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Physiological Consequences of Brain Insulin Action The brain is crucial for the regulation of w hole-body metabolism and behavior. The p ancreas-derived hormone insulin modulates brain function and affects energy metabolism as well as cognition. This is partially achieved by modulating several types of brain cell populations including those relevant to sati- ety and reward. Importantly, brains of Alzheimer’s disease patients exhibit a signature of brain insulin resistance with perturbed brain metabolism. This book will cover the basics of insulin signaling in the brain and will describe concepts of insulin resistance, a feature of type 2 diabetes. Moreover, insulin’s effect on cognitive function will be pointed out and the association between brain insulin resistance and neurodegenerative diseases discussed. Additionally, potential behavioral and pharmacological concepts which can affect brain insulin signaling will be summarized. Key Features: • Summarizes insulin and the closely related I GF-1 receptor signaling • Depicts concepts of insulin resistance • Highlights the importance of conserved brain insulin signaling for brain function, metabolism, and behavior • Describes potential behavioral and pharmacological approaches to support brain insulin signaling Oxidative Stress and Disease Series Editor: Enrique Cadenas, MD, PhD Helmut Sies, MD University of Southern California School of Pharmacy Los Angeles, California PUBLISHED TITLES Mitochondria in Liver Disease edited by Derick Han and Neil Kaplowitz Fetal and Early Postnatal Programming and its Influence on Adult Health edited by Mulchand S. Patel and Jens H. Nielsen Biomedical Application of Nanoparticles edited by Bertrand Rihn The Biology of the First 1,000 Days edited by Crystal D. Karakochuk, Kyly C. Whitfield, Tim J. Green, and Klaus Kraemer Hydrogen Peroxide Metabolism in Health and Disease edited by Margreet C M Vissers, Mark Hampton, and Anthony J. 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Davison Physiological Consequences of Brain Insulin Action edited by André Kleinridders For more information about this series, please visit: https://www.crcpress.com/Oxidative-Stress-and-Disease/book-series/CRCOXISTRDIS Physiological Consequences of Brain Insulin Action Edited by André Kleinridders First edition published 2023 by CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 and by CRC Press 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN CRC Press is an imprint of Taylor & Francis Group, LLC © 2023 André Kleinridders Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. 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ISBN: 9780367529482 (hbk) ISBN: 9780367529512 (pbk) ISBN: 9781003079927 (ebk) DOI: 10.1201/9781003079927 Typeset in Joanna by codeMantra CONTENTS Series Preface / vii 7 • INSULIN AND BRAIN REWARD SYSTEMS / 105 Preface / ix Brian C. Liu, Qingchen Zhang, and Acknowledgements / xi Emmanuel N. Pothos Editor / xiii 8 • THE IMPACT OF INSULIN ON Contributors / xv BRAIN SEROTONERGIC SYSTEM: Abbreviations / xxi CONSEQUENCES ON DIABETES- ASSOCIATED MOOD DISORDERS / 125 1 • MOLECULAR MECHANISMS OF BRAIN Hugo Martin, Sebastian Bullich, INSULIN SIGNALING / 1 Bruno P. Guiard, and Xavier Fioramonti Simran Chopra, Robert Hauffe, and André Kleinridders 9 • ORGAN CROSS-TALK REGULATES ( BRAIN) INSULIN ACTION / 139 2 • INSULIN/ IGF SIGNALING IN EARLY BRAIN Thomas Laeger DEVELOPMENT / 21 Selma Yagoub and Rachel Lippert 10 • INSULIN RESISTANCE AS A RISK FACTOR FOR ALZHEIMER’S DISEASE / 157 3 • INSULIN SIGNALING MODULATES Miren Ettcheto, Amanda Cano, Elena NEURONAL METABOLISM / 35 Sanchez-Lopez, Carme Auladell, Qian Huang, Jialin Fu, Kelly Anne Jaume Folch, and