, adipocytes regulate fatty acid mobilization in response to catabolic and anabolic stimuli. However, adipose tissue is not only a reserve organ; it is also an endocrine organ able to release hormones, peptides, and cytokines (adipokines) that affect both the energetic status and the immune system [1]. Leptin is one of the most important hormones secreted by adipose tissue [2] and its implication in energetic homeostasis at central level has been largely described [3]. Rather than a ―fasting signal‖, leptin is a signal of starvation, in that a falling serum leptin concentration leads to neurohumoral and behavioural changes, trying to preserve energy reserves for vital functions. Thus, during fasting period and after reduction of body fat mass, there is a decrease in leptin levels that leads to a reduction in total energy expenditure to provide enough energy for the function of vital organs, that is, the brain, the heart, and the liver [4]. Even though these effects of leptin decrease are aimed to improve the survival chances under starving conditions, the fall in leptin levels may lead to immune suppression [5], in addition to other neuroendocrine alterations affecting adrenal, thyroid, and sexual/reproductive function [6]. At least, these alterations observed during fasting parallel the decrease in circulating leptin levels. In fact, both ob/ob mice (lacking leptin secretion) and db/db mice (lacking leptin receptor) are not only obese but they also show the immune/endocrine deficiencies observed during starvation [5, 7]. Moreover, it has been recently shown that leptin withdrawal during 8 days in experimental animals leads to the same effects regarding central control of endocrine systems including sexual function [8]. Even in humans, it has been found that leptin levels are associated with immune response in malnourished infants, which have low plasma leptin and impaired immune response [9]. Moreover, leptin signaling deficiency impairs humoral and cellular immune responses. The leptin receptor Ob-Rb is expressed by B and T lymphocytes, suggesting that leptin regulates directly the B and T cell responses [10]. The leptin modulation of the immune system is also mediated by the regulation of hematopoiesis and lymphopoiesis [7, 11] Thus, seven days of provision of recombinant leptin promoted substantial lymphopoiesis, with a twofold increase of the numbers of B cells in the marrow of obese mice while doubling and tripling, respectively, the numbers of pre-B and immature B cells. Twelve days of supplementation brought these subpopulations to near-normal proportions. Leptin treatment also facilitated myelopoiesis such that the marrow of the obese mice contained normal numbers of monocytes and granulocytes after 7 days [12]. Leptin signalling maintains B- cell homeostasis by inhibiting apoptosis and by inducing cell cycle entry through the activation of expressions of Bcl-2 and cyclin D1- [13]. Modulation of the immune system by leptin is exerted at the development, proliferation,antiapoptotic,

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Role of Leptin in the Activation of the Immune System

73

maturation, and activation levels [14]. In fact, leptin receptors have been found in neutrophils, monocytes, and lymphocytes, and the leptin receptor belongs to the family of class I cytokine receptors. Moreover, leptin activates similar signalling pathways to those engaged by other members of the family [15]. The overall leptin action in the immune system is a proinflammatory effect, activating proinflammatory cells, promoting T-helper 1 responses, and mediating the production of the other proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-2, or IL-6. Leptin receptor is also upregulated by proinflammatory signals. In this chapter, we will summarize data from literature that demonstrate the positive regulation of the immune response by leptin (Figure 1) [15].

2. LEPTIN ACTIVATION OF INNATE IMMUNITY

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

The primary amino acid sequence of leptin indicated that it could belong to the longchain helical cytokine family [16], such as IL-2, IL-12, and GH. In fact, leptin receptor (ObR) shows sequence homology to members of class I cytokine receptor (gp130) superfamily [17] that includes the receptor for IL-6, leucocyte inhibitory factor (LIF), and granulocyte colony-stimulating factor (G-CSF). Moreover, Ob-R has been shown to have the signaling capabilities of IL-6-type cytokine receptors [17], activating JAK-STAT, PI3K, and MAPK signaling pathways [15]. In this context, a role for leptin in the regulation of innate immunity has been proposed [15, 18]. Consistent with this role of leptin in the mechanisms of immune response and host defense, circulating leptin levels are increased upon infectious and inflammatory stimuli such as LPS, turpentine, and cytokines [19, 20]. On the other hand, unlike other members of the IL-6 family, it is not clear that leptin may induce the expression of acute phase proteins, and contradictory data have been provided [20, 21]. The role of leptin regulating innate immunity has been previously reviewed [6].

2.1. Leptin Activation of Monocytes/Macrophages Studies of rodents with genetic abnormalities in leptin or leptin receptors revealed obesity-related deficits in macrophage phagocytosis and the expression of proinflammatory cytokines both in vivo and in vitro, whereas exogenous leptin upregulated both phagocytosis and the production of cytokines [22]. Besides, phenotypic abnormalities in macrophages from leptin-deficient, obese mice have been found [23]. More importantly, leptin deficiency increases susceptibility to infectious and inflammatory stimuli and is associated with dysregulation of cytokine production [20]. More specifically, murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system. In this context, leptin levels increase acutely during infection and inflammation, and may represent a protective component of the host response to inflammation [24]. Human leptin was found to stimulate proliferation and activation of human circulating monocytes in vitro, promoting the expression of activation markers: CD69, CD25, CD38, and CD71, in addition to increasing the expression of monocytes surface markers, such as HLA-DR, CD11b, and CD11c [25]. Besides, leptin potentiates the stimulatory effect of LPS or PMA on the proliferation and activation of human monocytes. Moreover, leptin dose-dependently stimulates the production

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

74

Patricia Fernández-Riejos, Souad Najib, José Santos-Alvarez et al.

of proinflammatory cytokines by monocytes, that is, TNF-α and IL-6 [26] and enhances CCchemokine ligand expression in cultured murine macrophage, through activation of a JAK2STAT3 pathway [26]. The presence of both isoforms of the leptin receptor was also assessed. Later, it was found that leptin directly induces the secretion of interleukin 1 receptor antagonist in human monocytes [27] and upregulates IP-10 (interferon-gamma-inducible protein) in monocytic cells [28]. Moreover, in human monocytes it has been shown that leptin increased both statin-inhibitable free radical and cholesterol productions in vitro [29]. In addition, it accelerates cholesteryl ester accumulation in human monocyte-derived macrophages by increasing ACAT-1 expression via JAK2 and PI3K, thereby suppressing cholesterol efflux [30]. In alveolar macrophages leptin augments leukotriene synthesis [31]. A possible role of leptin as a trophic factor to prevent apoptosis has also been found in serum-depleted human monocytes [32], which is further supporting the role of leptin as a growth factor for the monocyte. Moreover, leptin regulates monocyte function as assessed by in vitro experiments measuring free radical production. Thus, leptin was shown to stimulate the oxidative burst in control monocytes [33], and binding of leptin at the macrophage cell surface increases lipoprotein lipase expression through oxidative stress- and PKC-dependent pathways. In this line, leptin has been found to increase oxidative stress in macrophages [34]. Finally, leptin could act as a monocyte/macrophage chemoattractant inducing in vitro maximal chemotactic responses at 1 ng/mL [35], mediating the inflammatory infiltrate [36], and inducing tissue factor expression in human peripheral blood mononuclear cells [37]. On the other hand, human leptin seems to downregulate oxidative burst in previously activated monocytes [33]. Dendritic cells belong more to the same cell lineage than to monocytes/macrophages and also present leptin receptors (OBRb) on the cell surface [38]. Thus, leptin has also been found to increase the production of IL-8, IL-12, IL-6, and TNF-α, whereas it decreases MIP-1-α production by dendritic cells. Similar to leptin effect on monocytes,it may increase the survival of dendritic cells, and it may also increase the expression of surface molecules, such as CD1a, CD80, CD83, or CD86. Leptin induces functional and morphological changes in human dendritic cells (DCs), directing them towards Th1 priming and promoting DC survival via the PI3K-Akt signaling pathway [39]. The involvement of leptin signaling in DCs survival and maturation has been observed in leptin receptor- (Ob-R-) deficient db/db mice. Db/db mice displayed markedly reduced expression of costimulatory molecules and a Th2-type cytokine profile, with poor capacity to stimulate allogenic T cell proliferation. Consistent with their impaired DCs phenotype and function, db/db DCs showed significantly downregulated activities of the PI3K/Akt pathway as well as STAT-3 and IkappaB-alpha. Moreover, the reduced DCs yielded in db/db bone marrow culture was attributed to significantly increased apoptosis, which was associated with dysregulated expression of Bcl-2 family genes [40]. The expression of leptin and leptin receptors has been demonstrated on mast cells, suggesting paracrine and/or autocrine immunomodulatory effects of leptin on mast cells [41].

2.2. Leptin Activation of Neutrophils Human polymorphonuclear neutrophils (PMN) have been found to express leptin receptor in vitro and in vivo [42, 43]. However, Zarkesh-Esfahani et al. [44] demonstrated that neutrophils only express the short form of the leptin receptor, which is enough to signal

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Role of Leptin in the Activation of the Immune System

75

inside the cell, enhancing the expressionof CD11b and preventing apoptosis [43, 44]. Leptin delayed the cleavage of Bid and Bax, the mitochondrial release of cytochrome c and second mitochondria-derived activator of caspase, as well as the activation of both caspase-8 and caspase-3 in these cells [43]. Therefore, leptin seems to behave as a survival cytokine for PMN, similar to G-CSF. Leptin promotes neutrophils chemotaxis [20, 45]. In fact, the chemoattractant effect is comparable to that of well-known formyl-methionyl-leucylphenylalanine (FMLP). Otherwise, when leptin acts as a uremic toxin it interferes with neutrophil chemotaxis [46] and inhibits neutrophil migration in response to classical neutrophilic chemoattractants and leptin is endowed with chemotactic activity toward neutrophils. The two activities, inhibition of the cell response to chemokines and stimulation of neutrophil migration, could be detected at similar concentrations. On the contrary, neutrophils exposed to leptin did not display detectable [Ca2+]imobilization, oxidant production, or beta2-integrin upregulation [47]. Moreover, leptin also has a stimulating effect on intracellular hydrogen peroxide production in PMN although this effect seems to be mediated by the activation of monocytes [43]. More specifically, leptin modulates neutrophil phagocytosis of Klebsiella pneumoniae [48] and in diabetic patients‘ neutrophils, an increase in leptin serum levels has been correlated with the degree of CD11b expression [49]. On eosinophils, leptin could upregulate cell surface expression of adhesion molecules ICAM-1 and CD18 but suppress ICAM-3 and L-selectin.Moreover, leptin could also stimulate the chemokinesis of eosinophils and induce the release of inflammatory cytokines IL-1beta and IL-6 and chemokines IL-8, growth-related oncogene-alpha, and MCP-1 [50].

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

2.3. Natural Killer (NK) Cells HumanNK cells constitutively express both long and short forms of Ob receptor.Moreover, the leptin receptors can signal in NK cells, since leptin activates STAT3 phosphorylation in NK cells. Moreover, leptin increases IL-2 and perforin gene expression at the transcription levels in NK cells. Consistent with this role of leptin regulating NK cells, db/db mice have been found to have impaired NK cell function [51, 52]. Leptin actions in NK cells include cell maturation, differentiation, activation, and cytotoxicity [21]. Leptin enhances both the development and the activation of NK cells [51], increasing IL-12 and reducing the expression of IL-15 [52]. Besides, leptin mediates the activation of NK cells indirectly by modulation of IL-1β, IL-6, and TNF-α by monocytes and macrophages [37].

3. LEPTINMODULATION OF ADAPTIVE IMMUNE RESPONSE The role of leptin in cell-mediated immunity has been obtained working with ob/ob mice [19]. These mice have a decreased sensitivity of T cells to activating stimuli. Besides, these animals show atrophy of lymphoid organs [5–7], with a decrease in the number of circulating T cells and an increase in the number of monocytes. Besides, ob/ob mice have a decrease in the number of TNKCD4+ in the liver [53]. The ability of leptin preventing thymic atrophia is due to a direct antiapoptotic effect on T cells [7]. Thus, leptin treatment increases thymic expression of interleukin-7, an important soluble thymocyte growth factor produced by

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

76

Patricia Fernández-Riejos, Souad Najib, José Santos-Alvarez et al.

medullary thymic epithelial cells (TECs). The hormone leptin has an intrathymic role in maintaining healthy thymic epithelium and promoting thymopoiesis, which is revealed when thymus homeostasis is perturbed by endotoxemia. In this case, leptin treatment decreases in vivo apoptosis of double positive thymocytes and promotes proliferation of double negative thymocytes [54]. In the thymus, Fyn acts as a tyrosine kinase that transduces the leptin signal independently of JAK2 activation and mediates some of the immunomodulatory effects of leptin in this tissue. The tyrosine kinase, Fyn, is constitutively associated with the Ob-R in thymic cells. Following a leptin stimulus, Fyn undergoes an activating tyrosine phosphorylation and a transient association with IRS1 [55]. Acute deficiency of leptin has a potent effect on the immune system, which is even higher than that observed in ob/ob mice (genetic defect). Acute hypoleptinemic mice show a higher decrease in the total number of thymocytes, and double number of apoptotic cells than ob/ob mice. Moreover, the acute deficiency of leptin also causes a decrease in splenic cellularity, which does not occur in ob/ob mice, even though they have a smaller spleen than control mice [8]. Both ob/ob and db/db mice show defects in cell-mediated immune response which lead to impaired reaction of delayed hypersensibility, suppression of skin allograft rejection, and inhibition of footpad swelling by recall antigens [6, 56–58]. In recent studies, leptin enhanced in vivo lymphocyte proliferation in Siberian hamsters (Phodopus sungorus) and increased splenocyte proliferation in mice [59] as well as it increased percentage of T cells, particularly CD4+ Th cells, in peritoneal fluid of patients with endometriosis [60]. Lord et al. 1998 [5], demonstrated that mouse lymphocytes express the long form of leptin receptor, and that leptin modulates in these cells cytokine production. Besides, leptin also regulates the number and activation of T lymphocytes. The proliferative response to leptin in mice seems to be produced in naive T cells (CD4+CD45RA+), whereas it has been shown that leptin inhibits proliferation of memory T cells (CD4+CD45RO+) [5]. Leptin provides a survival signal in double positive T cells (CD4+CD8+) and simple positive CD4+CD8− thymocytes during thymic maturation [7]. Furthermore, leptin treatment with or without IL-2 and PHA has preferential effects on cell proliferation of CD4 T cells compared to that of CD8 T cells. ObR expression is markedly higher in peripheral CD4 T cells than that in CD8 T cells. These data provide evidence that the effects of leptin on differentiation and proliferation of CD4 T cells might be closely related to the expression of leptin receptor [61]. In addition, leptin promotes the expression of adhesion molecules in CD4+ T cells, such as VLA-2 (CD49b) or ICAM-1 (CD54) [5, 19]. More recently, we have reviewed the role of human leptin on T cell response [15]. Human leptin alone is not able to activate human peripheral blood lymphocytes in vitro [24] even though leptin receptor is present and activated in T lymphocytes upon leptin stimulation, fully triggering the intracellular signal transduction, as we have also assessed [62, 63]. However, when T lymphocytes are costimulated with PHA or concanavalin A (Con A), leptin dose-dependently enhances the proliferation and activation of cultured T lymphocytes, achieving maximal effect at 10 nM concentration [64]. Thus, leptin increases the expression of early activation markers such as CD69, as well as the expression of late activation markers, such as CD25, or CD71 in both CD4+ and CD8+ T lymphocytes in the presence of suboptimal concentrations of activators such as PHA (2 μg/mL) and after stimulation with PMA-ionomycin [65]. However, when maximal concentrations of PHA or Con A are employed, leptin has no further effect. These effects of leptin on T lymphocytes are observed even in the absence of monocytes, suggesting

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Role of Leptin in the Activation of the Immune System

77

a direct effect of human leptin on circulating T lymphocytes when they are costimulated [64]. The activation of T cells induces the expression of the long isoform of the Ob receptor [65]. The need for costimulation with mitogens to get the effect of leptin in lymphocytes may be partly explained by this effect of activation, increasing leptin receptor expression in T lymphocytes. Besides, these data suggest that the leptin receptor may be regulated in a similar way to other cytokine receptors, such as the IL-2 receptor (CD25). Human leptin not only modulates the activation and proliferation of human T lymphocytes but also enhances cytokine production induced by submaximal concentrations of PHA [64]. Thus, human leptin enhances the production of IL-2 and IFN-γ in stimulated T lymphocytes. It had been previously shown in mice that leptin can enhance cognate T cell response, skewing cytokine responses towards a Th1 phenotype in mice [5]. These data are in agreement with the observation of the leptin effect on anti-CD3 stimulation of T cells, which increases the production of the proinflammatory cytokine IFN-γ [66]. The effect of leptin polarizing T cells towards a Th1 response seems to be mediated by stimulating the synthesis of IL-2, IL-12, and IFN-gamma and the inhibition of the production of IL-10 and IL-4 [37, 64]. Th1 polarization has been correlated with hyperleptinemia in hemodialysis patients [67] and the protection of ob/ob mice in Th1- as well as in Th2-dependent inflammation is provided by a decreased expression of the key transcription factors for Th1 and Th2 polarization, T-bet and GATA-3 in naive ob/ob T cells. In this case, leptin was found to be necessary in T-helper 1- (Th1-) dependent inflammatory processes acting as a critical regulator of CD4+ T cell polarization in vitro and in vivo [68]. These data regarding leptin modulation of Th1-type cytokine production are in line with the observed effects of leptin stimulating TNF-α and IL-6 production by monocytes [25], further suggesting the possible role of human leptin in the regulation of the immune system inducing a proinflammatory response. On peripheral blood mononuclear cells of patients with ankylosing spondylitis, leptin exerts proinflammatory effect [69] as well as it enhances the proinflammatory cytokines in normal colonocytes and in HT29 xenografted tumor colonocytes. Colonocyte-derived products after leptin treatment stimulated perforin and granzyme B expressions in normal CD8 (+) T cells in vitro [70]. In addition, leptin alone or in combination with IL-1 enhanced the expression of iNOS and COX-2 and production of NO, PGE (2), IL-6, and IL-8. The effects of leptin are mediated through activation of transcription factor nuclear factor-kappaB (NF-kappaB) and mitogenactivated protein kinase (MAPK) pathway c-Jun NH (2)-terminal kinase (JNK).The increased synthesis of proinflammatory mediators is mediated by nitric oxide (NO) in human osteoarthritic cartilage [71]. On the other hand, leptin promotes T cell survival and Jurkat T lymphocytes survival [72] by modulating the expression of antiapoptotic proteins, such as Bcl-xL in stressinduced apoptosis [73]. This trophic effect of leptin on T cell is consistent with the reduction in lymphocyte numbers observed in fasted mice, that might be explained by the acute decrease in leptin levels [7, 20].The role of leptin modulating T cell function in humans has been finally defined by clinical studies in specific and rare cases of patients with monogenic obesity. In human obesity due to congenital leptin deficiency, there is a T cell hyporesponsiveness (in addition to the expected neuroendocrine/metabolic dysfunction), and not only leptin treatment in these patients is an effective lowering body weight but it can also revert T cell response to mitogen activation in vitro [74]. The few identified leptin-deficient children have immune deficiency. The leptin replacement therapy enhanced T-cell responsiveness in these children [75]. In addition, leptin has been necessary in nonagenarians (≥90 years old) to maintain functional naive CD8 T cells and a healthy immune system [76].

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

78

Patricia Fernández-Riejos, Souad Najib, José Santos-Alvarez et al.

The leptin receptor is highly expressed on the cell surface of Tregs. Leptin can act as a negative signal for the proliferation of human Foxp3 (+) CD4 (+) CD25 (+) regulatory T (T(reg)) cells. In vitro, neutralization with leptin monoclonal antibody (mAb), during antiCD3 and anti-CD28 stimulation, resulted in T(reg) cell proliferation, which was interleukin-2 (IL-2) dependent. Together with the finding of enhanced proliferation of T (reg) cells observed in leptin- and ObR-deficient mice, these results suggest a potential for therapeutic interventions in immune and autoimmune diseases [77].

