Handbook of Experimental Pharmacology

Transcription

1 Handbook of Experimental Pharmacology Volume 209 Editor-in-Chief F.B. Hofmann, München Editorial Board J.A. Beavo, Seattle J.E. Barrett, Philadelphia D. Ganten, Berlin P. Geppetti, Florence M.C. Michel, Ingelheim C.P. Page, London W. Rosenthal, Berlin For further volumes:

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3 Hans-Georg Joost Editor Appetite Control

4 Editor Hans-Georg Joost German Institute of Human Nutrition Department of Pharmacology Arthur-Scheunert-Allee Nuthetal Germany ISSN e-issn ISBN e-isbn DOI / Springer Heidelberg Dordrecht London New York Library of Congress Control Number: # Springer-Verlag Berlin Heidelberg 2012 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Printed on acid-free paper Springer is part of Springer Science+Business Media (

5 Preface The marked and continuing increase in the prevalence of obesity during few decades is one of the most remarkable characteristics of Western civilization. It profoundly affects the society not only with its consequences for public health but also with its economical and sociological/cultural aspects. As has been demonstrated by artifacts such as the Venus of Willendorf as well as by historical reports, obesity occurred in almost all societies as a rare condition among the rich and privileged. However, in the last decades of the twentieth century, a marked increase in its prevalence commenced in the USA, in Europe, and subsequently, also in parts of Asia, reaching epidemic proportions. There is little doubt that this increase reflects the influence of an adipogenic environment: the unlimited availability of food in combination with the development of particularly palatable, less satiating foods (the so-called fast food), together with a mechanization of all tasks, causing an inactive, sedentary lifestyle. So far, all efforts to halt this epidemic by changes in diet and lifestyle had little success: Triglycerides lost during an intervention are rapidly regained once the individual returns to the previous food choice and eating behavior, and few individuals manage to continue their intervention indefinitely. This observation appears to reflect the influence of a powerful biological system that controls not only energy balance, i.e., caloric intake, but also food choice and nutritional preferences. It is obvious that such a biological system controlling energy balance can comprise targets for a pharmacological intervention. Consequently, considerable efforts have been made in the past to elucidate the molecular basis of this system, to identify potential targets for intervention, and to discover agents inhibiting food intake by a reduction of appetite. As this volume will summarize, these efforts have led to a broad understanding of the mechanisms controlling food intake, to the identification of numerous targets for intervention, and also to several agents with appetite-inhibiting potency. However, so far, none of these agents have met the high safety standards required for the chronic treatment of obesity. Agents such as sibutramine and rimonabant that were in use for some time have been withdrawn because of unacceptable side effects. Thus, this volume cannot describe established and accepted therapeutics. Rather, its aim is to summarize the state of knowledge of v

6 vi Preface potential target proteins and mechanism in order to point out promising directions of future research. Thereby, the volume addresses pharmacologists, physiologists, neuroendocrinologists, and all other scientists who are interested in the field of obesity research. The first part of the volume presents a comprehensive description of the central mechanisms controlling food intake, and thereby energy balance, in the mammalian organism. During the last two decades, research in this area has produced a remarkable wealth of information and has characterized the function of numerous peptides and their receptors in a neuroendocrine network of appetite control. Chapters covering leptin, neuropeptide Y, MSH, AGRP, NMU, the orexins and neuromedins, and their respective receptors highlight this plethora of information. In addition, the central effects of insulin in modulating this network are covered in the first section. An often overlooked aspect of the obesity problem is its analogy with addictive behavior. Thus, the concluding chapter of the first section covers the role of reward systems in appetite control. It has been believed that dysfunction of the neuroendocrine circuitry leads to obesity, e.g., by alterations such as leptin resistance, but so far, no fully convincing, comprehensive molecular mechanism has been proposed. Thus, the question as to why individuals are sensitive or resistant to the adipogenic environment remains to be answered. The circuits controlling food intake depend on peripheral signals from sensors that monitor the availability of nutrients. Solid evidence has been accumulated, indicating that the gastrointestinal tract plays a major role in generating these signals. Therefore, the second section of the volume includes chapters covering the peptides ghrelin, GLP-1, CCK, PYY, PP, and amylin, as well as their receptors. More recently, it has become apparent that the intestinal tract plays an even more important role because its microbiota appears to modulate energy balance and, consequently, adiposity. Although the underlying mechanisms are largely unknown, it was appropriate to add a chapter covering these novel aspects to the second section of the volume. Three separate chapters describing the sensing of nutrients are included in the third section of the volume. The availability of glucose is assessed by a complex system of glucosensors in the CNS; at low glucose levels, these neurons trigger the sensation of hunger. The consumption of fat is also monitored, but the underlying molecular mechanisms are less well known. The current status of knowledge is described in the second chapter of the third section, with particular focus on the fatty acid transporter CD36. The molecular mechanisms of chemosensation of glucose, fatty acids, and amino acids in the intestinal mucosa are described in the third chapter of the section. These processes are controlled by nutrient-binding receptors, transporters, or ion channels that trigger the secretion of intestinal hormones. Interestingly, receptors recognizing sweet taste have been found recently in the intestinal mucosa, as is also described in the final chapter of the section. The current status of antiobesity drugs is described in the fourth section of the volume. In contrast to the plethora of mechanistic information described in the first three sections of the volume, at present, there are no antiobesity drugs available for the therapy of morbid obesity. This situation is not due to a lack of effective agents