Leptin in Autoimmunity The role of leptin in regulating immune response has been assessed in vitro as well as in clinical studies. It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility by reducing Th cell priming and affecting thymic function [5, 7].On the other hand, leptin can promote autoreactivity. The Th1-promoting effects of leptin have been linked to an enhanced susceptibility to develop and to progress autoimmune responses. A number of studies have implicated a role of leptin in the pathogenesis of several autoimmune diseases, including type 1 diabetes (T1D), inflammatory bowel disease, and possibly rheumatoid arthritis [78]. This aspect is also of interest in relation to the well-known gender bias in susceptibility to autoimmunity. Autoimmune diseases are frequently more prevalent in females, and females are relatively hyperleptinemic. The modulation of circulating leptin levels has a pivotal role on some inflammatory and autoimmune conditions

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Leptin in Multiple Sclerosis (MS) It has been shown that leptin is involved in the induction and in the progression of EAE (experimental autoimmune encephalomyelitis), an animal model of MS [79, 80]. Leptin deficient mice are resistant to induction of active and adoptively transferred EAE. This protection is reversed by leptin administration and associates with a switch from Th2- to Th1type responses and an IgG1-to-IgG2a isotype switch. Similarly, in susceptible wild-type C57BL/6J mice, leptin worsens disease by increasing IFN-γ release and IgG2a production [79]. Normal wild-type mice show increased secretion of leptin in serum upon EAE induction, and brain inflammatory infiltrates stain positive for leptin. Leptin neutralization with leptin antagonists improves the EAE course by profoundly altering intracellular signalling of myelin-reactive T cells and increasing the number of regulatory forkhead/winged helix transcription factor 3+CD4+ T cells [81]. Importantly, a surge of serum leptin anticipates the onset of clinical manifestations of EAE. The peak of serum leptin correlates with inflammatory anorexia, weight loss, and the development of pathogenic T cell responses against myelin. Lymphomononuclear infiltrates in the CNS of EAE mice indicate in situ production of leptin in active, inflammatory lesions, thus representing a significant local source of leptin [80].In humans, the fact that increased leptin secretion occurs in acute phases of MS and correlates with CSF production of IFN-γ is of possible interest for the pathogenesis and clinical follow-up of patients with MS. Increased leptin secretion is present

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Role of Leptin in the Activation of the Immune System

79

in the serum and in the CSF of patients with MS and does not correlate with body mass index (BMI) [82]. The increase of leptin in the CSF is higher than in the serum, suggesting possible secondary in situ synthesis of leptin in the CNS and/or an increased transport across the blood-brain-barrier following enhanced systemic production. Recent reports have shown increased secretion of serum leptin before relapses in patients with MS during treatment with IFN-γ and a capacity of leptin to enhance in vitro secretion of TNF-α, IL-6, and IL-10 from PBMCs of patients with MS in acute phase of the disease but not in patients with stable disease Moreover, ObR was up-regulated on T cells of MS patients during relapse and was associated with increased phosphorilated-STAT3 levels [83]. The expression of leptin receptor (ObR) was higher in CD8+ T cells and monocytes from relapsing-remitting multiple sclerosis patients (RRMS) in relapse than in patients in remission and in controls. Relapsing patients showed high levels of pSTAT3 and low expression of SOCS3 and leptin administration induced an up-regulation of pSTAT3 only in monocytes from patients in relapse [84]. The serum leptin levels remain higher in RRMS patients during remission than in controls [85]. In view of all of these considerations, we suggest that leptin could be one of the many proinflammatory factors that act in concert to promote the pathogenic (autoreactive) Th1 responses targeting neuroantigens in MS. Even, it could affect on pro- and antiinflammatory cytokine production by PBMCs collected from MS patients, may be this connected with leptin increase the susceptiveness of MS [86]. In summary, there is an association of leptin with disease activity in patients with MS [87].

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Leptin in Rheumatoid Arthritis Ag-induced arthritis is an animal model of rheumatoid arthritis. It can be induced following the administration of methylated BSA into the knees of leptin-deficient mice (ob/ob), +/? and wild-type mice (+/+).Ob/ob mice develope less severe arthritis compared with control mice. The levels of IL-1beta and TNF-alpha mRNA in the synovium of arthritic knees are lower in ob/ob than in +/? mice. In vitro Ag-specific T cell proliferative responses are significantly decreased in ob/ob mice with lower IFN-gamma and higher IL-10 production, suggesting a shift toward a Th2-type response in ob/ob and db/db mice. The serum levels of anti-methylated BSA Abs of any isotype are significantly decreased in arthritic ob/ob mice compared with controls. Moreover, B lymphocytes express leptin receptor mRNA thus leptin would contribute to the mechanisms of joint inflammation in Aginduced arthritis by regulating both humoral and cell-mediated immune responses [88] In addition, in synovial fibroblast, leptin increases IL-8 production via the OBRl/JAK2/STAT3 pathway, as well as the activation of IRS1/PI3K/Akt/NF-kappaB-dependent pathway and the subsequent recruitment of p300 [89]. It is reported that fasting leads to an improvement of clinical and biological measures of disease activity, which is associated with a marked decrease in serum leptin in rheumatoid arthritis (RA) patients. These features suggest that leptin may also influence the inflammatory mechanisms of arthritis in humans, even there is a strong correlation between serum leptin level and other markers as bone mass density changes [90]. So, serum leptin levels are higher in RA patients with high disease activity, correlate well with disease activity, and decrease significantly when disease is well controlled [91]. Moreover, the leptin concentrations are significantly higher in patients with active erosive RA [92]. Although a significant inverse correlation between inflammation and leptin

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

80

Patricia Fernández-Riejos, Souad Najib, José Santos-Alvarez et al.

concentrations exists in patients with active RA, plasma leptin concentrations did not significantly differ from those in healthy controls. This suggests that active chronic inflammation may lower plasma leptin concentrations. In the other hand two weeks' treatment with anti-TNF did not change plasma leptin concentrations [93] and in longer therapy, the beneficial effect of on cardiovascular mortality in RA does not seem to be mediated by reduction in serum levels of leptin [94]. In summary, regulation of leptinemia is complex and it is necessary additional studies to clarify if leptin is a real actor or a simple mediator in the inflammatory process of RA.

BIBLIOGRAPHY S. E. Wozniak, L. L. Gee, M. S. Wachtel, and E. E. Frezza, ―Adipose tissue: the new endocrine organ? A review article,‖ Digestive Diseases and Sciences, vol. 54, no. 9, pp. 1847–1856, 2009. [2] Y. Zhang, R. Proenca,M.Maffei, M. Barone, L. Leopold, and J. M. Friedman, ―Positional cloning of themouse obese gene and its human homologue,‖ Nature, vol. 372, no. 6505, pp. 425– 432, 1994. [3] J. S. Flier, ―The adipocyte: storage depot or node on the energy information superhighway?‖ Cell, vol. 80, no. 1, pp. 15–18, 1995. [4] R. S. Ahima, D. Prabakaran, C. Mantzoros, et al., ―Role of leptin in the neuroendocrine response to fasting,‖ Nature, vol. 382, no. 6588, pp. 250–252, 1996. [5] G.M. Lord, G.Matarese, J. K.Howard, R. J. Baker, S. R. Bloom, and R. I. Lechler, ―Leptin modulates the T-cell immune response and reverses starvation- induced immunosuppression,‖ Nature, vol. 394, no. 6696, pp. 897–901, 1998. [6] G. Fantuzzi and R. Faggioni, ―Leptin in the regulation of immunity, inflammation, and hematopoiesis,‖ Journal of Leukocyte Biology, vol. 68, no. 4, pp. 437–446, 2000. [7] J. K. Howard, G. M. Lord, G. Matarese, et al., ―Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice,‖ The Journal of Clinical Investigation, vol. 104, no. 8, pp. 1051–1059, 1999. [8] J. M. Montez, A. Soukas, E. Asilmaz, G. Fayzikhodjaeva, G. Fantuzzi, and J. M. Friedman, ―Acute leptin deficiency, leptin resistance, and the physiologic response to leptin withdrawal,‖ Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 7, pp. 2537–2542, 2005. [9] A. Palacio, M. Lopez, F. Perez-Bravo, F. Monkeberg, and L. Schlesinger, ―Leptin levels are associated with immune response in malnourished infants,‖ Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 7, pp. 3040–3046, 2002. [10] N. Busso, A. So, V. Chobaz-P´eclat, et al., ―Leptin signalling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis,‖ Journal of Immunology, vol. 168, no. 2, pp. 875–882, 2002.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

[1]

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Role of Leptin in the Activation of the Immune System

81

[11] B.D. Bennett, G. P. Solar, J.Q. Yuan, J. Mathias,G.R.Thomas, and W.Matthews, ―A role for leptin and its cognate receptor in hematopoiesis,‖ Current Biology, vol. 6, no. 9, pp. 1170–1180, 1996. [12] K. Claycombe, L. E. King, and P. J. Fraker, ―A role for leptin in sustaining lymphopoiesis andmyelopoiesis,‖ Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 6, pp. 2017–2021, 2008. [13] Q.L. Lam, S. Wang, O. K. Ko, P.W. Kincade, and L. Lu, ―Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1,‖ Proceedings of the National Academy of Sciences of the United States of America, 2010 Jul 19. [Epub ahead of print] [14] A. Stofkova, ―Leptin and adiponectin: from energy and metabolic dysbalance to inflammation and autoimmunity,‖ Endocrine Regulations, vol. 43, no. 4, pp. 157– 168, 2009. [15] V. Sánchez-Margalet, C.Martín-Romero, J. Santos-Alvarez, R. Goberna, S. Najib, and C. Gonzalez-Yanes, ―Role of leptin as an immunomodulator of blood mononuclear cells: mechanisms of action,‖ Clinical and Experimental Immunology, vol. 133, no. 1, pp. 11–19, 2003. [16] T. Madej, M. S. Boguski, and S. H. Bryant, ―Threading analysis suggests that the obese gene product may be a helical cytokine,‖ FEBS Letters, vol. 373, no. 1, pp. 13–18, 1995. [17] L. A. Tartaglia, M. Dembski, X. Weng, et al., ―Identification and expression cloning of a leptin receptor, OB-R,‖ Cell, vol. 83, no. 7, pp. 1263–1271, 1995. [18] G. M. Lord, G.Matarese, J. K. Howard, and R. I. Lechler, ―The bioenergetics of the immune system,‖ Science, vol. 292, no. 5518, pp. 855–856, 2001. [19] G. Matarese, ―Leptin and the immune system: how nutritional status influences the immune response,‖ European Cytokine Network, vol. 11, no. 1, pp. 7–13, 2000. [20] R. Faggioni, K. R. Feingold, and C. Grunfeld, ―Leptin regulation of the immune response and the immunodeficiency of malnutrition,‖ FASEB Journal, vol. 15, no. 14, pp. 2565–2571, 2001. [21] G. Matarese, S. Moschos, and C. S. Mantzoros, ―Leptin in immunology,‖ Journal of Immunology, vol. 174, no. 6, pp. 3137–3142, 2005. [22] S. Loffreda, S. Q. Yang, H. Z. Lin, et al., ―Leptin regulates proinflammatory immune responses,‖ FASEB Journal, vol. 12, no. 1, pp. 57–65, 1998. [23] F.-Y. J. Lee, Y. Li, E. K. Yang, et al., ―Phenotypic abnormalities in macrophages from leptin-deficient, obese mice,‖ American Journal of Physiology, vol. 276, no. 2, pp. C386–C394, 1999. [24] P. Sarraf, R. C. Frederich, E. M. Turner, et al., ―Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia,‖ Journal of Experimental Medicine, vol. 185, no. 1, pp. 171–175, 1997. [25] J. Santos-Alvarez, R. Goberna, and V. Sánchez-Margalet, ―Human leptin stimulates proliferation and activation of human circulating monocytes,‖ Cellular Immunology, vol. 194, no. 1, pp. 6–11, 1999. [26] N. Kiguchi, T. Maeda, Y. Kobayashi, Y. Fukazawa, and S. Kishioka, ―Leptin enhances CC-chemokine ligand expression in cultured murine macrophage,‖

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

82

[27]

[28]

[29]

[30]

[31]

[32]

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

[33]

[34]

[35]

[36]

[37]

[38]

Patricia Fernández-Riejos, Souad Najib, José Santos-Alvarez et al.

Biochemical and Biophysical Research Communications, vol. 384, no. 3, pp. 311– 315, 2009. C. Gabay, M. G. Dreyer, N. Pellegrinelli, R. Chicheportiche, and C. A. Meier, ―Leptin directly induces the secretion of interleukin 1 receptor antagonist in human monocytes,‖ Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 2, pp. 783–791, 2001. C. A. Meier, R. Chicheportiche, M. Dreyer, and J. M. Dayer, ―IP-10, but not RANTES, is upregulated by leptin in monocytic cells,‖ Cytokine, vol. 21, no. 1, pp. 43–47, 2003. Z. Balogh, G. F´oris, B. Koszt´aczky, et al., ―The concentration dependent biphasic effect of leptin on endogenous cholesterol synthesis in human monocytes,‖ Peptides, vol. 28, no. 10, pp. 2081–2083, 2007. S. Hongo, T. Watanabe, S. Arita, et al., ―Leptin modulates ACAT1 expression and cholesterol efflux from human macrophages,‖ American Journal of Physiology, vol. 297, no. 2, pp. E474–E482, 2009. P. Mancuso, C. Canetti, A. Gottschalk, P. K. Tithof, and M. Peters-Golden, ―Leptin augments alveolar macrophage leukotriene synthesis by increasing phospholipase activity and enhancing group IVC iPLA2 (cPLA2γ) protein expression,‖ American Journal of Physiology, vol. 287, no. 3, pp. L497–L502, 2004. S. Najib and V. Sánchez-Margalet, ―Human leptin promotes survival of human circulating blood monocytes prone to apoptosis by activation of p42/44 MAPK pathway,‖ Cellular Immunology, vol. 220, no. 2, pp. 143–149, 2002. C. Sánchez-Pozo, J. Rodriguez-Baño, A. Domínguez-Castellano, M. A. Muniain, R. Goberna, and V. Sánchez-Margalet, ―Leptin stimulates the oxidative burst in control monocytes but attenuates the oxidative burst in monocytes from HIVinfected patients,‖ Clinical and Experimental Immunology, vol. 134, no. 3, pp. 464– 469, 2003. F. Maingrette and G. Renier, ―Leptin increases lipoprotein lipase secretion by macrophages: involvement of oxidative stress and protein kinase C,‖ Diabetes, vol. 52, no. 8, pp. 2121–2128, 2003. M. L. Gruen, M. Hao, D. W. Piston, and A. H. Hasty, ―Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis,‖ American Journal of Physiology, vol. 293, no. 5, pp. C1481–C1488, 2007. C. A. Curat, A. Miranville, C. Sengen`es, et al., ―From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes,‖ Diabetes, vol. 53, no. 5, pp. 1285–1292, 2004. E. Napoleone, A. Di Santo, C. Amore, et al., ―Leptin induces tissue factor expression in human peripheral blood mononuclear cells: a possible link between obesity and cardiovascular risk?‖ Journal of Thrombosis and Haemostasis, vol. 5, no. 7, pp.1462–1468, 2007. B. Mattioli, E. Straface, M. G. Quaranta, L. Giordani, and M. Viora, ―Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming,‖ Journal of Immunology, vol. 174, no. 11, pp. 6820–6828, 2005.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Role of Leptin in the Activation of the Immune System

83

[39] B. Mattioli, L. Giordani, M. G. Quaranta, and M. Viora, ―Leptin exerts an antiapoptotic effect on human dendritic cells via the PI3K-Akt signaling pathway,‖ FEBS Letters, vol. 583, no. 7, pp. 1102–1106, 2009. [40] Q. L. K. Lam, S. Liu, X. Cao, and L. Lu, ―Involvement of leptin signaling in the survival and maturation of bone marrow derived dendritic cells,‖ European Journal of Immunology, vol. 36, no. 12, pp. 3118–3130, 2006. [41] J. Taildeman, C. A. P´erez-Novo, I. Rottiers, et al., ―Human mast cells express leptin and leptin receptors,‖ Histochemistry and Cell Biology, vol. 131, no. 6, pp. 703–711, 2009. [42] F. Caldefie-Chezet, A. Poulin, A. Tridon, B. Sion, and M.-P. Vasson, ―Leptin: a potential regulator of polymorphonuclear neutrophil bactericidal action?‖ Journal of Leukocyte Biology, vol. 69, no. 3, pp. 414–418, 2001. [43] A. Bruno, S. Conus, I. Schmid, and H.-U. Simon, ―Apoptotic pathways are inhibited by leptin receptor activation in neutrophils,‖ Journal of Immunology, vol. 174, no. 12, pp. 8090– 8096, 2005. [44] H. Zarkesh-Esfahani, A. G. Pockley, Z. Wu, P. G. Hellewell, A. P. Weetman, and R. J. M. Ross, ―Leptin indirectly activates human neutrophils via induction of TNFα,‖ Journal of Immunology, vol. 172, no. 3, pp. 1809–1814, 2004. [45] F. Caldefie-Chezet, A. Poulin, andM.-P. Vasson, ―Leptin regulates functional capacities of polymorphonuclear neutrophils,‖ Free Radical Research, vol. 37, no. 8, pp. 809–814, 2003. [46] L. Ottonello, P. Gnerre, M. Bertolotto, et al., ―Leptin as a uremic toxin interferes with neutrophil chemotaxis,‖ Journal of the American Society of Nephrology, vol. 15, no. 9, pp. 2366– 2372, 2004. [47] F. Montecucco, G. Bianchi, P. Gnerre, M. Bertolotto, F. Dallegri, and L. Ottonello, ―Induction of neutrophil chemotaxis by leptin: crucial role for p38 and Src kinases,‖ Annals of the New York Academy of Sciences, vol. 1069, pp. 463–471, 2006. [48] S. I. Moore, G. B. Huffnagle, G.-H. Chen, E. S. White, and P. Mancuso, ―Leptin modulates neutrophil phagocytosis of Klebsiella pneumoniae,‖ Infection and Immunity, vol. 71, no.7, pp. 4182–4185, 2003. [49] K. Mastej and R. Adamiec, ―Neutrophil surface expression of adhesion molecule CD11b in patients with type 2 diabetes,‖ Przegla¸d Lekarski, vol. 66, no. 5, pp. 228–232, 2009. [50] C. K. Wong, P. F.-Y. Cheung, and C. W.-K. Lam, ―Leptin mediated cytokine release and migration of eosinophils: implications for immunopathophysiology of allergic inflammation,‖ European Journal of Immunology, vol. 37, no. 8, pp. 2337– 2348, 2007. [51] Z. Tian, R. Sun, H. Wei, and B. Gao, ―Impaired natural killer(NK) cell activity in leptin receptor deficient mice: leptin as a critical regulator in NK cell development and activation,‖ Biochemical and Biophysical Research Communications, vol. 298, no. 3, pp. 297–302, 2002. [52] Y. Zhao, R. Sun, L. You, C. Gao, and Z. Tian, ―Expression of leptin receptors and response to leptin stimulation of human natural killer cell lines,‖ Biochemical and Biophysical Research Communications, vol. 300, no. 2, pp. 247–252, 2003.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

84

Patricia Fernández-Riejos, Souad Najib, José Santos-Alvarez et al.

[53] A. La Cava and G. Matarese, ―The weight of leptin in immunity,‖ Nature Reviews Immunology, vol. 4, no. 5, pp. 371–379, 2004. [54] A. L. Gruver, M. S. Ventevogel, and G. D. Sempowski, ―Leptin receptor is expressed in thymus medulla and leptin protects against thymic remodeling during endotoxemia induced thymus involution,‖ The Journal of Endocrinology, vol. 203, no. 1, pp. 75–85, 2009. [55] A. Girasol, G. G. Albuquerque, E. Mansour, et al., ―Fyn mediates leptin actions in the thymus of rodents,‖ PLoS One, vol. 4, no. 11, article e7707, 2009. [56] Z. Li, H. Lin, S. Yang, and A. M. Diehl, ―Murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system,‖ Gastroenterology, vol. 123, no. 4, pp. 1304–1310, 2002. [57] M. Guebre-Xabier, S. Yang, H. Z. Lin, R. Schwenk, U. Krzych, and A. M. Diehl, ―Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potentialmechanism for sensitization to liver damage,‖ Hepatology, vol. 31, no. 3, pp. 633–640, 2000. [58] M. A. Mandel and A. A. F. Mahmoud, ―Impairment of cell-mediated immunity in mutation diabetic mice (db/db),‖ Journal of Immunology, vol. 120, no. 4, pp. 1375– 1377, 1978. [59] G. E. Demas, ―In vivo but not in vitro leptin enhances lymphocyte proliferation in Siberian hamsters (Phodopus sungorus),‖ General and Comparative Endocrinology, vol. 166, no. 2, pp. 314–319, 2010. [60] Ł.Milewski, E. Barcz, P. Dziunycz, et al., ―Association of leptin with inflammatory cytokines and lymphocyte subpopulations in peritoneal fluid of patients with endometriosis,‖ Journal of Reproductive Immunology, vol. 79, no. 1, pp. 111–117, 2008. [61] S. Y. Kim , J. H. Lim, S. W. Choi , M. Kim , S. T. Kim , M. S. Kim , Y. S. Cho, E. Chun, and K. Y. Lee. Preferential effects of leptin on CD4 T cells in central and peripheral immune system are critically linked to the expression of leptin receptor. Biochem. Biophys. Res. Commun. 2010 Apr 9; 394(3):562-8. [62] V. Sanchez-Margalet and C. Martin-Romero, ―Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway,‖ Cellular Immunology, vol. 211, no. 1, pp. 30–36, 2001. [63] C. Martín-Romero and V. Sánchez-Margalet, ―Human leptin activates PI3K and MAPK pathways in human peripheral blood mononuclear cells: possible role of Sam68,‖ Cellular Immunology, vol. 212, no. 2, pp. 83–91, 2001. [64] C. Martín-Romero, J. Santos-Alvarez, R. Goberna, and V. Sánchez-Margalet, ―Human leptin enhances activation and proliferation of human circulating T lymphocytes,‖ Cellular Immunology, vol. 199, no. 1, pp. 15–24, 2000. [65] V. Sánchez-Margalet, C. Martín-Romero, C. González-Yanes, R. Goberna, J. Rodríguez-Baño, and M. A. Muniain, ―Leptin receptor (Ob-R) expression is induced in peripheral blood mononuclear cells by in vitro activation and in vivo in HIV infected patients,‖ Clinical and Experimental Immunology, vol. 129, no. 1, pp. 119–124, 2002.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Role of Leptin in the Activation of the Immune System

85

[66] G. M. Lord, G. Matarese, J. K. Howard, S. R. Bloom, and R. I. Lechler, ―Leptin inhibits the anti-CD3-driven proliferation of peripheral blood T cells but enhances the production of proinflammatory cytokines,‖ Journal of Leukocyte Biology, vol. 72, no. 2, pp. 330–338, 2002. [67] M.-L. Liu, Z.-Y. Huang, X.-C. Zhong, et al., ―Th1 polarization and low-T3 syndrome are correlated with hyperleptinemia in hemodialysis patients,‖ Journal of Nephrology, vol. 22, no. 4, pp. 515–522, 2009. [68] A. Batra, B. Okur, R. Glauben, et al., ―Leptin: a critical regulator of CD4+ T-cell polarization in vitro and in vivo,‖ Endocrinology, vol. 151, no. 1, pp. 56–62, 2010. [69] M.-C. Park, S.-J. Chung, Y.-B. Park, and S.K. Lee, ―Proinflammatory effect of leptin on peripheral blood mononuclear cells of patients with ankylosing spondylitis,‖ Joint BoneSpine, vol. 76, no. 2, pp. 170–175, 2009. [70] M. Abolhassani, N. Aloulou, M. T. Chaumette, et al., ―Leptin receptor-related immune response in colorectal tumors: the role of colonocytes and interleukin-8,‖ Cancer Research, vol. 68, no. 22, pp. 9423–9432, 2008. [71] E. Moilanen, K. Vuolteenaho, A. Koskinen, et al., ―Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage—mediator role of NO in leptininduced PGE 2, IL-6, and IL-8 production,‖ Mediators of Inflammation, vol. 2009, Article ID 345838, 10 pages, 2009. [72] P. Fernández-Riejos, R. Goberna, and V. Sánchez-Margalet, ―Leptin promotes cell survival and activates Jurkat T lymphocytes by stimulation of mitogen-activated protein kinase,‖ Clinical and Experimental Immunology, vol. 151, no. 3, pp. 505– 518, 2008. [73] Y. Fujita, M. Murakami, Y. Ogawa, et al., ―Leptin inhibits stress-induced apoptosis of T lymphocytes,‖ Clinical and Experimental Immunology, vol. 128, no. 1, pp. 21– 26, 2002. [74] I. S. Farooqi, G. Matarese, G. M. Lord, et al., ―Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency,‖ The Journal of Clinical Investigation, vol. 110, no. 8, pp. 1093–1103, 2002. [75] G. J. Paz-Filho, T. Delibasi, H. K. Erol, M.L. Wong, and J. Licinio, ―Cellular immunity before and after leptin replacement therapy, ‖J. Pediatr Endocrinol. Metab. 2009 Nov;22(11):1069-74. [76] J. Chen, J. Li, F. C. Lim, et al., ―Maintenance of na¨ıve CD8 T cells in nonagenarians by leptin, IGFBP3 and T3,‖ Mechanisms of Ageing and Development, vol. 131, no. 1, pp. 29–37, 2010. [77] G. Matarese, V. De Rosa, and A. La Cava, ―Regulatory CD4 T cells: sensing the environment,‖ Trends in Immunology, vol. 29, no. 1, pp. 12–17, 2008. [78] M. Ozata, I. C. Ozdemir, and J. Licinio, ―Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin mediated defects,‖ Journal of Clinical Endocrinology and Metabolism, vol 84, pp. 3686–3695, 1999.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

86

Patricia Fernández-Riejos, Souad Najib, José Santos-Alvarez et al.

[79] G. Matarese, A. Di Giacomo,V. Sanna, G. M. Lord, J. K. Howard, A. DiTuoro, S. R. Bloom, R. I. Lechler, S. Zappacosta, and S. Fontana, ―Requirement for leptin in the induction and progression of autoimmune encephalomyelitis,‖ The Journal of Immunology, vol 166, pp. 5909–5916, 2001. [80] V. Sanna, A. Di Giacomo, A. La Cava, R. I. Lechler,S. Fontana, S. Zappacosta, and G. Matarese, ‖Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses,‖ Journal of Clinical Investigation, vol 111, pp. 241–250, 2003. [81] G. Matarese, C. Procaccini, and V. De Rosa, ―The intricate interface between immune and metabolic regulation: a role for leptin in the pathogenesis of multiple sclerosis?‖Journal of Leukocyte Biology vol 84, pp. 893-899, 2008. [82] G. Matarese, P. B. Carrieri, A. La Cava, F. Perna, V. De Rosa, D. Aufiero, S. Fontana, S. Zappacosta, ‖Leptin increase in multiple sclerosis associates with reduced number of CD4+CD25+ regulatory T cells‖ Procceedings of National Academy of Sciences USA, vol 102, pp. 5150–515, 2005. [83] A. P. Batocchi, M. Rotondi, M. Caggiula, G. Frisullo, F. Odoardi, V. Nociti,C. Carella, P. A. Tonali, and M. Mirabella, ―Leptin as a marker of multiple sclerosis activity in patients treated with interferon-BETA,―Journal of Neuroimmunology, vol. 139, pp. 150–154, 2003. [84] G. Frisullo, F. Angelucci, M. Mirabella , M. Caggiula, K. Patanella , V. Nociti , P. A. Tonali, A. P. Batocchi, ―Leptin enhances the release of cytokines Journal of Clinical Immunology, vol 24 nº3, pp. 287-93, 2004 [85] G. Frisullo, M. Mirabella, F. Angelluci, M. Caggiula, R. Morosetti, C. Sancricca, A. K. Patanella, V. Nociti, R. Iorio, A. Bianco, V. Tomassini, C. Pozzilli, P. A. Tonali, G. Matarese, A. P. Batocchi, and ―The effect of disease activity on leptin, leptin receptor and suppressor of cytokine signalling-3 expression in relapsing-remitting multiple sclerosis―, Journal of Neuroimmunology, vol. 192 nº1-2, 174-83, 2007 [86] Z. L. Chen, D. M. Wang, J. F. Duan, S. Q. Wen, Y. F. Tang, and Z. X. Li.―Leptin enhances the release of cytokines by peripheral blood mononuclear cells from acute multiple sclerosis patients,‖ Neurosciences Bulletin, vol. 22 nº 2, pp.115-7, 2006 [87] G. Matarese, P. B. Carrieri, S. Montella, V. De Rosa and A. La Cava, ―Leptin as a metabolic link to multiple sclerosis― Nature Reviews Neurology, 2010 Jul 6. [Epub ahead of print] [88] N. Busso, A. So, V. Chobaz-Péclat, C. Morard, E. Martinez-Soria, D. Talabot-Ayer and C. Gabay, ―Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis‖, Journal of Immunology, vol. 168, nº 2, pp. 875-82, 2002. [89] K. M. Tong, D. C. Shieh, C. P. Chen, C. Y. Tzeng, S. P. Wang, K. C. Huang, Y. C. Chiu, Y. C. Fong, and C. H. Tang, Leptin induces IL-8 expression via leptin receptor, IRS-1, PI3K, Akt cascade and promotion of NF-kappaB/p300 binding in human synovial fibroblasts. Cellular Signaling vo. 20 nº8, pp. 1478-88, 2008. [90] M. Wisłowska, M. Rok, B. Jaszczyk, K. Stepień, and M. Cicha, ―Serum leptin in rheumatoid artritis,‖ Rheumatology International, vol. 27 nº10, pp. 947-54, 2007.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Role of Leptin in the Activation of the Immune System

87

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

[91] S. W. Lee, M. C. Park, Y. B. Park, and S. K. Lee, ―Measurement of the serum leptin level could assist disease activity monitoring in rheumatoid arthritis. Rheumatology Internacional, vol. 27 nº 6, pp. 537-40, 2007. [92] B. Targońska-Stepniak, M. Majdan, and M. Dryglewska, ―Leptin serum levels in rheumatoid arthritis patients: relation to disease duration and activity,‖ Rheumatology International, vol. 28, nº 6, pp. 585-91, 2008. [93] C. Popa, M. G. Netea, T. R. Radstake, P. L. van Riel, P. Barrera, and J. W. van der Meer, ―Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis‖, Annals Rheumatology Disease, vol. 64 nº 8, pp. 1195-8, 2005. [94] M. A. González-Gay, M. T. Garcia-Unzueta, A. Berja, C. Gonzalez-Juanatey, J. A. Miranda-Filloy, T. R. Vazquez-Rodriguez, J. M. de Matias, J. Martín, P. H. Dessein, and J. Llorca, ―Anti-TNF-alpha therapy does not modulate leptin in patients with severe rheumatoid arthritis,‖ Clinical and Experimental Rheumatology vol. 27 nº 2, pp. 222-8, 2009.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

In: Leptin: Hormonal Functions, Dysfunctions and Clinical Uses ISBN: 978-1-61122-891-5 Editors: Rose M. Hemling and Arthur T. Belkin ©2011 Nova Science Publishers, Inc.

Chapter 5

ROLE OF LEPTIN IN THE MAMMARY GLAND DEVELOPMENT, LACTATION AND IN NEONATAL PHYSIOLOGY Mario Baratta University of Turin, Italy

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ABSTRACT The biology of leptin has been studied most extensively in the central nervous system for the regulation of food intake and energy balance. In recent years, a growing number of publications have reported several activities of this adipose-secreted protein in different organs. These effects appear to be independent of the regulation of food intake or at least not directly correlated to it, but rather related to the hormonal regulation of these particular tissues. Thus leptin is now also considered to be a hormonal factor that informs several hormonal circuits and biological peripheral functions of the nutrition status of the organism. Evidences are reported the role of leptin to regulate mammogenesis during a virgin, pregnancy and involution. In mammary gland, leptin has been observed to exert also an autocrine and/or paracrine activity which affects the development of duct, formation of gland alveolus, expression of milk protein gene and onset involution of mammary gland. Findings with experimental rodent models reveal that exposures to leptin during the in utero and pubertal periods when the mammary gland is undergoing extensive modeling and re-modeling, may alter susceptibility to develop mammary tumors. Leptin synthesis has been found also in the placenta both in human and in livestock animals suggesting a role in controlling growth of the foetus and neonate. Furthermore, colostrum and milk contain high amounts of leptin, in particular during the first few days of lactation, that cause a correlation between milk leptin and plasma leptin, body weight and body mass index. Furthermore, other studies suggest that milk leptin may control appetite. Lastly, since nutrition or neonatal stress can program the immune system, leptin change that occurs in mothers and neonates can imprint hormonal or metabolic changes that influence later life degenerative and chronic diseases. Address: Dept. of Veterinary Morphophysiology, University of Turin, Via Leonardo da Vinci 44, 10095, Grugliasco, (TO), Italy. Tel. + 39-0116709146, Fax. +39-0112369146. Email: [email protected].

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

90

Mario Baratta

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

INTRODUCTION Leptin, discovered in 1994 [1], is considered one of the main peripheral signals that affect food intake and body weight. It was shown that the concentration of leptin in the blood varied with the amount of adipose tissue in the body and the treatment with this protein decreases appetite and reduces the massive obesity of leptin deficient (ob/ob) mice [2]. Leptin is a protein made up of 167 amonoacids with a signal-sequence in the aminoterminal end constituted by 21 aminoacids that is cleavaged during translocation into the microsomes. The length of the molecule in plasma is, therefore, 146 aminoacids. The Ob gene that encodes leptin has been localized in humans on the 7 31.3 cromosome and is formed by three exons and two introns. Transcription and translation occur mainly in adipose tissue [3;4]. The structure is a complex constituted by four helices similar to that of cytochines. This sequence has been reported to be highly preserved in all mammalian species with an homology of over 80%. Leptin production and secretion by adipocytes is under complex regulation: insulin, glucocorticoids and cytokines, including TNF and interleukin-1, that stimulate secretion, while sympathetic nervous activity via catecholamines, testosterone and PPAR- agonists inhibit leptin secretion [4;5]. Thyroid hormones decrease leptin secretion in rodents, but their effects in humans, if any, are controversial [6]. Estrogens may also increase leptin production, although some have found no effect [4]. GH appears to decrease leptin production in human adipocytes, but increases it in rat adipocytes [4]. The leptin receptor exists in at least 6 isoforms, one of which (Ob Rb), the so-called ‗long form‘, is thought to be the most important for transmitting the leptin signal in cells located in the hypothalamus but receptors are found in a variety of tissues [7]. In physiological conditions the amount of leptin produced by fat tissue is directly correlated both to the adipose tissue mass and to the mRNA expressed in the tissue. It has been further shown that leptin production is two-fold higher in the female than in male and that it is affected by growth and energy consumption. Leptin is secreted in humans in a circadian and pulsatile pattern (maximal secretion from midnight to 7 AM with a pulse frequency of 32 pulses/24 hours, each lasting 33 min). The half-life in blood is approximately 25 min and is not modified by body condition (normal or obese). Within the hypothalamus, leptin decreases expression of the orexegenic peptides, neuropeptide Y and Agouti-related peptide, and increases expression of the anorexigenic peptides, POMC and CART, resulting in a decrease in appetite [8;9]. In recent years, a growing number of publications have reported several activities of this adipose-secreted protein in different organs [10]. Many tissues besides the adipose tissue have been shown to be able to produce leptin and its receptors. Evidences are reported the role of leptin to regulate mammogenesis during a virgin, pregnancy and involution. It has also been shown as leptin and leptin receptor are overexpressed in human breast tumor tissue compared with non-cancerous breast epithelium [11]. Additionally, the expression of leptin was positively correlated with expression of the leptin receptor, suggesting that leptin acts on mammary tumor cells via autocrine pathway. Another interesting study has described as in primary breast tumors, the expression of leptin and leptin receptor was found in 85 and 75% of primary tumors with a good correlation among leptin, its receptor expression and tumor size [12].

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Role of Leptin in the Mammary Gland Development...

91

Other studies have focused the interest on the role of leptin secreted in the milk on the development of the newborn, on the control of appetite and feeding behaviour. A great interest has arisen in particular on the possibile correlation between leptin levels in breast milk and the occurrence of degenerative syndrome such as obesity in later stages of growth. This review aims to focus the role of leptin in the specific phase of reproduction regulation that involves foetus growth, mammary gland, neonate physiology and its effect in some related-dysfunctions such as the onset of breast cancer and chilhood obesity.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

MAMMARY GLAND STRUCTURE AND FUNCTION The mammary gland undergoes extensive cyclic remodelling throughout the whole reproductive life of the animal. In the classical experimental model, the mouse, the gland remains quiescent until the third week of age: at this stage club-shaped structures called terminal end buds (TEBs) form at the end of the ducts, facing the fat-pad [13]. Side branches (also termed secondary branches) are formed too: they generates from the primary branches and fill the spaces between them. When the TEBs reach the boundaries of the fat pad (around the eighth week of age), the cells stop to divide and the club-shaped structures disappear. TEBs proliferation is subject to fine regulations by positive and negative stimuli [14]: endocrine hormones play an important role though mediated by the stroma. As a matter of fact GH and estrogen (mainly) do not act on ductal cells, but rather induce stromal cells to produce paracrine signals like IGF-1 which will promote mitosis in TEBs. An important negative regulator is TGF-β1 which inhibits matrix-degrading proteases which are secreted by cap cells in TEBs to allow the penetration in the fat pad. Moreover TGF-β1 produced by stromal cells could indirectly inhibit ductal elongation by reducing HGF levels, a cytokine whose receptor (c-Met) is expressed in epithelial cells and which is very important in tubulogenesis [15]. During the whole life of the animal, the mammary gland undergoes moderate remodelling during every oestral cycle due to the change in the hormonal status. However is only at pregnancy that the mammary gland is subject to a massive remodelling [15]: initially (from day two to six post-coitum) progesterone and prolactin stimulate the proliferation of epithelial cells in order to increase the secreting surface area and lobular structures appear throughout the ductal tree. The following stage is differentiation of the lobuloalveoli: epithelial luminal cells become polarized in order to prepare themselves to synthesize milk proteins. An important signal transducer of prolactin stimulation is STAT5 [16]: after translocation in the nucleus this molecule can activate transcription of multiple genes involved in the establishment of epithelial polarity, cell-cell interactions, stromalepithelial interactions and milk protein expression during lactation. When lactation is over, the mammary gland undergoes another massive remodelling: the countless lobuloalveolar structures are no longer needed until the next pregnancy and so they must be eliminated. The main responsible for the first (reversible) phase of involution is apoptosis [16,17]: soon after weaning cells from the alveolar structures starts to detach and to shed into the lumen. Several members of the Bcl-2 genes family are involved in the process, but a primary role must be surely ascribed to Leukaemia inhibiting factor (LIF) whose expression is induced by milk stasis. This factor, along with TGF-β3, activates STAT3, which is a signal transducer that is fundamental for the initiation of the apoptotic process.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

92

Mario Baratta

This first reversible phase lasts for 48 hours: the following stage comprises an extensive modification of the mammary gland morphology [17], since the alveoli start to collapse and adipocytes begin to refill. Activation of matrix metalloproteases results in removal of extracellular matrix and activation of plasminogen which leads to a second wave of apoptosis. Also phagocytosis plays an important role at this point: the removal of the large number of cells and debris is carried out by professional and non-professional phagocytes. After six days from weaning most of the secretory epithelium has been removed and the mammary gland is carried back to a pre-pregnant state.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

LEPTIN AND THE MAMMARY GLAND Recent studies have shown that leptin plays a critical role in the regulation of the development of ducts [18], formation of gland alveolus, gene expression of milk protein [19] and the onset involution of mammary gland [20]. Importantly, OB-Rb is the only leptin receptor isoform that contains intracellular tyrosine residues [7]. Ligand binding to the OBRb results in activation of JAK2 by transphosphorylation and the subsequent tyrosine phosphorylation of tyrosine residues on the intracellular OB-Rb [21] then stimulates the activation of STAT proteins [22]. Several studies report the expression of leptin and leptin receptor during different phases of mammary gland development and propose its role during processes such as mammogenesis, lactogenesis, galactopoiesis and involution. However, these studies only reported the quantification of leptin mRNA level by real-time quantitative RT [23-26]. Recently, an interesting study in goat has reported a strong synthesis of leptin by mammary adipocytes at the virgin stage and at the beginning of pregnancy [27], further the gland alveolar epithelial cell itself could secrete leptin in late pregnancy and first lactation, whereas during lactation, when the mammary gland was full of functioning gland alveolus, leptin protein amount remained lower because of the effect of prolactin which has an inhibitory effect [23]. In involution, the mammary fat pad is regenerated and leptin protein amount recovered to the virgin level. Thus, the expression of leptin and OB-Rb has positively correlated during the whole development cycle of the mammary gland. These sequential changes of leptin and OB-Rb cellular location indicate that leptin induce OB-Rb expression, and leptin together with OB-Rb acts as a paracrine and autocrine factor to regulate mammary gland growth, development and function. Ligand binding to OB-Rb results in the activation of JAK2 by transphosphorylation and the subsequent tyrosine phosphorylation of tyrosine residues on the intracellular OB-Rb, which then initiates the transmission of downstream phosphotyrosine-dependent signals [28]. Two tyrosine residues in the intracellular domain of OB-Rb become phosphorylated to mediate OB-Rb signalling; Tyr985 controls the tyrosine phosphorylation of SHP-2, and Tyr1138 controls STAT3 activation. Leptin, like other cytokines, is effective in influencing the growth of various cell types [29-31] and, in mammary gland, it has been demonstrated that at physiological concentration induced the proliferation of ductal epithelial cells by activated the ERK Ser/Thr kinases transmission [32]. In vitro and in vivo studies report that leptin affects milk protein expression and that leptin-deficient mice induced to become pregnant delivered normally, but failed to lactate [20;33] supporting the hypothesis that leptin plays an important role in regulating milk

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Role of Leptin in the Mammary Gland Development...