7 Preface vii but to the presence of serious side effects which cannot be tolerated under conditions of a chronic therapy. The section describes the agents that have been in use and later withdrawn (reuptake inhibitors of catecholamines, e.g., sibutramine; cannabinoid antagonists, e.g., rimonabant) or have been investigated in clinical trials (HT-receptor antagonists, e.g., lorcaserine; MCH-receptor antagonists; antiepileptics, e.g., topiramate, zonisamide). Efforts are still being made to develop strategies minimizing the side effects of existing agents, for instance, by reduced dosage in drug combinations. An interesting strategy to prevent the psychiatric side effects of cannabinoid antagonists is the design of peripherally restricted derivatives. In addition, bombesin-3-receptor agonists, a more recently identified, promising group of appetite-inhibiting agents, are covered in a separate chapter. I am deeply grateful to the authors of the volume who have contributed excellent, informative, and comprehensive chapters to this volume. All authors are distinguished experts in their fields and have contributed important original data to our understanding of appetite control. They have quite different scientific backgrounds, and, together, they represent all relevant disciplines. Thereby, the topics are presented from different points of view, not exclusively from that of pharmacology. Thus, I believe that they have written a timely and unique overview on one of the most important areas of current research. I do hope that this volume will contribute to generate novel ideas, findings, and solutions to the pressing problem of obesity. Potsdam-Rehbrücke, Germany H.-G. Joost

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9 Contents Part I The Neuroendocrine, Hypothalamic Circuitry Regulating Hunger, Satiety, and Energy Expenditure Leptin Receptors... 3 Elizabeth C. Cottrell and Julian G. Mercer The Role of Neuropeptide Y in Energy Homeostasis Adam P. Chambers and Stephen C. Woods The Neuroendocrine Circuitry Controlled by POMC, MSH, and AGRP.. 47 Heike Biebermann, Peter Kühnen, Gunnar Kleinau, and Heiko Krude Neuropeptides Controlling Energy Balance: Orexins and Neuromedins Joshua P. Nixon, Catherine M. Kotz, Colleen M. Novak, Charles J. Billington, and Jennifer A. Teske The Central Insulin System and Energy Balance Denovan P. Begg and Stephen C. Woods Peripheral Signals Modifying Food Reward John R.W. Menzies, Karolina P. Skibicka, Emil Egecioglu, Gareth Leng, and Suzanne L. Dickson Part II Gastrointestinal Hormones and Factors The Role of Ghrelin in the Control of Energy Balance Henriette Kirchner, Kristy M. Heppner, and Matthias H. Tschöp Anorexigenic Effects of GLP-1 and Its Analogues Baptist Gallwitz ix

10 x Contents CCK, PYY and PP: The Control of Energy Balance K. Simpson, J. Parker, J. Plumer, and S. Bloom Effects of Amylin on Eating and Adiposity Thomas Alexander Lutz Intestinal Microbiota and Obesity Michael Blaut and Susanne Klaus Part III Nutrient Sensing Sensing of Glucose in the Brain Bernard Thorens Role of CD36 in Oral and Postoral Sensing of Lipids M. Chevrot, C. Martin, P. Passilly-Degrace, and P. Besnard Intestinal Sensing of Nutrients Gwen Tolhurst, Frank Reimann, and Fiona M. Gribble Part IV Agents Modifying Food Intake Reuptake Inhibitors of Dopamine, Noradrenaline, and Serotonin Ulrich Kintscher 5-HT 2C Receptor Agonists and the Control of Appetite Jason C.G. Halford and Joanne A. Harrold Central and Peripheral Cannabinoid Receptors as Therapeutic Targets in the Control of Food Intake and Body Weight Stefan Engeli Antiobesity Effects of Melanin-Concentrating Hormone Receptor 1 (MCH-R1) Antagonists Hyae Gyeong Cheon Appetite-Modifying Effects of Bombesin Receptor Subtype-3 Agonists Ishita Deb Majumdar and H. Christian Weber Weight-Reducing Side Effects of the Antiepileptic Agents Topiramate and Zonisamide J. Antel and J. Hebebrand Index