93

production at least during the last phase of pregancy and first lactation. In lactation, leptin stimulated phosphorylation of STAT5, which regulate milk protein synthesis, since a STAT5binding site is found in the promoter of β-casein [34]. This factor has been also proposed to exert a role also during involution because in conditional knock-out mice lacking the STAT3 gene in epithelial cells, the involution process was strongly delayed [35], in this case leptin shows to increase that apoptosis process by stimulating JAK-STAT3 pathway as it has been previously reported in vitro [36].

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

LEPTIN RELEVANCE IN BREAST CANCER PREVENTION Findings with experimental rodent models reveal that exposures to dietary factors during the in utero and pubertal periods when the mammary gland is undergoing extensive modeling and re-modeling, alter susceptibility to develop mammary tumors. Similar observations have been made in humans: childhood exposure to genistein in soy or to some other bioactive food components reduces later breast cancer risk, although they may have no effect if consumed during adulthood. Thus, food components may be more effective in affecting cancer risk in some periods of life than others. Many of these dietary exposures modify fetal and postnatal hormonal environment, including changing the concentrations of estrogens and leptin. The hormonal alterations then may induce persistent epigenetic changes by affecting gene promoter regions or by inducing histone modifications that affect chromatin transcription. The targets of epigenetic changes are likely to be TEBs, the structures where carcinogeninduced mammary tumors in rats and mice are initiated. Similar structures in women, called terminal ductal lobular units, are the sites where most human breast cancers rise. Cancer is initiated only when the epigenetically altered cells are exposed to carcinogens during adult life but cancer initiating exposures do not necessarily cause cancer, because the cells can either repair the damage or undergo apoptosis. Thus, the most likely molecular targets of early life dietary exposures are genes that regulate DNA adduct formation, repair DNA damage or induce apoptosis, such as genes affecting cellular metabolism, tumor suppressor genes or genes promoting cell survival. Adult intake of some bioactive dietary components reduces cancer risk increased by early life dietary exposures or inhibits tumor growth by reversing epigenetic changes in various molecular targets. Human studies indicate that high birth weight is associated with increased risk of developing premenopausal breast cancer [37;38]. This could be due to elevated levels of estrogens during pregnancy, but may also be related to increased maternal and/or cord blood concentrations of insulin/insulin like growth factor 1 (IGF-1) and leptin [39;40]. All of these factors have been linked to high birth weight. It was recently reported that rat pups‘ birth weight can be increased by feeding pregnant dams an obesity-inducing diet and the high birth weight was associated with higher susceptibility to develop 7,12-dimethylbenz[a]anthracene – induced mammary tumors [41;42]. At least in rat, leptin, but not estrogens levels were significantly elevated in pregnant dams fed the birth weight increasing obesity-inducing diet [41]. Maternal dietary exposures of leptin and estrogens during pregnancy that modify offspring‘s later breast cancer risk appear to alter expression of genes that provide protection against breast cancer development by affecting tumor suppressor functions, but also genes

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

94

Mario Baratta

that regulate metabolic processes and possibly inflammation [43]. Persistent epigenetic changes are not limited to exposures that take place during the fetal period; these changes can be induced by exposures that occur during the postnatal period, although it is not known at which point the epigenome looses its ability to acquire lifelong modifications. Neonatal exposure to leptin normalizes the programmed effects of fetal undernutrition on end-points that included weight gain and plasma levels of glucose and insulin; however, it is not known whether this is a result of leptin affecting epigenetic regulation of gene expression [44;45]. High birth weight rats, which develop mammary tumors earlier than the control rats, exhibit significantly reduced mammary estrogen receptor (ER)–α expression [41]. Maternal exposure to leptin also reduces mammary ER-α content, indicating that elevated fetal leptin levels may have caused down-regulation of ER-α. High birth weight is also associated with increased activation of Mitogen-Activated Protein Kinase (MAPK) in an adult mammary gland [41]. Increased expression of growth factors, such as transforming growth factor (TGF)-α and EGF, leads to overactivation of MAPK. Microarray analysis data indicate that high birth weight and fetal leptin exposure are both associated with increased expression of TGF-α mRNA [43]. High birth weight also is associated with reduced expression of TGF-βinducible early response gene (TIEG), a unique regulator of TGF-β signal transduction pathway. Another interesting correlation has been found between high levels of vascular endotelial growth factor (VEGF) and leptin because they are strongly linked to worse prognosis of breast cancer. Leptin signalling upregulates VEGF in human and mouse mammary tumor cells [46]. Leptin signalling regulates VEGF mainly through HIF-1α and NFκB. The impressive impact of leptin signalling inhibition on tumor growth, angiogenesis and reactive stroma emphasize the idea that leptin is an important regulator of the tumor microenvironment and angiogenesis [46;47]. Leptin signalling and its crosstalk could lead to the promotion of angiogenesis, growth and survival of breast cancer cells that could be further sustained by increased adiposity and the associated higher levels of leptin. Very recently leptin has been also proposed to activate telomerase and transcription of Human Telomerase Reverse Transcriptase (hTERT) by enhancing the binding of STAT3 to the hTERT promoter in breast cancer cells [48]. Telomerase is a ribonucleoprotein complex composed of the catalytic subunit hTERT and RNA subunit human telomerase RNA. Overactivity of telomerase occurs in about 90% cancer cells whereas normal cells exhibit undetectable level of activity. Activation of telomerase is required for cancer cells to maintain their malignant phenotype and therefore provides a potential target for the treatment of cancer. Specifically in breast cancer cells, increased telomerase activity has been demonstrated to be associated with tumor size, lymph node status and decreased free-survival rate [49]. Therefore, the significance of leptin on telomerase induction in cancer cell lines should be involved in the promotion of malignant phenotype and blocking leptin signaling may be valuable for the treatment of breast cancer with elevated leptin levels. Thus, leptin has been characterized as a growth factor for breast cancer. Treatment with leptin activity by pegylated leptin peptide receptor antagonist 2 demonstrated a therapeutic effect on breast cancer xenografts [50] suggesting that leptin signaling may be a potential target for the treatment of breast cancer.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Role of Leptin in the Mammary Gland Development...

95

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

THE RELATIONSHIP BETWEEN LEPTIN AND OFFSPRING GROWTH Leptin has been found in the placenta [51;52], where it passes through to the fetus during its transition to the neonate [53], so both maternal and fetal concentrations of leptin are increased during pregnancy. Leptin is detectable in cord blood from the second trimester of intrauterine life and correlates with adiposity at birth [54]. Interestingly, serum leptin concentration correlates with body mass index in infants (BMI) [55]. These observations lead to assume a relationship between leptin and the physiology of fetus. In fact, in obese subjects, endogenous leptin, even at high circulating levels, fails to exert its normal effects, and administration of exogenous leptin does not significantly reduce adiposity. This condition, known as ―leptin resistance‖, appears to be due to reduced transport of leptin into the brain and reduced expression of leptin receptor in the arcuate nucleus or an increased concentration of supressor of cytokine signalling -3 (SOCS3), which suppresses leptin signaling by inhibiting leptin-induced STAT activation [56]. Studies conducted in mice have shown that by acting on the brain during a critical neonatal period that coincides with a naturally occurring leptin surge, leptin promotes the formation of neural circuits that control food intake and adiposity later in life [57]. In humans, cord blood leptin concentration has been observed to be inversely related to rates of intrauterine growth, suggesting the role of leptin in promoting fetus growth: smallfor-gestational age neonates have lower leptin levels at birth than appropriate-for-gestational age infants, and large-for-gestational age neonates have higher leptin levels than other infants [58]. Cord blood leptin seems to be a predictor of weight gain also in later life; in fact lower cord blood leptin levels have been observed to be associated with smaller size at birth but more pronounced weight gain in the first 6 months of life and higher BMI at 3 years of age [59]. Leptin is also produced by the mammary gland, and has been found in the colostrum and milk of several species, including humans [60], pigs [61], sheep [62], goats [63], cattle [64] and horses [65]. Thus, even if the source of milk leptin may be directly transferred from the mother‘s circulation there are evidences of a local production and secretion from the mammary epithelium; however, the relative contribution of both sources is not completely clear. It apperas that the breast milk is a continued source of leptin for the infants after delivery and the newborns who are breastfed will continue to receive a significant measurable amount of leptin from their mother. Leptin concentration in breast milk changes also during lactation [66;67] showing a differential pattern of function and, finally, leptin concentration in breast milk varies widely among people [60;68;69]. It has been reported that there is a positive correlation between leptin concentration in milk and maternal plasma leptin levels and adiposity [69]. Thus, the amount of leptin supplied to infants through breast milk depends on the mother‘s adiposity. Lean mothers with very low plasma leptin concentrations produce milk with little or no significant leptin, similar in this sense to infant formula, which does not have leptin as an ingredient [70]. Conversely, only breast-fed infants nursed by mothers with relatively significant adiposity are exposed to significant amounts of leptin in milk. Studies in preterm infants showed lower levels of serum leptin than in term infants [71]. It was speculated that a critical adipose storage level has to be attained before increased amounts of leptin are adequately produced. Given that circulating leptin can be influenced by metabolic

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

96

Mario Baratta

hormones, such as corticosteroids and insulin, lower leptin levels in preterm infants may also reflect an immaturity of the ‗adipoinsular‘ axis [72]. The function of leptin in neonatal physiology is discussed with controversial hypothesis. It is accepted that relatively increased concentrations of milk leptin occur at parturition, which coincides with the time when neonates are best able to absorb large proteins through the gastrointestinal tract, but different researchers are not convinced that the neonate can absorb leptin ingested orally. However, leptin receptors have been identified in gastric epithelial cells and the absorptive cells of mouse and human small intestine [73], suggesting that leptin can pass from milk to infant blood. For example elevated blood serum leptin was found in neonatal suckled compared with delay suckled piglets [74] as previously reported in mice [75]. Further blood leptin was greater in rat pups fed milk plus leptin vs. milk alone [68], in neonatal pigs suckled vs. being fed milk replacer [76], in neonatal calves fed colostrum vs. milk replacer [77], and in breast-fed compared with formula-fed human infants [78]. In addition, one study reported that leptin is absorbed through the neonatal stomach in rat pups [79] and leptin concentrations in neonatal foals increased significantly after nursing [80]. Experimental studies show that exogenous leptin is still biologically active even after its absorption [81;82]. It was found that breastfed infants eat less but more frequently when compared with formulafed ones [83]. Furthermore, breastfed infants are leaner than formulafed ones because of the decrease of energy intake [84]. Recently, the role of milk leptin in the neonatal period has been proposed in humans for the relationship between obesity and early life programming [85] that confirmed a small protective effect of breast-feeding against later obesity, and suggested that early ingestion of leptin in milk by the neonate might influence later growth and development.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

MILK LEPTIN AND OBESITY Some studies have shown a clear association between overnutrition during infancy and later obesity [86]. In this sense, a vigorous breastfeeding style, with a high energy intake, has been associated with greater adiposity later on [87]. Considering nutrition during lactation, there is increasing epidemiological evidence suggesting that breastfeeding compared with infant formula confers protection against obesity later in life [88-90]. A meta-analysis of the existing studies on duration of breastfeeding and risk of becoming overweight [90] strongly supports a dose-dependent association between a longer duration of breastfeeding and a decrease in the risk of becoming overweight. A number of hypotheses can be raised as to the potential causes for the protective effect of breastfeeding, including differences in suckling patterns and in milk composition [91]. Bioactive components in milk could potentially have physiological effects in the neonate that could be apparent in the short- and medium-term as well as later in life and in ageing. Human milk composition can be affected by the mother‘s diet, various diseases and other environmental factors, and has a dynamic nature, with changes during lactation that are assumed to match the changing needs of the growing infant over time [92]. Currently, a key challenge is to determine the relationship between milk components and health/disease outcomes later in life, including the identification of the involved bioactive components and their mechanisms of action. Determining the optimum range of levels of these compounds in

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Role of Leptin in the Mammary Gland Development...

97

artificial infant formula, or how they could be optimized in breast milk by encouraging appropriate diets and/or lifestyle conditions for mothers, are of great importance. The role of leptin to regulate food intake in early childhood has been supported by several observations. Firstly, the administration of physiological oral doses of leptin during the suckling period is capable of inhibiting food intake, without affecting body weight gain during this period [79] and that exogenous leptin supplied by maternal milk regulate shortterm feeding in neonates and exert other biological effects, at a time in which both the adipose tissue and appetite regulatory systems are immature [79]. Secondly, neonate rats that were orally treated with physiological amounts of leptin during the suckling period were more resistant to the age-related increase of body weight in adulthood [93], and also more resistant to dietary obesity induced by high-fat diet feeding [94]. Thus, considering the evidence for the beneficial effects of breast milk compared with formula feeding in the prevention against obesity in later life, leptin has been now considered the bioactive component, or at least one of them, responsible for the beneficial role of breastfeeding compared with formula feeding [95]. Modulation of food preferences may also provide a mechanism through which obesity may be programmed [96]. When these rats were fed a chow or a high-fat diet from weaning, those that received physiological doses of oral leptin during the suckling period had a lower body weight and less adiposity in adulthood; they also had greater insulin sensitivity and showed a lower preference for fat-rich food than their controls [93]. In humans, the failure to control obesity is generally associated with increased appetite and preference for high energy dense food, in addition to other factors such as reduced physical activity and increased lipogenic metabolism [97]. Thus, changes in food preferences in favour of less energy dense foods is of interest to prevent obesity, particularly when energy-dense foods are widely available in developed societies. Other studies have also shown that changes during the perinatal period may influence long-term appetite and food preferences. In particular, exposure to a maternal low-protein diet during fetal life has been described to enhance fat preferences [98]. Consequently, breast milk leptin could play a role in the short-term control of food intake in neonates by acting as a satiety signal and could also exert a long-term effect on energy balance and body weight regulation.

THE ROLE OF EARLY LIFE LEPTIN IN LATER LIFE DEGENERATIVE AND CHRONIC DISEASES The thrifty phenotype hypothesis proposes that the epidemiological associations between poor fetal and infant growth and the subsequent development of type 2 diabetes and the metabolic syndrome result from the effects of poor nutrition in early life, which produces permanent changes in glucose-insulin metabolism [99]. This hypothesis emphasizes the importance of early life environment in programming the susceptibility to chronic diseases in later life. The programming is an epigenetic phenomena, which means that the fetal genome may suffer alterations to induce adaptative responses during stressful states occurring during the critical period of development. It has been generally accepted that the response to fetal malnutrition entrains not only (presumably advantageous) selective preservation of key organs but also metabolic

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

98

Mario Baratta

adaptations of advantage for postnatal survival. Thus, the thrifty phenotype is not only thrifty with respect to antenatal life, but also in relation to the use of poor nutritional resources postnatally. The poorly nourished mother essentially gives the fetus a forecast of the nutritional environment into which it will be born. Processes are set in motion which lead to a postnatal metabolism adapted to survival under conditions of poor nutrition. The adaptations only become detrimental when the postnatal environment differs from the mother's forecast, with an over abundance of nutrients and consequent obesity. Similar observations have been made in relation to cold exposure. Offspring of sheep exposed to cold during pregnancy are, on delivery, better adapted to respond to cold conditions after birth. Both children with low weight at birth and those with high birth weight, as well as neonates suffering from IUGR (a reflection of the consequences of different nutritional or hormonal imbalances and of other pathological events these children encountered during the intrauterine life), have an increased risk of developing obesity, diabetes mellitus and hypertension later in life [100-102]. Leptin levels are also altered in these children, which points to the role of this hormone in regulating intrauterine growth and development and defining the risk for pathology in later life [103]. Furthermore, breast feeding and leptin level in brest milk seem to be essential for adaptation during postnatal life. It is not clear, however, how formula milk may influence the balance of leptin and what health consequences of the changes are induced by artificial feeding. Leptin signals to the CNS indicates the status of energy resources in terms of availability and promotes specific adaptative reactions, such as setting up a low metabolic waste regimen and influences the overall physiological intrauterine and early life growth and development [100;104-106]. Later life degenerative outcomes seem to result from the action of environmental factors (e.g., altered nutrition in early life) and the subsequent metabolic and hormonal events they trigger, and leptin is an important mediator of these reactions. Birth weight is strongly related to leptin levels, whereas maternal diseases and fetal pathology have also been associated with short-term changes in leptin levels. The nutrition of the mother during pregnancy, along with the diet of the infant afterwards, also influences leptin levels. It is reasonable to infer that leptin plays a role in linking early life events and conditions with long-term consequences.

REFERENCES [1]

[2] [3] [4] [5] [6] [7]

Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese gene and its human homologue. Nature 1-121994;372:425-432. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P: OB protein: A peripheral signal linking adiposity and central neural networks. Appetite 1996;26:302. Ahima RS, Saper CB, Flier JS, Elmquist JK: Leptin regulation of neuroendocrine systems. Front Neuroendocrinol. 2000;21:263-307. Friedman JM, Halaas JL: Leptin and the regulation of body weight in mammals. Nature 22-10-1998;395:763-770. Harris RB: Leptin--much more than a satiety signal. Annu Rev Nutr 2000;20:45-75. Ahima RS, Flier JS: Leptin. Annu. Rev. Physiol. 2000;62:413-437. Tartaglia LA: The leptin receptor. J. Biol. Chem. 7-3-1997;272:6093-6096.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Role of Leptin in the Mammary Gland Development... [8] [9] [10] [11]

[12]

[13] [14] [15]

[16] [17]

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

[18]

[19]

[20] [21] [22]

[23]

[24]

[25]

99

Spiegelman BM, Flier JS: Obesity and the regulation of energy balance. Cell 23-22001;104:531-543. Williams G, Harrold JA, Cutler DJ: The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box. Proc. Nutr. Soc. 2000;59:385-396. Baratta M: Leptin--from a signal of adiposity to a hormonal mediator in peripheral tissues. Med. Sci. Monit. 2002;8:RA282-RA292. Ishikawa M, Kitayama J, Nagawa H: Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin. Cancer Res. 1-7-2004;10:43254331. Jarde T, Caldefie-Chezet F, Damez M, Mishellany F, Penault-Llorca F, Guillot J, Vasson MP: Leptin and leptin receptor involvement in cancer development: a study on human primary breast carcinoma. Oncol. Rep. 2008;19:905-911. Hinck L, Silberstein GB: Key stages in mammary gland development: the mammary end bud as a motile organ. Breast Cancer Res. 2005;7:245-251. Silberstein GB: Tumour-stromal interactions. Role of the stroma in mammary development. Breast Cancer Res. 2001;3:218-223. Oakes SR, Hilton HN, Ormandy CJ: The alveolar switch: coordinating the proliferative cues and cell fate decisions that drive the formation of lobuloalveoli from ductal epithelium. Breast Cancer Res. 2006;8:207. Hennighausen L, Robinson GW: Information networks in the mammary gland. Nat. Rev. Mol. Cell Biol. 2005;6:715-725. Watson CJ: Involution: apoptosis and tissue remodelling that convert the mammary gland from milk factory to a quiescent organ. Breast Cancer Res. 2006;8:203. Hu X, Juneja SC, Maihle NJ, Cleary MP: Leptin--a growth factor in normal and malignant breast cells and for normal mammary gland development. J. Natl. Cancer Inst. 20-11-2002;94:1704-1711. Feuermann Y, Mabjeesh SJ, Shamay A: Leptin affects prolactin action on milk protein and fat synthesis in the bovine mammary gland. J. Dairy Sci. 2004;87:29412946. Baratta M, Grolli S, Tamanini C: Effect of leptin in proliferating and differentiated HC11 mouse mammary cells. Regul. Pept. 15-5-2003;113:101-107. Ghilardi N, Skoda RC: The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line. Mol. Endocrinol. 1997;11:393-399. Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA: Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr. Rev. 1998;19:225-268. Aoki N, Kawamura M, Matsuda T: Lactation-dependent down regulation of leptin production in mouse mammary gland. Biochim. Biophys. Acta 19-4-1999;1427:298306. Bonnet M, Delavaud C, Laud K, Gourdou I, Leroux C, Djiane J, Chilliard Y: Mammary leptin synthesis, milk leptin and their putative physiological roles. Reprod. Nutr. Dev. 2002; 42:399-413. Ren MQ, Wegner J, Bellmann O, Brockmann GA, Schneider F, Teuscher F, Ender K: Comparing mRNA levels of genes encoding leptin, leptin receptor, and

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

100

[26]

[27] [28]

[29]

[30]

[31]

[32]

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

[33]

[34]

[35]

[36]

[37]

[38]

[39]

Mario Baratta

lipoprotein lipase between dairy and beef cattle. Domest Anim. Endocrinol. 2002;23:371-381. Sayed-Ahmed A, Kulcsar M, Rudas P, Bartha T: Expression and localisation of leptin and leptin receptor in the mammary gland of the dry and lactating nonpregnant cow. Acta Vet. Hung 2004;52:97-111. Li M, Li Q, Gao X: Expression and function of leptin and its receptor in dairy goat mammary gland. J. Dairy Res. 2010;77:213-219. Bjorbaek C, Uotani S, da SB, Flier JS: Divergent signaling capacities of the long and short isoforms of the leptin receptor. J. Biol. Chem. 19-12-1997;272:3268632695. Akther A, Khan KH, Begum M, Parveen S, Kaiser MS, Chowdhury AZ: Leptin: a mysterious hormone; its physiology and pathophysiology. Mymensingh Med. J. 2009;18:S140-S144. Motta M, Accornero P, Baratta M: Leptin and prolactin modulate the expression of SOCS-1 in association with interleukin-6 and tumor necrosis factor-alpha in mammary cells: a role in differentiated secretory epithelium. Regul. Pept. 15-92004;121:163-170. Silva LF, Etchebarne BE, Nielsen MS, Liesman JS, Kiupel M, VandeHaar MJ: Intramammary infusion of leptin decreases proliferation of mammary epithelial cells in prepubertal heifers. J. Dairy Sci. 2008;91:3034-3044. Banks AS, Davis SM, Bates SH, Myers MG, Jr.: Activation of downstream signals by the long form of the leptin receptor. J. Biol. Chem. 12-5-2000;275:14563-14572. Mounzih K, Qiu J, Ewart-Toland A, Chehab FF: Leptin is not necessary for gestation and parturition but regulates maternal nutrition via a leptin resistance state. Endocrinology 1998;139:5259-5262. Liu X, Robinson GW, Wagner KU, Garrett L, Wynshaw-Boris A, Hennighausen L: Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev. 15-1-1997;11:179-186. Kritikou EA, Sharkey A, Abell K, Came PJ, Anderson E, Clarkson RW, Watson CJ: A dual, non-redundant, role for LIF as a regulator of development and STAT3mediated cell death in mammary gland. Development 2003;130:3459-3468. Motta M, Accornero P, Taulli R, Bernabei P, Desrivieres S, Baratta M: Leptin enhances STAT-3 phosphorylation in HC11 cell line: effect on cell differentiation and cell viability. Mol. Cell Endocrinol. 15-1-2007;263:149-155. McCormack VA, dos SS, I, De Stavola BL, Mohsen R, Leon DA, Lithell HO: Fetal growth and subsequent risk of breast cancer: results from long term follow up of Swedish cohort. BMJ 1-2-2003;326:248. Vatten LJ, Nilsen TI, Tretli S, Trichopoulos D, Romundstad PR: Size at birth and risk of breast cancer: prospective population-based study. Int. J. Cancer 10-42005;114: 461-464. Delvaux T, Buekens P, Thoumsin H, Dramaix M, Collette J: Cord C-peptide and insulin-like growth factor-I, birth weight, and placenta weight among North African and Belgian neonates. Am. J. Obstet. Gynecol. 2003;189:1779-1784.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Role of Leptin in the Mammary Gland Development...

101

[40] Vatten LJ, Nilsen ST, Odegard RA, Romundstad PR, Austgulen R: Insulin-like growth factor I and leptin in umbilical cord plasma and infant birth size at term. Pediatrics 2002; 109:1131-1135. [41] de AS, Khan G, Hilakivi-Clarke L: High birth weight increases mammary tumorigenesis in rats. Int. J. Cancer 1-10-2006;119:1537-1546. [42] de AS, Wang M, Goel S, Foxworth A, Helferich W, Hilakivi-Clarke L: Excessive weight gain during pregnancy increases carcinogen-induced mammary tumorigenesis in Sprague-Dawley and lean and obese Zucker rats. J. Nutr. 2006;136:998-1004. [43] Hilakivi-Clarke L: Nutritional modulation of terminal end buds: its relevance to breast cancer prevention. Curr. Cancer Drug Targets 2007;7:465-474. [44] Vickers MH, Gluckman PD, Coveny AH, Hofman PL, Cutfield WS, Gertler A, Breier BH, Harris M: Neonatal leptin treatment reverses developmental programming. Endocrinology 2005;146:4211-4216. [45] Vickers MH, Gluckman PD, Coveny AH, Hofman PL, Cutfield WS, Gertler A, Breier BH, Harris M: The effect of neonatal leptin treatment on postnatal weight gain in male rats is dependent on maternal nutritional status during pregnancy. Endocrinology 2008;149:1906-1913. [46] Gonzalez-Perez RR, Xu Y, Guo S, Watters A, Zhou W, Leibovich SJ: Leptin upregulates VEGF in breast cancer via canonic and non-canonical signalling pathways and NFkappaB/HIF-1alpha activation. Cell Signal 2010;22:1350-1362. [47] Gonzalez RR, Cherfils S, Escobar M, Yoo JH, Carino C, Styer AK, Sullivan BT, Sakamoto H, Olawaiye A, Serikawa T, Lynch MP, Rueda BR: Leptin signaling promotes the growth of mammary tumors and increases the expression of vascular endothelial growth factor (VEGF) and its receptor type two (VEGF-R2). J. Biol. Chem. 8-9-2006;281:26320-26328. [48] Ren H, Zhao T, Wang X, Gao C, Wang J, Yu M, Hao J: Leptin upregulates telomerase activity and transcription of human telomerase reverse transcriptase in MCF-7 breast cancer cells. Biochem. Biophys. Res. Commun. 26-3-2010;394:59-63. [49] Clark GM, Osborne CK, Levitt D, Wu F, Kim NW: Telomerase activity and survival of patients with node-positive breast cancer. J. Natl. Cancer Inst. 17-121997;89:1874-1881. [50] Rene GR, Watters A, Xu Y, Singh UP, Mann DR, Rueda BR, Penichet ML: Leptinsignaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer. Breast Cancer Res. 2009;11:R36. [51] Ashworth CJ, Hoggard N, Thomas L, Mercer JG, Wallace JM, Lea RG: Placental leptin. Rev. Reprod. 2000;5:18-24. [52] Hoggard N, Hunter L, Duncan JS, Williams LM, Trayhurn P, Mercer JG: Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta. Proc. Natl. Acad. Sci. USA 30-9-1997;94:11073-11078. [53] Matsuda J, Yokota I, Iida M, Murakami T, Naito E, Ito M, Shima K, Kuroda Y: Serum leptin concentration in cord blood: relationship to birth weight and gender. J. Clin. Endocrinol. Metab. 1997;82:1642-1644.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

102

Mario Baratta

[54] Tsai PJ, Yu CH, Hsu SP, Lee YH, Chiou CH, Hsu YW, Ho SC, Chu CH: Cord plasma concentrations of adiponectin and leptin in healthy term neonates: positive correlation with birthweight and neonatal adiposity. Clin. Endocrinol. (Oxf) 2004;61:88-93. [55] Savino F, Liguori SA, Fissore MF, Palumeri E, Calabrese R, Oggero R, Silvestro L, Miniero R: Looking for a relation between serum leptin concentration and body composition parameters in healthy term infants in the first 6 months of life. J. Pediatr Gastroenterol. Nutr. 2008;46:348-351. [56] Myers MG, Cowley MA, Munzberg H: Mechanisms of leptin action and leptin resistance. Annu. Rev. Physiol. 2008;70:537-556. [57] Bouret SG, Simerly RB: Minireview: Leptin and development of hypothalamic feeding circuits. Endocrinology 2004;145:2621-2626. [58] Koistinen HA, Koivisto VA, Andersson S, Karonen SL, Kontula K, Oksanen L, Teramo KA: Leptin concentration in cord blood correlates with intrauterine growth. J. Clin. Endocrinol. Metab. 1997;82:3328-3330. [59] Mantzoros CS, Rifas-Shiman SL, Williams CJ, Fargnoli JL, Kelesidis T, Gillman MW: Cord blood leptin and adiponectin as predictors of adiposity in children at 3 years of age: a prospective cohort study. Pediatrics 2009;123:682-689. [60] Houseknecht KL, McGuire MK, Portocarrero CP, McGuire MA, Beerman K: Leptin is present in human milk and is related to maternal plasma leptin concentration and adiposity. Biochem. Biophys. Res. Commun. 26-111997;240:742-747. [61] Estienne MJ, Harper AF, Barb CR, Azain MJ: Concentrations of leptin in serum and milk collected from lactating sows differing in body condition. Domest Anim. Endocrinol. 2000;19:275-280. [62] McFadin EL, Morrison CD, Buff PR, Whitley NC, Keisler DH: Leptin concentrations in periparturient ewes and their subsequent offspring. J. Anim. Sci. 2002;80:738-743. [63] Whitley NC, Walker EL, Harley SA, Keisler DH, Jackson DJ: Correlation between blood and milk serum leptin in goats and growth of their offspring. J. Anim. Sci. 2005; 83:1854-1859. [64] Parola R, Macchi E, Fracchia D, Sabbioni A, Avanzi D, Motta M, Accornero P, Baratta M: Comparison between plasma and milk levels of leptin during pregnancy and lactation in cow, a relationship with beta-lactoglobulin. J. Anim. Physiol. Anim. Nutr. (Berl) 2007;91:240-246. [65] Romagnoli U, Macchi E, Romano G, Motta M, Accornero P, Baratta M: Leptin concentration in plasma and in milk during the interpartum period in the mare. Anim. Reprod. Sci. 2007;97:180-185. [66] Bielicki J, Huch R, von MU: Time-course of leptin levels in term and preterm human milk. Eur. J. Endocrinol. 2004;151:271-276. [67] Ilcol YO, Hizli ZB, Ozkan T: Leptin concentration in breast milk and its relationship to duration of lactation and hormonal status. Int. Breastfeed. J. 2006;1:21.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Role of Leptin in the Mammary Gland Development...

103

[68] Casabiell X, Pineiro V, Tome MA, Peino R, Dieguez C, Casanueva FF: Presence of leptin in colostrum and/or breast milk from lactating mothers: a potential role in the regulation of neonatal food intake. J. Clin. Endocrinol. Metab. 1997;82:4270-4273. [69] Miralles O, Sanchez J, Palou A, Pico C: A physiological role of breast milk leptin in body weight control in developing infants. Obesity (Silver Spring) 2006;14:13711377. [70] Resto M, O'Connor D, Leef K, Funanage V, Spear M, Locke R: Leptin levels in preterm human breast milk and infant formula. Pediatrics 2001;108:E15. [71] Ng PC, Lee CH, Lam CW, Chan IH, Wong E, Fok TF: Resistin in preterm and term newborns: relation to anthropometry, leptin, and insulin. Pediatr Res. 2005;58:725730. [72] Ng PC, Lam CW, Lee CH, Wong GW, Fok TF, Chan IH, Ma KC, Wong E: Leptin and metabolic hormones in preterm newborns. Arch Dis. Child Fetal. Neonatal. Ed. 2000;83:F198-F202. [73] Barrenetxe J, Villaro AC, Guembe L, Pascual I, Munoz-Navas M, Barber A, Lostao MP: Distribution of the long leptin receptor isoform in brush border, basolateral membrane, and cytoplasm of enterocytes. Gut 2002;50:797-802. [74] Whitley NC, O'Brien DJ, Quinn RW, Keisler DH, Walker EL, Brown MA: Milk leptin in sows and blood leptin and growth of their offspring. J. Anim. Sci. 2009;87:1659-1663. [75] Dessolin S, Schalling M, Champigny O, Lonnqvist F, Ailhaud G, Dani C, Ricquier D: Leptin gene is expressed in rat brown adipose tissue at birth. FASEB J. 1997;11:382-387. [76] Weiler HA, Kovacs H, Murdock C, Adolphe J, Fitzpatrick-Wong S: Leptin predicts bone and fat mass after accounting for the effects of diet and glucocorticoid treatment in piglets. Exp. Biol. Med. (Maywood ) 2002;227:639-644. [77] Blum JW, Zbinden Y, Hammon HM, Chilliard Y: Plasma leptin status in young calves: effects of pre-term birth, age, glucocorticoid status, suckling, and feeding with an automatic feeder or by bucket. Domest Anim. Endocrinol. 2005;28:119133. [78] Savino F, Nanni GE, Maccario S, Costamagna M, Oggero R, Silvestro L: Breastfed infants have higher leptin values than formula-fed infants in the first four months of life. J. Pediatr Endocrinol. Metab. 2004;17:1527-1532. [79] Sanchez J, Oliver P, Miralles O, Ceresi E, Pico C, Palou A: Leptin orally supplied to neonate rats is directly uptaken by the immature stomach and may regulate shortterm feeding. Endocrinology 2005;146:2575-2582. [80] Berg EL, McNamara DL, Keisler DH: Endocrine profiles of periparturient mares and their foals. J. Anim. Sci. 2007;85:1660-1668. [81] Kraeft S, Schwarzer K, Eiden S, Nuesslein-Hildesheim B, Preibisch G, Schmidt I: Leptin responsiveness and gene dosage for leptin receptor mutation (fa) in newborn rats. Am. J. Physiol. 1999;276:E836-E842. [82] Stehling O, Doring H, Nuesslein-Hildesheim B, Olbort M, Schmidt I: Leptin does not reduce body fat content but augments cold defense abilities in thermoneutrally reared rat pups. Pflugers Arch 1997;434:694-697.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

104

Mario Baratta

[83] Locke R: Preventing obesity: the breast milk-leptin connection. Acta Paediatr 2002; 91:891-894. [84] de GC, Blom WA, Smeets PA, Stafleu A, Hendriks HF: Biomarkers of satiation and satiety. Am. J. Clin. Nutr. 2004;79:946-961. [85] Cottrell EC, Ozanne SE: Developmental programming of energy balance and the metabolic syndrome. Proc. Nutr. Soc. 2007;66:198-206. [86] Sveger T, Lindberg T, Weibull B, Olsson UL: Nutrition, overnutrition, and obesity in the first year of line in Malmo, Sweden. Acta Paediatr. Scand. 1975;64:635-640. [87] Agras WS, Kraemer HC, Berkowitz RI, Korner AF, Hammer LD: Does a vigorous feeding style influence early development of adiposity? J. Pediatr. 1987;110:799804. [88] Armstrong J, Reilly JJ: Breastfeeding and lowering the risk of childhood obesity. Lancet 8-6-2002;359:2003-2004. [89] Gillman MW, Mantzoros CS: Breast-feeding, adipokines, and childhood obesity. Epidemiology 2007;18:730-732. [90] Harder T, Bergmann R, Kallischnigg G, Plagemann A: Duration of breastfeeding and risk of overweight: a meta-analysis. Am. J. Epidemiol. 1-9-2005;162:397-403. [91] Demmelmair H, von RJ, Koletzko B: Long-term consequences of early nutrition. Early Hum. Dev. 2006;82:567-574. [92] Kunz C, Rodriguez-Palmero M, Koletzko B, Jensen R: Nutritional and biochemical properties of human milk, Part I: General aspects, proteins, and carbohydrates. Clin. Perinatol. 1999;26:307-333. [93] Sanchez J, Priego T, Palou M, Tobaruela A, Palou A, Pico C: Oral supplementation with physiological doses of leptin during lactation in rats improves insulin sensitivity and affects food preferences later in life. Endocrinology 2008;149:733740. [94] Pico C, Oliver P, Sanchez J, Miralles O, Caimari A, Priego T, Palou A: The intake of physiological doses of leptin during lactation in rats prevents obesity in later life. Int. J. Obes. (Lond) 2007;31:1199-1209. [95] Palou A, Pico C: Leptin intake during lactation prevents obesity and affects food intake and food preferences in later life. Appetite 2009;52:249-252. [96] Langley-Evans SC, Bellinger L, McMullen S: Animal models of programming: early life influences on appetite and feeding behaviour. Matern. Child Nutr. 2005;1:142-148. [97] Rissanen A, Hakala P, Lissner L, Mattlar CE, Koskenvuo M, Ronnemaa T: Acquired preference especially for dietary fat and obesity: a study of weightdiscordant monozygotic twin pairs. Int. J. Obes. Relat. Metab. Disord. 2002;26:973-977. [98] Bellinger L, Lilley C, Langley-Evans SC: Prenatal exposure to a maternal lowprotein diet programmes a preference for high-fat foods in the young adult rat. Br. J. Nutr. 2004;92:513-520. [99] Hales CN, Barker DJ: The thrifty phenotype hypothesis. Br Med Bull 2001;60:520.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Role of Leptin in the Mammary Gland Development...

105

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

[100] Barker DJ: The developmental origins of chronic adult disease. Acta Paediatr Suppl. 2004;93:26-33. [101] Dunger DB, Ong KK: Endocrine and metabolic consequences of intrauterine growth retardation. Endocrinol. Metab. Clin. North Am. 2005;34:597-615, ix. [102] Holt RI, Byrne CD: Intrauterine growth, the vascular system, and the metabolic syndrome. Semin. Vasc. Med. 2002;2:33-43. [103] Alexe DM, Syridou G, Petridou ET: Determinants of early life leptin levels and later life degenerative outcomes. Clin. Med. Res. 2006;4:326-335. [104] Bouret SG, Draper SJ, Simerly RB: Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2-4-2004;304:108-110. [105] El-Haddad MA, Desai M, Gayle D, Ross MG: In utero development of fetal thirst and appetite: potential for programming. J. Soc. Gynecol. Investig. 2004;11:123130. [106] McMillen IC, Muhlhausler BS, Duffield JA, Yuen BS: Prenatal programming of postnatal obesity: fetal nutrition and the regulation of leptin synthesis and secretion before birth. Proc. Nutr. Soc. 2004;63:405-412.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

In: Leptin: Hormonal Functions, Dysfunctions and Clinical Uses ISBN: 978-1-61122-891-5 Editors: Rose M. Hemling and Arthur T. Belkin ©2011 Nova Science Publishers, Inc.

Chapter 6

GENDER DIFFERENCE IN LEPTIN PRODUCTION AND LEPTIN SENSITIVITY Haifei Shi Cellular, Molecular and Structural Biology Program, Department of Zoology, Miami University, Oxford, Ohio USA

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ABSTRACT Obesity and its related health disorders are increasing. Leptin, a hormone product of the obese (ob) gene, is proportional to peripheral energy stores, provides negative feedback signals to the central nervous system, plays a key role in the regulation of caloric intake and energy expenditure, and thus regulates body weight and body fat. Men and women become overweight or obese in different ways, and suffer different consequences. Specifically, men and women differ in terms of how and where they store body fat, the levels of leptin they synthesize and secrete in proportion to their body fat, and the way they respond to endogenous and exogenous leptin to regulate energy balance and body fat. Leptin is mainly produced in adipose (fat) tissues, and its level is associated with adiposity. Interestingly, serum leptin levels are greater in females than in males with equivalent amount of body fat. There are several possible reasons for the gender difference in circulating leptin levels. One contributing factor is that leptin gene is expressed predominantly in subcutaneous compared to visceral omental fat tissue. Women are more likely to deposit fat subcutaneously; whereas men are more likely to deposit fat in the abdominal region. The health risks associated with obesity vary depending on the location of adipose tissue. Excess fat mass in the abdominal region, especially visceral omental fat, carries a much greater risk for metabolic disorders than does fat tissue distributed subcutaneously. A second contributing factor is that the reproductive hormones influence leptin production. Estrogens stimulate, whereas androgens suppress, leptin synthesis and secretion. Another potential contributing factor is that males and females respond differentially to certain conditions, such as over or under nutrition or stress, to change their circulating leptin levels. Besides gender differences in leptin production, secretion, and circulating levels, males and females respond differentially to leptin. Female brains are relatively sensitive to leptin, and females are more reliant on leptin as an adiposity negative feedback signal.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

108

Haifei Shi Males are more reliant on insulin, another adiposity signal. Estrogens enhance leptin sensitivity and thus its function, whereas androgens induce leptin resistance and thus its dysfunction. Reviewing the gender differences in the regulation of leptin production, secretion and its sensitivity under normal physiological or pathophysiological conditions is the focus of this chapter.

Keywords: Fat distribution; Gonadal steroids; Subcutaneous adipose tissue; Intra-abdominal adipose tissue; Estrogen; Estrogen receptor

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

1. INTRODUCTION The prevalence of obesity and its associated health disorders have reached epidemic proportion with enormous costs in both human lives and healthcare dollars spent (Wang, Beydoun et al. 2008). Obesity is a leading cause for the development of adverse metabolic effects, including noninsulin dependent diabetes mellitus, dyslipidemia, and cardiovascular disease (Eckel, Barouch et al. 2002). It has been estimated that 47 million individuals in the United States have obesity-related metabolic diseases (Ford, Giles et al. 2002). In addition, obesity is associated with over 300,000 premature deaths every year in the United States alone (Allison, Fontaine et al. 1999). Clinicians and basic research scientists have been attempting to identify key hormones and signals that regulate body weight and body fat. Leptin, the product of the obese (ob) gene, was discovered over a decade ago. It is a protein hormone secreted by adipocytes (fat cells). Leptin exerts a spectrum of regulatory functions involved in multitude of diseases, including reproductive, metabolic, psychiatric and inflammatory disorders. Importantly, leptin plays critical roles in the regulation of energy homeostasis and metabolism, and thus is considered as a peripheral metabolic signal that contributes to body weight and body fat regulation through modulating feeding behavior and energy expenditure. Gender differences exist in terms of how and where males and females store body fat, leptin they secrete in proportion to their fat, and the way their brains respond to the leptin signal to regulate food intake and body weight. It has been proposed that reproductive steroid hormones such as estrogens and androgens may interact with the metabolic signal leptin to mediate gender-specific regulation of energy homeostasis. The goal of this chapter is to explore what we know about these distinct gender differences in the regulation of leptin production and secretion as well as its sensitivity under normal physiological or pathophysiological conditions. A full understanding of gender difference in leptin remains to be established. Elucidating the mechanisms by which reproductive hormones and other contributing factors regulate the production and physiologic roles of leptin, thus modulate the way in which fat is accumulated and stored, is a critical area of research due to the prevalence of obesity and the metabolic syndrome, the rapid increase in propensity for these diseases following menopause, and imply that strategies for reducing body weight in males and females might differ.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Gender Difference in Leptin Production and Leptin Sensitivity

109

2. GENDER DIFFERENCE IN LEPTIN PRODUCTION AND SECRETION A distinct gender difference in serum leptin levels has been reported and observed from many previous studies. Leptin is differentially expressed in men and women. Serum leptin levels are significantly higher in women as compared to men, and this difference persist even after controlling for differences in age or plotted against some index of adiposity such as body mass index (BMI), body fat mass, or percentage of body fat (Rosenbaum and Leibel 1999). In addition, there is a linear relationship with increasing adiposity associated with increasing serum leptin levels. This linear expression is usually higher in females than in males (Havel, Kasim-Karakas et al. 1996; Ostlund, Yang et al. 1996). Furthermore, the level of ob mRNA in adipose tissues is greater in women than in men. Various mechanisms have been postulated to explain this gender difference, including relatively greater body fat contents of females, gender difference in body fat distribution, reproductive hormones and pubertal stage, or gender difference in genetics.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

2.1. Gender Difference in Adiposity and Fat Distribution Regulates Leptin Production Leptin is mainly produced in and secreted from adipose tissues. Therefore, the amount of circulating leptin is related to the amount of total adiposity. Interestingly, in addition to providing information about whole-body adiposity, leptin also provides information about the body fat distribution and the size of constituent adipocytes. Specifically, leptin is secreted at a higher rate from subcutaneous fat than from intra-abdominal visceral fat (Montague, Prins et al. 1997; Montague, Prins et al. 1998), thus circulating leptin correlates better with total subcutaneous fat than with total body fat (Masuzaki, Ogawa et al. 1995; Dua, Hennes et al. 1996; Demerath, Towne et al. 1999; Rosenbaum and Leibel 1999; Clegg, Riedy et al. 2003). Fat mass is the primary determinant of serum leptin in mammals and leptin secretion also correlates with fat cell volume. Lepin gene expression is greater in larger than smaller adipocytes. In obese subjects, subcutaneous adipocytes of females are significantly larger than omenal adipocytes (Fried and Kral 1987). Therefore, cell size may explain in part, the greater leptin production in subcutaneous versus intra-abdominal visceral omental adipose tissue, and explain the gender difference on serum leptin levels. Mammals, including human beings, are susceptible to sustained weight gain in the modern environment with sufficient and convenient nutrient access. Although both men and women can get fat, they get fat in different ways, and suffer different consequences. Women have a significantly greater subcutaneous adipose tissue mass and men have greater omental adipose tissue mass. Thus, gender difference in the body fat distribution exists, with women having more subcutaneous fat and men having more intra-abdominal visceral fat. Fat accumulation at the adipose depot within the abdominal viscera is associated with greater risk for developing metabolic disorders, such as cardiovascular problems, type-2 diabetes mellitus, certain cancers and other disorders. Therefore, obesity-related metabolic disorders are much lower in premenopausal women than men. Men and postmenopausal women accumulate more fat in the intra-abdominal depot than do pre-menopausal women, and

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

110

Haifei Shi

therefore have a greater risk of developing metabolic complications associated with obesity. In females, estrogens are responsible for body adiposity. Reductions in circulating estrogens, which occurs following ovariectomy (OVX) in experimental rodent models, results in increased body adiposity which can be ameliorated by exogenous estradiol-17β administration (Clegg, Riedy et al. 2003; Clegg, Brown et al. 2006). In women, menopause is has been associated with increased in adiposity and shifts in body fat distribution, which can be altered by exogenous hormone replacement therapy (Samaras, Hayward et al. 1999; Ryan, Nicklas et al. 2002). Several previous studies have investigated the direct in vitro effects of androgens and estrogens on leptin production and secretion in adipose tissues. In male rats, dihydrotestosterone decreases adipose tissue leptin mRNA, whereas in female rats, 17 βestradiol, the major component of estrogens, increases adipose tissue leptin mRNA levels (Kristensen, Pedersen et al. 1999). In vitro studies using human omental adipose tissue have shown that there is a greater leptin release from female adipose tissue than male adipose tissue (Casabiell, Pineiro et al. 1998). In addition, estradiol stimulated leptin secretion in fat tissue from women, but not in fat tissue from men. Androgenic factors inhibit leptin secretion in omental adipose tissue from women without affecting the secretion in samples from men in vitro (Pineiro, Casabiell et al. 1999). The above studies imply that adipose tissue from men and women are different, which would play important roles in establishing the gender difference in circulating leptin levels. Type of adipose tissue, subcutaneous or visceral (omental), could be critical. Estrogens or androgens affect leptin production in human omental fat tissue, but such effects disappear in subcutaneous tissue explants in vitro (Kristensen, Pedersen et al. 2000). Leptin mRNA is expressed predominantly by subcutaneous adipocytes. Leptin gene expression / leptin production is greater in subcutaneous than omental adipocytes from the same individual (Montague, Prins et al. 1997; Lefebvre, Laville et al. 1998; Van Harmelen, Reynisdottir et al. 1998). Females have a larger proportion of body mass as fat, and females are more likely to deposit fat subcutaneously whereas men are more likely to deposit visceral fat. Currently, the differential adiposity between the genders is the most accepted explanation to the gender difference in the circulating leptin levels.

2.2. Sex Steroid Hormones Regulate Leptin Production Circulating leptin levels are higher in women than in men. As mentioned above, women have more body fat and greater subcutaneous fat distribution than men, thus it is difficult to relate sex steroid hormones to leptin concentrations. However there have been in vivo, human and non-human animals, and in vitro studies cited below suggest that reproductive hormone influences leptin production and thus is one of the contributing factor to the gender difference in the circulating leptin levels. Although generally estrogenic hormones stimulate whereas androgenic hormones suppress the synthesis and production of leptin, a full understanding of such gender differences remains to be established.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Gender Difference in Leptin Production and Leptin Sensitivity

111

2.2a. Estrogens Regulate Leptin Production and Secretion In humans, several studies reported a correlation between serum leptin and estrogen levels, as estrogen levels decrease with menopause, leptin levels also decrease (Hardie, Rayner et al. 1996; Shimizu, Shimomura et al. 1997; Rosenbaum and Leibel 1999). However discrepancies exist, some studies reported no change in leptin levels with menopause (Havel, Kasim-Karakas et al. 1996; Saad, Damani et al. 1997; Hadji, Hars et al. 2000; Milewicz, Bidzinska et al. 2000; Jenkins, Samaras et al. 2001). Similar discrepancies exist in results with hormone replacement therapy (HRT) in postmenopausal women and leptin levels, with some studies reporting an increase in leptin with HRT (Elbers, De Roo et al. 1999; Konukoglu, Serin et al. 2000) and others reporting no change in leptin level with HRT (Havel, Kasim-Karakas et al. 1996; Kristensen, Pedersen et al. 1999; Gower, Nagy et al. 2000; Hadji, Hars et al. 2000; Jenkins, Samaras et al. 2001). The effects of menopause and HRT on leptin levels may be a result of increases in body adiposity, body mass index, and central fat distribution during menopause and reversal of these by HRT. In women leptin fluctuations during the menstrual cycle directly correlate with estrogen, but not with progesterone (Mannucci, Ognibene et al. 1998; Quinton, Smith et al. 1999). The most convincing evidence that the sex steroid hormones affect leptin production and secretion comes from studies on cross-sex administration of sex steroid hormones to trans-sexuals, which indicate that estrogen and anti-androgen administration to male-to-female trans-sexuals greatly increases the serum leptin levels, and testosterone administration to female-to-male trans-sexuals decreases the serum leptin levels (Elbers, Asscheman et al. 1997). Therefore the sex steroid milieu plays an important role in the regulation of leptin production and secretion. As in humans, estrogens regulate circulating leptin level and ob gene expression in rodents. Estrogen treatment decreases the serum leptin levels in male mice (Nedvídková, Haluzík et al. 1997). However, ovariectomy or estradiol administration does not alter leptin levels in female mice (Pelleymounter, Baker et al. 1999). Female rats have higher circulating levels of leptin than males (Pinilla, Seoane et al. 1999; Watanobe and Suda 1999). A significant increase in circulating leptin level has been observed following the weight gain associated with ovariectomy in female rats (Ainslie, Morris et al. 2001; Meli, Pacilio et al. 2004; Clegg, Brown et al. 2006). These results are in contrast with one study that observed no change in plasma leptin concentration in ovariectomized females, despite observing that the ovariectomized rats weighed significantly more than sham-operated females (Kimura, Irahara et al. 2002). Estradiol treatment increases ob mRNA levels in white fat tissue of ovariectomized rats (Shimizu, Shimomura et al. 1997; Brann, De Sevilla et al. 1999). Using ovary-intact instead of ovariectomized rats, Rocha et al. reported that estradiol treatment reduced body fat mass but did not change plasma leptin concentration or ob gene expression in white adipose tissue (Rocha, Grueso et al. 2001). These discrepancies and varying results could be caused by the time of the blood samples and weight gain in the ovariectomized animals, indicating that the animal models (ovary-intact vs. ovariectomized) and assay time may be critical for studying the physiological roles of estrogen and leptin in regulating energy balance and body fat. There are many in vitro studies investigated the roles of estrogens in leptin production. Ovariectomy has also been reported to decrease leptin gene expression in white fat cells of rats, and this decrease can be reversed by estrogen replacement (Shimizu, Shimomura et al. 1997; Yoneda, Saito et al. 1998; Brann, De Sevilla et al. 1999; Machinal, Dieudonne et al. 1999). However, some studies reported no effect on leptin gene expression in white adipose

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

112

Haifei Shi

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

tissues by ovariectomy (Wu-Peng, Rosenbaum et al. 1999; Luukkaa, Savontaus et al. 2001). These discrepancies could be caused by differences in leptin secretion and regulation in various adipose sites. For example, although leptin gene expression reduces in subcutaneous and retroperitoneal white adipose tissues of ovariectomized rats as compared to controls, leptin gene expression increases in mesenteric white adipose tissues of the ovariectomized rats (Shimizu, Shimomura et al. 1997). In addition, ovariectomy results in a greater decrease in leptin gene expression in perirenal adipocytes than in subcutaneous adipocytes (Machinal, Dieudonne et al. 1999). Basal leptin production is equivalent in epididymal fat fragments from males and parametrial fat fragments from females. Estradiol increases leptin secretion in both male and female adipose fragments, but the effect is greater in female adipose tissue (Kristensen, Pedersen et al. 1999). Progesterone, testosterone, dihydrotestosterone and dehydroepiandrostenedione-sulphate have no effect on leptin secretion. Parametrial fat from ovariectomized rats has lower leptin secretion compared to sham-operated controls, and estradiol treatment of ovariectomized rats maintains a normal leptin secretion in adipose tissue fragments. Therefore, the regional distribution of adipose tissues may greatly influence leptin levels and its regulation by sex steroid hormones.

2.2b. Androgens Regulate Leptin Production and Secretion Serum leptin levels are inversely correlated with testosterone in men (Blum, Englaro et al. 1997; Wabitsch, Blum et al. 1997; Luukkaa, Pesonen et al. 1998; Isidori, Caprio et al. 1999; Kristensen, Pedersen et al. 1999; Erturth and Ahrén 2000). Administration of testosterone to men decreases the levels of leptin, and testosteone replacement therapy normalizes elevated serum leptin levels in hypogonadal men (Jockenhovel, Blum et al. 1997; Kapoor, Clarke et al. 2007). Testosterone treatment resulted in an increase in serum testosterone, dihydrotestosterone and estradiol, and the androgen (testosterone plus dihydrotestosterone) / estrogen ratio is the only significant determinant of serum leptin levels. Although this could be due to the aromatization of androgens to estrogen, inhibition of estrogen biosynthesis with an aromatase inhibitor does not affect serum leptin levels in young men (Luukkaa, Rouru et al. 2000). In aging and obese men, there is an increased aromatase activity and conversion of androgens to estrogen, which is associated with increased plasma leptin (Zumoff, Strain et al. 1990; Jockenhovel, Blum et al. 1997; Morley and Perry 2000). Testosterone replacement decreases the level of leptin in elderly men (Lambert, Sullivan et al. 2003), and androgen blockage in patients with advanced prostate cancer greatly increases leptin levels (Nowicki, Bryc et al. 2001). In contrast, this inverse relationship between testosterone and leptin levels is not observed in girls undergoing puberty and adolescents (Blum, Englaro et al. 1997), suggesting that such inverse relationship between testosterone and leptin levels may not exist in females possibly due to different genetic background. Androgens are also involved in the regulation of leptin production in rodents. Administration of testosterone to ovariectomized female rats decreases the expression of ob mRNA but does not change plasma leptin levels (Wu-Peng, Rosenbaum et al. 1999). In male rats of similar body weights, castration leads to a rise in plasma leptin levels, which is abolished with testosterone administration (Pinilla, Seoane et al. 1999; Watanobe and Suda 1999). In addition, castration almost doubles the ob gene expression in perirenal adipocytes, but a two-fold decrease of ob gene expression in subcutaneous adipocytes (Machinal, Dieudonne et al. 1999). Opposite finding is reported from a separate study, which showed that serum leptin levels were decreased by castration in obese rats, and testosterone

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Gender Difference in Leptin Production and Leptin Sensitivity

113

supplement reversed this decrease (Shimizu, Ohtani et al. 1998). In addition, this study also found that serum leptin increases as the serum testosterone rises in male rats from immaturity to young adults (Shimizu, Ohtani et al. 1998; Nazian 2001). A difference in neonatal gonadal steroid milieu might permanently affect leptin secretion (Watanobe and Habu 2003). In neonatally castrated male rats, an one hundred percent increase in leptin levels is observed as compared to intact males. This increase in leptin levels is prevented by testosterone when given neonatally, but not after one month of age (Watanobe and Habu 2003). Neonatal testosterone has no effect on leptin titers in female rats in later life, possibly due to different genetic background between males and females. In vitro studies have been done to determine a direct action of androgens on leptin production from isolated and cultured adipocytes. Androgen exposure decreases ob gene expression in, but not leptin secretion from, perirenal and subcutaneous adipocytes of normal female rats, and this decrease is prevented by anti-androgens (Machinal, Dieudonne et al. 1999). However, 17-beta estradiol exposure increases both ob gene expression in, and leptin secretion from, subcutaneous, perirenal and parametrial adipocytes of ovariectomized female rats, and these increases are prevented by anti-estrogens (Machinal, Dieudonne et al. 1999). Cultured epididymal fat tissue from adult rats with higher testosterone levels secrets more leptin than those from immature rats (Nazian 2001). Castration of immature rats with or without testosterone replacement does not change the ability of the epididymal fat to secrete leptin. However, exposure of the epididymal fat in vitro to testosterone results in an enhanced secretion of leptin into the media. In summary, estrogens appear to increase leptin production, while androgens appear to decrease its production. However, many discrepancies exist in the previous studies. If sex steroid hormones are going to directly regulate the production of leptin, a sex steroid hormone response element should be present in the leptin gene. Indeed, leptin gene has a consensus sequence of the estrogen response element in its promoter region (Shimizu, Shimomura et al. 1997). If a leptin-luciferase reporter construct is transfected into estrogen receptor-positive or estrogen receptor-negative cell cultures, estradiol stimulates leptin-luciferase activity and anti-estrogens inhibit leptin-luciferase activity in the leptin-producing cell cultures with estrogen receptors alpha, but not the cell cultures with estrogen receptor beta (O'Neil, Burow et al. 2001). This study not only suggests that the leptin gene has an estrogen response element, but also indicates that leptin promoter activation may depend upon coactivators present in leptin-producing cells. In addition, different effects of estrogen may be due to the type of estrogen receptor expressed in target tissue.

2.3. Other Gender-Related Factors Regulate Leptin Production Leptin is considered as an adiposity hormone that provides negative feedback signals to the central nervous system to regulate caloric intake and energy expenditure, and thus regulates body weight and body fat. Leptin is detectable from the umbilical cord blood serum. Interestingly leptin level is positively correlated with birth weights of newborn infants of both sexes (Matsuda, Yokota et al. 1997; Jahan, Zinnat et al. 2009), even though fetuses do not control their energy balance or body fat amount, but rather completely rely on trans-placental uptake of their energy supply. Furthermore, cord serum leptin concentrations of female babies are higher compared to the male babies, whereas the serum concentrations of estradiol and

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

114

Haifei Shi

testosterone do not differ between female and male babies (Matsuda, Yokota et al. 1997; Jahan, Zinnat et al. 2009). There is no correlation between sex hormone concentrations and leptin levels of these healthy newborns. A cross-sectional study of a large population of children of both sexes reported that, at any age and at any pubertal stage studied, including the child development age group without any sex-related hormonal changes, the girls always had higher leptin concentration than the boys (Garcia-Mayor, Andrade et al. 1997). These differences in serum leptin concentrations between boys and girls could not be explained by differences in body weight, body fat, height, age, or sex steroid hormones. It is unlikely that the gender difference in newborn and children leptin levels is due either to body fat content or body fat distribution, or to reproductive hormone status. Thus the gender difference in leptin production and secretion may be attributed to other factors than body fat or steroid hormones. The sexual dimorphism in leptin production and secretion observed in the very early life may indicate the genetic difference in leptin production between males and females. However, this issue needs to be explored further to explain gender differences in leptin production.

3. GENDER DIFFERENCE IN LEPTIN SENSITIVITY

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Leptin is secreted from adipose tissue, enters the brain from the blood, and interacts with specific receptors on neurons in the hypothalamus and other brain areas. Increased activity of leptin locally in the vicinity of the ventral hypothalamus causes an overall catabolic response (i.e., reduced food intake, increased energy expenditure, increased sympathetic activation, and loss of body weight) whereas decreased leptin causes an overall anabolic response (i.e., increased food intake, decreased energy expenditure, suppressed sympathetic activation, and increased body weight) (Schwartz, Woods et al. 2000).

3.1. Differential Leptin Sensitivity in Males and Females Females carry more subcutaneous fat and secrete more leptin. Leptin is a better correlate of total body fat in females. Females are more reliant on leptin as an adiposity signal than males, and female brains are relatively sensitive to leptin as an adiposity negative feedback signal. Males, on the other hand, carry more fat viscerally and secrete more insulin, insulin is a better correlate of total body fat in males, and the brains of males are more sensitive to the catabolic actions of insulin (Clegg, Riedy et al. 2003). These observations, besides having fundamental importance for the regulation of energy balance, imply that strategies for reducing body weight in males and females might differ.

3.2. Sex Steroid Hormones Determine the Gender Difference in Leptin Sensitivity Ovarian hormone estrogen determines the sex differences in the sensitivity of the brain to adiposity signal leptin. Previous studies investigated leptin sensitivity using either peripheral

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Gender Difference in Leptin Production and Leptin Sensitivity

115

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

or central leptin administration in estrogen-treated or estrogen-deficient ovariectomized rodents. Ovariectomy does not alter subcutaneously administered leptin's ability to reduce food intake or body fat in rats (Chen and Heiman 2001) or mice (Pelleymounter, Baker et al. 1999), suggesting that estrogen might not directly mediate leptin's effect. On the contrary, the ability of central leptin administration to reduce food intake is greater in ovary-intact females than in males (Clegg, Riedy et al. 2003; Clegg, Brown et al. 2006) or in ovariectomized females (Ainslie, Morris et al. 2001; Clegg, Brown et al. 2006). Conversely, administration of estradiol to ovariectomized females restored their central leptin sensitivity and changed their body fat distribution to mirror that of intact females (Clegg, Riedy et al. 2003; Clegg, Brown et al. 2006). Additionally, altering the sex hormone milieu in males with estradiol administration increased sensitivity to central leptin administration and increased subcutaneous fat deposition (Clegg, Riedy et al. 2003; Clegg, Brown et al. 2006).

3.2a. Estrogens Change Central Leptin Sensitivity Estrogen alters sensitivity to centrally administered leptin. Peripheral or central administration of 17 β-estradiol to ovariectomised females restores the central leptin sensitivity (Clegg, Brown et al. 2006). In addition, administration of 17 β-estradiol increases sensitivity to central leptin, decreases sensitivity to central insulin in males (Clegg, Brown et al. 2006). These findings suggest that gonadal steroids interact with the adiposity message conveyed to the brain by leptin and insulin, resulting in differential sensitivity to these signals in males and females (Clegg, Brown et al. 2006). Central leptin signaling might affect hypothalamic Era gene expression. Female mice that lack leptin receptors specifically in the proopiomelanocortin neurons (POMC Lepr-KO), one critical population of leptin receptors, have normal circulating estradiol but reduced hypothalamic ERα mRNA level (Shi, Sorrell et al. 2010). Additionally, POMC Lepr-KO females accumulate greater percentage of visceral adipose tissue than male POMC Lepr-KO mice do (Shi, Sorrell et al. 2010). Therefore, the combination of estrogen and functional leptin signaling is required for sex-specific fat distribution. Lack of either estrogen or functional leptin signaling would lead to visceral obesity. 3.2b. Estrogens Influence Leptin Receptor Expression Estrogen levels appear to regulate the expression of the leptin receptors during the estrous cycle. Leptin receptor expression levels are lowest in proestrus, the point of the estrus cycle with the highest levels of estradiol, in the choroid plexus, and these changes correspond inversely with levels of circulating estradiol over the 4-day estrous cycle in the rat (Bennett, Lindell et al. 1998). Estradiol might regulate leptin receptor expression independent of leptin levels. Although circulating leptin does not change during the estrous cycle, leptin receptor expression is highest during estrous and metestrous in the hypothalamic arcuate nucleus, a central controller for the regulation of energy homeostasis (Bennett, Lindell et al. 1998), providing a potential mechanism for cyclic variations in energy intake and activity seen in females. During normal estrous cycle, high estrogen levels are associated with low expression of the leptin receptors. Ovariectomy has been reported to cause a marked reduction in expression of long form of the leptin receptor in the hypothalamus and estradiol replacement restores its expression (Meli, Pacilio et al. 2004), suggesting development of leptin resistance when estrogen is experimentally removed. This is consistent with the fact that there is an estrogen response element in the leptin receptor gene.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

116

Haifei Shi

Estrogens influence hypothalamic leptin receptor expression. Ovariectomy causes a significant (Kimura, Irahara et al. 2002; Meli, Pacilio et al. 2004) or a 50% but statistically non-significant (Ainslie, Morris et al. 2001) reduction in expression of the long form of leptin receptor in the hypothalamus; and estradiol replacement restores its expression (Kimura, Irahara et al. 2002; Meli, Pacilio et al. 2004). Since only leptin receptor mRNA expression has been measured, it is unknown how estrogen may impact the leptin protein or leptin signaling. The differences in leptin sensitivity caused by the presence or absence of estrogen may occur downstream of leptin transcription and translation. More research in this area is warranted.

3.3. Potential Mechanisms for Sexual Dimorphic Leptin Sensitivity

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

3.3a. Overlapping Signaling Pathway between Estrogen and Leptin Estrogen and leptin have similar molecular effects with overlapping cellular signaling pathway. Signal transducer and activator of transcription 3 (STAT3) is a downstream target of leptin signaling and is activated by leptin. Similarly, intraperitoneal estrogen administration induces tyrosine phosphorylation of STAT3 in the hypothalamus in less than 30 min (Gao, Mezei et al. 2007). These findings provide molecular support for the interaction between estrogen and leptin in the regulation of energy homeostasis. 3.3b. Estrogen Is a Potential Adiposity Signal that Closely Interacts with Leptin Signaling Estrogen, a possible adiposity signal, closely interacts with leptin signaling. Adiposity signals such as leptin transduce hormonal input into neurobiological responses to make compensatory adjustments by regulating food intake and energy expenditure, and consequently regulating body fat distribution (Schwartz, Woods et al. 2000). Estrogen also fulfils these criteria and thus can be considered another potential adiposity signal. Specifically, it is released from the ovaries, crosses the blood brain barrier, binds to estrogen receptors located in key hypothalamic nuclei, and reduces food intake and body weight. Additionally, when delivered directly into the central ventricular system, it decreases food intake possibly through its actions on the same neurons that are responsible for leptin‘s anorectic responses (Gao and Horvath 2008). Estrogen and leptin have overlapping targeted nuclei. Hypothalamic cells that are immunoreactive for estrogen receptors also express leptin receptors (Diano, Kalra et al. 1998). The extensive hypothalamic colocalization of the long form of the leptin and estrogen receptors, leptin receptor and estrogen receptor alpha in the critical brain regions that modulate energy homeostasis, including arcuate nucleus, ventromedial hypothalamic nucleus and parvicellular portion of the paraventricular nucleus, suggests a closely coupled interaction between these peripheral signals in the regulation of behavioral and neuroendocrine mechanisms of energy homeostasis at a central level (Diano, Kalra et al. 1998). In addition to anatomic overlapping of their receptors, there is a complex interaction between estrogens and leptin signaling in the regulation of energy balance and body fat. Estrogens interact with leptin to mediate its inhibition of feeding behavior. Estrogens cross the blood–brain barrier, bind to estrogen receptors throughout the brain including several

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Gender Difference in Leptin Production and Leptin Sensitivity

117

hypothalamic nuclei, and reduce food intake and body weight. Neurons in the arcuate nucleus express both estrogen receptors and the long form of leptin receptor (Diano, Kalra et al. 1998). Estrogens reportedly influence leptin receptor expression. Ovariectomy causes a marked reduction in expression of the long form of leptin receptor in the hypothalamus, and estradiol replacement restores its expression (Kimura, Irahara et al. 2002; Meli, Pacilio et al. 2004). Additionally, when delivered locally into the cerebral ventricles, estradiol decreases food intake through its actions on the same proopiomelanocortin neurons that are responsible for leptin's anorectic responses (Gao, Mezei et al. 2007). Thus, there is a closely coupled interaction between leptin and estrogens on proopiomelanocortin neurons in the regulation of behavioral and neuroendocrine mechanisms of energy homeostasis (Shi, Seeley et al. 2009).

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

CONCLUSION Obesity-related metabolic disorders are much lower in premenopausal women than men; however, there is a dramatic increase following menopause in women. The health risks associated with obesity vary depending on the location of adipose tissue. Adipose tissue distributed in the abdominal visceral carry a much greater risk for metabolic disorders than does adipose tissue distributed subcutaneously. There are distinct sex-dependent differences in the regional fat distribution. Women carry more fat subcutaneously whereas men carry more fat viscerally. Males and females differ with respect to their regulation of energy homeostasis. Leptin is a hormone secreted by the adipocytes to serve as a signal to the central nervous system to regulate energy homeostasis. Peripheral adiposity hormone leptin and sex hormones directly influence energy balance. Key areas within the hypothalamus integrate the peripheral adiposity signal leptin to maintain overall adiposity levels, and these brain regions are directly influenced by sex hormones. As a result, males and females also appear to have important differences in the systems that regulate energy balance and body weight. Specifically, females store energy in the subcutaneous depot when energy is surfeit and utilize subcutaneous fat under energy-challenged conditions in which less energy is taken in than is expended in metabolism. Females tend to adjust the energy expenditure whereas males adjust the energy intake side of the energy balance equation. Males and females respond differently to leptin, the adiposity signal, with females being more sensitive to leptin than males. There appears to have commonality among the intracellular signaling pathways activated by leptin and estrogen. Leptin signaling activates the phosphoinositide 3-kinase (PI3K) / STAT3 pathway and their actions depend on PI3K activation (Niswender and Schwartz 2003). Estrogen also activates the PI3K/STAT3 signaling cascade (Malyala, Zhang et al. 2008). More research is needed to better understand the cross-talk between leptin and estrogen signaling at a molecular level. These large differences between males and females in the regulation of energy homeostasis suggest the need for potentially different strategies for males and females to produce therapeutic weight loss. Unfortunately very little work actually addresses these potentially important differences between males and females. It is our contention that much more research must be done to understand how males and females differ and how approaches to weight loss can be tailored to each sex.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

118

Haifei Shi

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

REFERENCES Ainslie, D. A., M. J. Morris, et al. (2001). "Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y." Int. J. Obes. Relat. Metab. Disord. 25(11): 1680-1688. Allison, D. B., K. R. Fontaine, et al. (1999). "Annual deaths attributable to obesity in the United States." JAMA 282(16): 1530-1538. Bennett, P. A., K. Lindell, et al. (1998). "Differential expression and regulation of leptin receptor isoforms in the rat brain: effects of fasting and oestrogen." Neuroendocrinology 67(1): 29-36. Blum, W. F., P. Englaro, et al. (1997). "Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone." J. Clin. Endocrinol. Metab. 82(9): 2904-2910. Brann, D. W., L. De Sevilla, et al. (1999). "Regulation of leptin gene expression and secretion by steroid hormones." Steroids 64(9): 659-663. Casabiell, X., V. Pineiro, et al. (1998). "Gender differences in both spontaneous and stimulated leptin secretion by human omental adipose tissue in vitro: dexamethasone and estradiol stimulate leptin release in women, but not in men." J. Clin. Endocrinol. Metab. 83(6): 2149-2155. Chen, Y. and M. L. Heiman (2001). "Increased weight gain after ovariectomy is not a consequence of leptin resistance." Am. J. Physiol. Endocrinol. Metab. 280(2): E315-322. Clegg, D. J., L. M. Brown, et al. (2006). "Gonadal hormones determine sensitivity to central leptin and insulin." Diabetes 55(4): 978-987. Clegg, D. J., C. A. Riedy, et al. (2003). "Differential sensitivity to central leptin and insulin in male and female rats." Diabetes 52(3): 682-687. Demerath, E. W., B. Towne, et al. (1999). "Serum leptin concentration, body composition, and gonadal hormones during puberty." Int. J. Obes. Relat. Metab. Disord. 23(7): 678685. Diano, S., S. P. Kalra, et al. (1998). "Leptin receptors in estrogen receptor-containing neurons of the female rat hypothalamus." Brain Res. 812(1-2): 256-259. Dua, A., M. I. Hennes, et al. (1996). "Leptin: a significant indicator of total body fat but not of visceral fat and insulin insensitivity in African-American women." Diabetes 45(11): 1635-1637. Eckel, R. H., W. W. Barouch, et al. (2002). "Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on the Pathophysiology of Obesity-Associated Cardiovascular Disease." Circulation 105(24): 2923-2928. Elbers, J. M. H., H. Asscheman, et al. (1997). "Reversal of the sex difference in serum leptin levels upon cross-sex hormone administration in transsexuals." J. Clin. Endocrinol. Metab. 82(10): 3267-3270. Elbers, J. M. H., G. W. d. V. De Roo, et al. (1999). "Effects of administration of 17βoestradiol on serum leptin levels in healthy postmenopausal women." Clin. Endocrinol. (Oxf) 51(4): 449-454.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Gender Difference in Leptin Production and Leptin Sensitivity

119

Erturth, E. M. and B. Ahrén (2000). "The negative association between serum free testosterone and leptin is dependent on insulin-like growth factor-binding protein 1 in healthy young and middle-aged men." Clin. Endocrinol. (Oxf) 52(4): 493-498. Ford, E., W. Giles, et al. (2002). "Prevalence of the metabolic syndrome among US adults findings from the third National Health and Nutrition Examination Survey." JAMA 287: 356 - 359. Fried, S. K. and J. G. Kral (1987). "Sex differences in regional distribution of fat cell size and lipoprotein lipase activity in morbidly obese patients." Int. J. Obes. 11(2): 129-140. Gao, Q. and T. L. Horvath (2008). "Cross-talk between estrogen and leptin signaling in the hypothalamus." Am. J. Physiol. Endocrinol. Metab. 294(5): E817-826. Gao, Q., G. Mezei, et al. (2007). "Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals." Nat. Med. 13(1): 89-94. Garcia-Mayor, R. V., M. A. Andrade, et al. (1997). "Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones, and pubertal stage." J. Clin. Endocrinol. Metab. 82(9): 2849-2855. Gower, B. A., T. R. Nagy, et al. (2000). "Leptin in postmenopausal women: influence of hormone therapy, insulin, and fat distribution." J. Clin. Endocrinol. Metab. 85(5): 17701775. Hadji, P., O. Hars, et al. (2000). "The influence of menopause and body mass index on serum leptin concentrations." Eur. J. Endocrinol. 143(1): 55-60. Hardie, L. J., D. V. Rayner, et al. (1996). "Circulating leptin levels are modulated by fasting, cold exposure and insulin administration in lean but not Zucker (fa/fa) rats as measured by ELISA." Biochem. Bioph. Res. Co 223(3): 660-665. Havel, P. J., S. Kasim-Karakas, et al. (1996). "Gender differences in plasma leptin concentrations." Nat. Med. 2(9): 949-950. Isidori, A. M., M. Caprio, et al. (1999). "Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels." J. Clin. Endocrinol. Metab. 84(10): 3673-3680. Jahan, S., R. Zinnat, et al. (2009). "Gender differences in serum leptin concentrations from umbilical cord blood of newborn infants born to nondiabetic, gestational diabetic and type-2 diabetic mothers." Int. J. Diabetes Dev. Ctries 29(4): 155-158. Jenkins, A. B., K. Samaras, et al. (2001). "Lack of heritability of circulating leptin concentration in humans after adjustment for body size and adiposity using a physiological approach." Int. J. Obes. Relat. Metab. Disord. 25(11): 1625-1632. Jockenhovel, F., W. F. Blum, et al. (1997). "Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men." J. Clin. Endocrinol. Metab. 82(8): 2510-2513. Kapoor, D., S. Clarke, et al. (2007). "The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes." Eur. J. Endocrinol. 156(5): 595-602. Kimura, M., M. Irahara, et al. (2002). "The obesity in bilateral ovariectomized rats is related to a decrease in the expression of leptin receptors in the brain." Biochem. Bioph. Res. Co 290(4): 1349-1353. Konukoglu, D., Ö. Serin, et al. (2000). "Plasma leptin levels in obese and non-obese postmenopausal women before and after hormone replacement therapy." Maturitas 36(3): 203-207.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

120

Haifei Shi

Kristensen, K., S. B. Pedersen, et al. (1999). "Regulation of leptin by steroid hormones in rat adipose tissue." Biochem. Biophys. Res. Commun. 259(3): 624-630. Kristensen, K., S. B. Pedersen, et al. (2000). "Interactions between sex steroid hormones and leptin in women. Studies in vivo and in vitro." Int. J. Obes. Relat. Metab. Disord. 24(11): 1438-1444. Lambert, C. P., D. H. Sullivan, et al. (2003). "Megestrol acetate-induced weight gain does not negatively affect blood lipids in elderly men: effects of resistance training and testosterone replacement." J. Gerontol. A Biol. Sci. Med. Sci. 58(7): 644-647. Lefebvre, A. M., M. Laville, et al. (1998). "Depot-specific differences in adipose tissue gene expression in lean and obese subjects." Diabetes 47(1): 98-103. Luukkaa, V., U. Pesonen, et al. (1998). "Inverse correlation between serum testosterone and leptin in men." J. Clin. Endocrinol. Metab. 83(9): 3243-3246. Luukkaa, V., J. Rouru, et al. (2000). "Acute inhibition of oestrogen biosynthesis does not affect serum leptin levels in young men." Eur. J. Endocrinol. 142(2): 164-169. Luukkaa, V., E. Savontaus, et al. (2001). "Effects of estrous cycle and steroid replacement on the expression of leptin and uncoupling proteins in adipose tissue in the rat." Gynecol. Endocrinol. 15(2): 103-112. Machinal, F., M.-N. Dieudonne, et al. (1999). "In vivo and in vitro ob gene expression and leptin secretion in rat adipocytes: Evidence for a regional specific regulation by sex steroid hormones." Endocrinology 140(4): 1567-1574. Malyala, A., C. Zhang, et al. (2008). "PI3K signaling effects in hypothalamic neurons mediated by estrogen." J. Comp. Neurol. 506(6): 895-911. Mannucci, E., A. Ognibene, et al. (1998). "Relationship between leptin and oestrogens in healthy women." Eur. J. Endocrinol. 139(2): 198-201. Masuzaki, H., Y. Ogawa, et al. (1995). "Human obese gene expression. Adipocyte-specific expression and regional differences in the adipose tissue." Diabetes 44(7): 855-858. Matsuda, J., I. Yokota, et al. (1997). "Serum leptin concentration in cord blood: relationship to birth weight and gender." J. Clin. Endocrinol. Metab. 82(5): 1642-. Meli, R., M. Pacilio, et al. (2004). "Estrogen and raloxifene modulate leptin and its receptor in hypothalamus and adipose tissue from ovariectomized rats." Endocrinology 145(7): 3115-3121. Milewicz, A., B. Bidzinska, et al. (2000). "Influence of obesity and menopausal status on serum leptin, cholecystokinin, galanin and neuropeptide Y levels." Gynecol. Endocrinol. 14(3): 196-203. Montague, C. T., J. B. Prins, et al. (1997). "Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution." Diabetes 46(3): 342-347. Montague, C. T., J. B. Prins, et al. (1998). "Depot-related gene expression in human subcutaneous and omental adipocytes." Diabetes 47(9): 1384-1391. Morley, J. E. and H. M. Perry (2000). "Androgen deficiency in aging men: Role of testosterone replacement therapy." J. Lab. Clin. Med. 135(5): 370-378. Nazian, S. J. (2001). "Leptin secretion from the epididymal fat pad is increased by the sexual maturation of the male rat." J. Androl. 22(3): 491-496. Nedvídková, J., M. Haluzík, et al. (1997). "The decrease of serum leptin levels in oestrogentreated male mice." Physiol. Res. 46(4): 291-294.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Gender Difference in Leptin Production and Leptin Sensitivity

121

Niswender, K. D. and M. W. Schwartz (2003). "Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities." Frontiers in Neuroendocrinology 24(1): 1-10. Nowicki, M., W. Bryc, et al. (2001). "Hormonal regulation of appetite and body mass in patients with advanced prostate cancer treated with combined androgen blockade." J. Endocrinol. Invest. 24(1): 31-36. O'Neil, J. S., M. E. Burow, et al. (2001). "Effects of estrogen on leptin gene promoter activation in MCF-7 breast cancer and JEG-3 choriocarcinoma cells: selective regulation via estrogen receptors alpha and beta." Mol. Cell Endocrinol. 176(1-2): 67-75. Ostlund, R., Jr, J. Yang, et al. (1996). "Relation between plasma leptin concentration and body fat, gender, diet, age, and metabolic covariates." J. Clin. Endocrinol. Metab. 81(11): 3909-3913. Pelleymounter, M. A., M. B. Baker, et al. (1999). "Does estradiol mediate leptin's effects on adiposity and body weight?" Am. J. Physiol. Endocrinol. Metab. 276(5): E955-963. Pineiro, V., X. Casabiell, et al. (1999). "Dihydrotestosterone, stanozolol, androstenedione and dehydroepiandrosterone sulphate inhibit leptin secretion in female but not in male samples of omental adipose tissue in vitro: lack of effect of testosterone." J. Endocrinol. 160(3): 425-432. Pinilla, L., L. Seoane, et al. (1999). "Regulation of serum leptin levels by gonadal function in rats." Eur. J. Endocrinol. 140(5): 468-473. Quinton, N. D., R. F. Smith, et al. (1999). "Leptin binding activity changes with age: the link between leptin and puberty." J. Clin. Endocrinol. Metab. 84(7): 2336-2341. Rocha, M., E. Grueso, et al. (2001). "The anorectic effect of oestradiol does not involve changes in plasma and cerebrospinal fluid leptin concentrations in the rat." J. Endocrinol. 171(2): 349-354. Rosenbaum, M. and R. L. Leibel (1999). "Role of gonadal steroids in the sexual dimorphisms in body composition and circulating concentrations of leptin." J. Clin. Endocrinol. Metab. 84(6): 1784-1789. Ryan, A. S., B. J. Nicklas, et al. (2002). "Hormone replacement therapy, insulin sensitivity, and abdominal obesity in postmenopausal women." Diabetes Care 25(1): 127-133. Saad, M. F., S. Damani, et al. (1997). "Sexual dimorphism in plasma leptin concentration." J. Clin. Endocrinol. Metab. 82(2): 579-584. Samaras, K., C. S. Hayward, et al. (1999). "Effects of postmenopausal hormone replacement therapy on central abdominal fat, glycemic control, lipid metabolism, and vascular factors in type 2 diabetes: a prospective study." Diabetes Care 22(9): 1401-1407. Schwartz, M. W., S. C. Woods, et al. (2000). "Central nervous system control of food intake." Nature 404(6778): 661-671. Shi, H., R. J. Seeley, et al. (2009). "Sexual differences in the control of energy homeostasis." Front Neuroendocrinol. 30(3): 396-404. Shi, H., J. E. Sorrell, et al. (2010). "The roles of leptin receptors on POMC neurons in the regulation of sex-specific energy homeostasis." Physiol. Behav. In Press, Corrected Proof. Shimizu, H., K. I. Ohtani, et al. (1998). "Orchiectomy and response to testosterone in the development of obesity in young Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats." Int. J. Obes. Relat. Metab. Disord. 22(4): 318-324.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

122

Haifei Shi

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Shimizu, H., Y. Shimomura, et al. (1997). "Estrogen increases in vivo leptin production in rats and human subjects." J. Endocrinol. 154(2): 285-292. Van Harmelen, V., S. Reynisdottir, et al. (1998). "Leptin secretion from subcutaneous and visceral adipose tissue in women." Diabetes 47(6): 913-917. Wabitsch, M., W. F. Blum, et al. (1997). "Contribution of androgens to the gender difference in leptin production in obese children and adolescents." J. Clin. Invest. 100(4): 808-813. Wang, Y., M. A. Beydoun, et al. (2008). "Will all Americans become overweight or obese? Estimating the progression and cost of the US obesity epidemic." Obesity 16(10): 23232330. Watanobe, H. and S. Habu (2003). "Manipulation of neonatal gonadal steroid milieu and leptin secretion in later life in male and female rats." Regul. Pept. 110(3): 219-224. Watanobe, H. and T. Suda (1999). "A detailed study on the role of sex steroid milieu in determining plasma leptin concentrations in adult male and female rats." Biochem. Biophys. Res. Commun. 259(1): 56-59. Wu-Peng, S., M. Rosenbaum, et al. (1999). "Effects of exogenous gonadal steroids on leptin homeostasis in rats." Obes. Res. 7(6): 586-592. Yoneda, N., S. Saito, et al. (1998). "The influence of ovariectomy on ob gene expression in rats." Horm. Metab. Res. 30(05): 263-265. Zumoff, B., G. W. Strain, et al. (1990). "Plasma free and non-sex-hormone-binding-globulinbound testosterone are decreased in obese men in proportion to their degree of obesity." J. Clin. Endocrinol. Metab. 71(4): 929-931.

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

In: Leptin: Hormonal Functions, Dysfunctions and Clinical Uses ISBN: 978-1-61122-891-5 Editors: Rose M. Hemling and Arthur T. Belkin ©2011 Nova Science Publishers, Inc.

Chapter 7

THE ROLE AND APPLICATION OF LEPTIN IN CONTROL OF FEMALE REPRODUCTIVE FUNCTIONS Alexander V. Sirotkin1, 2 1. Animal Production Research Centre, Luzianky, Slovakia 2. Constantine the Philosopher University, Nitra, Slovakia

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

ABSTRACT Leptin, a product of adipose and some other tissues, which production is promoted by food intake and other stimuli, can be an important hormone through which different external factors affect reproductive processes. Leptin can affect reproduction through the hypothalamo-hypophysial system and by direct action on gonads. Regarding the effects of leptin at CNS level, some reports demonstrated a stimulatory influence of leptin on production of hypothalamic GnRH and hypophysial hormones. Regarding direct effects on the ovary, leptin was found to affect growth, ovulation of ovarian follicles and corpus luteum development, ovarian cell proliferation, apoptosis, secretory activity, oocyte maturation and developmental competence, as well as fecundity. Extra- and intracellular mechanisms of leptin action at central and ovarian level can include hormones (GnRH, gonadotropins and other pituitary hormones, pro-opiomelanocortin, kisspeptin and neuropeptide Y, steroid and nonapeptide hormones, prostaglandins, IGF-I/IGFBP system, VEGF and their receptors), several protein kinases and transcription factors. Serum leptin level can be used to predict development of a number of reproductive disorders including ovarian cancer.

Keywords: Leptin, proliferation, apoptosis, hormone, oocyte, ovary

Alexander V. Sirotkin, Institute of Genetics and Reproduction, Animal Production Research Centre, Hlohovecká 2, 951 41 Luzianky near Nitra, Slovakia. Tel: +421-37-6546335, Fax: +421-37-6546480, E-mail: [email protected].

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

124

Alexander V. Sirotkin

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

1. INTRODUCTION Leptin is a 16 kDa protein hormone, product of adipose and some other tissues, which production is promoted by food intake, obesity and other factors. It is considered as an important hormone through which metabolic, nutritional and other external factors control a wide variety of physiological processes – food intake, growth, metabolism, energy expenditure, motivation, learning, memory, cognitive function, neuroprotection, immune response and more, including reproduction (Duggal et al., 2002b; Doucet and Cameron, 2007; Klok et al., 2007; Morrison, 2009). Reproductive function is sensitive to the metabolic state of the organism. Synchronization of reproduction with optimal conditions requires signalling substance(s) mediating effect of these conditions on reproductive processes. Puberty and start of reproduction is associated with increased production of leptin by adipose tissue and its receptors in hypothalamus (cow: Williams et al., 2002; Barb and Kraeling, 2004; pig: Barb and Kraeling, 2004; Barb et al., 2005,2008; humans: Pinelli and Tagliabue, 2007). Leptin can be mediator of effect of good nutritional conditions (food availability/developed adipose tissue – ruminants: Spicer, 2001; Miller et al., 2007; Wójcik-Gładysz et al., 2009; human: Klok et al., 2007; Pinelli and Tagliabue, 2007; rat: Duggal et al., 2002b; Tena-Sempere, 2007; mice: Leshan et al., 2009), breeding season (sheep: Zieba et al., 2008; siberian hamster, field vole: Tups, 2009; fruit bat: Banerjee et al., 2010), presence of mate (odorant stimuli – mice: Leshan et al., 2009), pregnancy (women: Henson and Castracane, 2006; Pinelli and Tagliabue, 2007; rat: Tups, 2009) and steroid hormones (women: Henson and Castracane, 2006) on reproductive processes. Leptin can affect reproduction both through the hypothalamo-hypophysial system and by direct action on gonads. The growing body of evidence demonstrates an importance of leptin in control of such key reproductive processes as ovarian cell proliferation, apoptosis, hormone release, oocyte maturation, ovarian follucullogenesis and luteogenesis and fecundity. The previous reviews concerning the role of leptin in control of female reproduction, do not include recent finding in this area (Smith et al., 2001; Spicer, 2001), or they are focused mainly on CNS targets of leptin (Barb and Kraeling, 2004; Barb and Hausman, 2005; Barb et al., 2005; Tena-Sempere, 2007; Castellano et al., 2009; Morrison, 2009; Tups, 2009; Hausman and Barb, 2010). The present paper aims to review contemporarily data concerning involvement of leptin in control of female reproduction at both CNS and ovarian level, to outline possible mechanisms of leptin action on target structures, as well as the areas of potential practical application of this hormone in control of ovarian functions and treatment of ovarian disorders. The role of leptin in control of embryogenesis, pregnancy and gestation, which has been described in a special review (Henson and Castracane, 2006) has not been discussed here.

2. INVOLVEMENT OF LEPTIN IN CONTROL OF FEMALE REPRODUCTION VIA HYPOTHALAMO-HYPOPHYSIAL SYSTEM Presence of leptin receptors in hypothalamic ventral premammillary nucleus, which cells are innervating and controlling GnRH-producing cells in anterior preoptic area and mediobasal hypothalamus have been demonstrated (rat: Reynoso et al., 2007; Donato et al., 2009; mice: Leshan et al., 2009; pig: Barb et al., 2005; Hausman and Barb, 2010; sheep:

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

The Role and Application of Leptin in Control of Female…

125

Miller et al., 2007; Backholer et al., 2010). Leptin receptors are present in other hypothalamic areas, for example producing pro-opiomelanocortin (mice: Hill et al., 2010; sheep: Backholer et al., 2010), kisspeptin and neuropeptide Y (rat: Castellano et al., 2009; sheep: Backholer et al. 2010) and agouti-related peptide (pig: Barb et al., 2005), whose are also involved in control of GnRH. There observations provide indirect evidence, that leptin can control hypothalamic signaling substances involved in control of reproduction. Effect of alteration in leptin level on these substances listed below provide direct evidence, that leptin can control physiological regulators of reproduction at hypothalamic and pituitary level and mediate effect of some external factors on these regulators.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

2.1. Leptin Controls Hypothalamic and Pituitary Hormones Regulating Reproductive Functions It is well documented, that food restriction can suppress reproductive processes through inhibition of production/accumulation of hypothalamic GnRH and production/release of pituitary gonadotropins (LH and FSH) (cow: Williams et al., 2002; Barb and Kraeling, 2004; pig: Barb et al. 2005; Hausman and Barb, 2010; sheep: Barb and Kraeling, 2004; Zieba et al., 2008; Wójcik-Gładysz et al., 2009). Fasting reduces both leptin and LH release and disrupts estrous cycles, whist leptin administration prevents effect of food restriction on these reproductive events (cow: Williams et al., 2002; Barb et al., 2008; pig: Barb et al., 2008; human: Klok et al., 2007; Pinelli and Tagliabue, 2007; rat: Donato et al., 2009; sheep: Munoz-Gutierrez et al., 2005; Miller et al., 2007; Wójcik-Gładysz et al,. 2009). In mares fasting reduces leptin, but not FSH and LH release (Gastal et al., 2010). Furthermore, leptin administration can activate secretion of hypothalamic LH-RH and hypophysial gonadotropins (cow: Smith et al., 2001; Spicer, 2001; Barb and Kraeling, 2004; sheep: Barb and Kraeling, 2004; Munoz-Gutierrez et al., 2005; Zieba et al., 2008; Wójcik-Gładysz et al., 2009; pig: Barb and Kraeling, 2004; Barb et al., 2005; Hausman and Barb, 2010; rat: Reynoso et al., 2007; Tena-Sempere, 2007; Donato et al., 2009). Direct and relatively independent stimulatory influence of leptin on GnRH and LH has been demonstrated (cow: Miller et al., 2002; Hausman and Barb, 2010; pig: Barb et al., 2005). Furthermore, leptin can activate release of pituitary GH (cow, pig: Barb and Kraeling, 2004; Barb et al., 2005), a known promoter of reproduction in these and other species (Sirotkin, 2005). In addition, the action of leptin on reproductive processes via pituitary prolaction and melatonin has been also proposed (sheep: Zieba et al., 2008). No effect of leptin on hormone receptors in hypothalamo-hypophysial system have been reported. These data suggest that good nutritional conditions can promote reproductive processes in different species via stimulation of leptin release, which in turm promotes production of hypothalamic GnRH and pituitary hormonal stimulators of reproduction.

2.2. Mechanisms of Leptin Action on Hypothalamic and Pituitary Hormones Regulating Reproductive Functions Presence of leptin receptors on GnRH neurons and action of leptin on these neurons (see above) demonstrates, that leptin can directly affect production of hypothalamic GnRH and

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

126

Alexander V. Sirotkin

GHRH-dependent pituitary gonadotropins. Furthermore, leptin directly affects LH secretion from the pituitary gland independent of CNS input (cow: Moiller et al., 2002; Barb et al., 2005; Hausman and Barb, 2010). Presence of leptin receptors also in hypothalamic neurons producing pro-opiomelanocortin (mice: Hill et al., 2010) and kisspeptin (mice, sheep: Backholer et al. 2010), morphological and functional interrelationships between hypothalamic and adipose tissue cells producing leptin, pro-opiomelanocortin, kisspeptin, neuropeptide Y (cow, sheep: Williams et al., 2002; Barb and Kraeling, 2004; Hausman and Barb, 2010; rat: Castellano et al., 2009; Donato et al., 2009; mice: Leshan et al., 2009) and agouti-related peptide (pig: Barb et al., 2005) were documented. Leptin can suppress neuropeptide Y and agouti-related peptide and up-regulate pro-opiomelanocortin (pig: Barb et al., 2005). The action of these molecules on hypothalamic GnRH and pituitary gonadotropins in-vivo and invitro (cow, sheep: Williams et al., 2002; Barb and Kraeling, 2004; Miller et al., 2007; Hausman and Barb, 2010; rat: Reynoso et al., 2007; Donato et al., 2009) or lesion of hypotlalamic structures producing these molecules on GnRH-gonadotropin axis (sheep: Miller et al., 2007; Backholer et al. 2010) suggest, that leptin can control GnRH not only directly, but via hypothalamic pro-opiomelanocortin, kisspeptin, agouti-related peptide and neuropeptide Y. It is proposed, that leptin control hypothalamic kisspeptin cells, whose in turn communicate with ether neuropeptide Y and/or proopiomelanocortin and agouti-related peptide cells (Bar bet al., 2005; Castellano et al., 2009; Backholer et al. 2010). Intracellular post-receptory mediators of leptin action on hypothalamic cells are poorly investigated. Glutamate and GABA are involved in the hypothalamic control of Gn-RH neurons. Leptin can affect both glutamate and LH-RH in rat hypothalamus, whilst inhibitor of nitric oxide synthase prevented this leptin effect. Therefore, hypothalamic leptin can affect hypothalamic GnRH via stimulation of nitric oxide production which in turn modifies the release of amino acid neurotransmitters involved in Gn-RH control (Reynoso et al., 2007). Leptin infusions decreased Fos immunoreactivity in the anteroventral periventricular nucleus and in gonadotropin releasing hormone neurons (rat: Donato et al., 2009; mice: Leishan et al., 2009) suggesting, that Fos can be involved in mediation leptin action on these structures. In Siberian hamster, field vole and rat leptin receptors in hypotalamus are coupled with the Janus kinase 2 (JAK2)-STAT3 signalling pathway including signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signalling (SOCS3), protein tyrosine phosphatase 1B (PTP1B) (Tups, 2009), It remain to be establish, whether this intracellular signalling systém mediates effect of leptin on hypothalamic regulators of reproduction.

3. INVOLVEMENT OF LEPTIN IN CONTROL OF FEMALE REPRODUCTION VIA DIRECT ACTION ON THE OVARY Regarding direct effects on the ovary, leptin and its receptors in ovaries have been described (rabbit: Zerani et al., 2004; rat: Duggal et al., 2002a; Ricci et al., 2006; da Silva et al., 2009; ewe: Muñoz-Gutiérrez et al., 2005; cow: Nicklin et al., 2007; Sarkar et al., 2010; women: Uddin et al., 2009; pig: Smolinska et al., 2009; mouse: Ye et al., 2009; fruit bat – Banerjee et al., 2010; mare: Gastal et al., 2010), whist their expression was changed during estrus cycles and pregnancy. These observations suggest the intraovarian production and

Hemling, Rose M., and Arthur T. Belkin. Leptin : Hormonal Functions, Dysfunctions and Clinical Uses, Nova Science Publishers, Incorporated, 2011.

The Role and Application of Leptin in Control of Female…

127

action of leptin, which can be involved in autocrine/paracrine regulation of ovarian functions. Effects of leptin on ovarian cell proliferation, apoptosis, secretory activity, oocyte maturation listed below provide direct evidence for involvement of leptin in direct control of these ovarian cell functions.

3.1. Leptin Controls Ovarian Cell Proliferation

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Regarding ovarian cell proliferation, leptin deficiency was not associated with changes in PCNA (a marker of DNA synthesis, replication/repair and of S/phase of mitosis; rat: Duggal et al., 2002b; mice: Hamm et al., 2004) or cell number (women: Huang et al., 2002).

From Sirotkin et al., 2008. Figure 1. Stimulatory effect of leptin additions (0, 1, 10 or 100 ng/ml) on the percentage of cultured human ovarian granulosa cells containing markers of proliferation PCNA, cyclin B1 (top) and protein kinase A (bottom). Data from immunocytochemistry. Values are mean±SEM; *significant (P