Antoni Camins Borges, and Weikang Cai 11 • BRAIN INSULIN ACTION IN THE 4 • REGULATION OF GLIAL FUNCTION BY CONTROL OF METABOLISM IN HUMANS / 177 INSULIN PEPTIDES / 53 Stephanie Kullmann Ana M. Fernandez, Laura Martinez- Rachadell, Patricia M iranda-Azpiazu, 12 • IMPACT OF DIETARY AND EXERCISE and Ignacio Torres Aleman INTERVENTIONS ON BRAIN INSULIN ACTION AND BRAIN FUNCTION / 195 Stefan Kabisch 5 • NEUROENDOCRINE INTERACTIONS IN THE CONTROL OF GLUCOSE- AND ENERGY HOMEOSTASIS / 63 13 • PHARMACOLOGICAL AND SURGICAL Kaj Kamstra and Alexander Tups INTERVENTIONS TO IMPROVE BRAIN INSULIN RESISTANCE / 219 Linus Haberbosch, Lukas Maurer, and 6 • HYPOTHALAMIC NEURONAL CIRCUITS ARE MODULATED BY INSULIN AND Reiner J umpertz-von Schwartzenberg IMPACT METABOLISM / 79 Tadeu de Oliveira Diz, Sabela Casado, Index / 237 Rubén Nogueiras, and Sulay Tovar v SERIES PREFACE PHYSIOLOGICAL CONSEQUENCES OF BRAIN INSULIN ACTION EDITOR: ANDRÉ KLEINRIDDERS THE EDITOR PHYSIOLOGICAL CONSEQUENCES OF BRAIN INSULIN ACTION Dr. André Kleinridders is a Professor for Experimental and Molecular Nutritional PHYSIOLOGICAL CONSEQUENCES OF BRAIN Medicine at the Institute of Nutritional Science INSULIN ACTION, focuses on different aspects at the University of Potsdam. Prof. Kleinridders’ of brain insulin and its regulation of a myriad of research programs address the impact of brain systemic effects ranging from starve-feed cycles insulin signaling on whole body pathophysiol- to behavioral patterns. This book is particularly ogy and behavior with implications for diabe- attractive because it places brain insulin signaling tes, obesity and neurodegeneration. His studies in the physiologic maintenance of whole-body focus on understanding the mechanisms of cen- homeostasis as well as impairment of brain insu- tral insulin resistance (involving impairment of lin signaling in the pathology of diabetes and obe- mitochondrial function) and its consequences sity. Moreover, brain insulin resistance is a critical on energy homeostasis and neurological altera- factor in the pathogenesis of Alzheimer’s dis- tions associated with aging. Dr. Kleinridders’ ease, sometimes termed diabetes type III, hence expertise in endocrinology and genetics expands the significance of brain insulin in modulation to areas of high significance for human patho- of cognitive functions. The book entails mecha- physiology, including metabolism, insulin signal- nistic aspects of brain insulin signaling and that ing, and insulin resistance, the latter an umbrella triggered by activation of the insulin-like growth term with implications for not only diabetes and factor receptor (IGF1R), the regulation of neuro- obesity but also for neurodegenerative disorders, nal circuits and how insulin modulates metabo- such as Alzheimer’s disease. His research focuses lism in different brain cell populations. How on insulin action in the brain and its effect on hypothalamic insulin signaling controls energy mitochondrial stress responses and reduction of metabolism, food intake, and behavior, is viewed diet-induced weight gain. His recent publica- among the systemic effects of brain insulin. tions establish Dr. Kleinridders’ unique research These chapters expand the effects of brain insu- focus on the role of brain insulin in human lin in terms of insulin resistance as it occurs in pathophysiology. type 2 diabetes and Alzheimer’s disease as well vii as diseases associated with protein misfolding. insulin resistance and its impairment of whole- Pharmacological and dietary interventions that body homeostasis and association with cognitive have the potential to overcome insulin resistance deficits. are also addressed. Overall, the major thrust of this book is the rec- ENRIQUE CADENAS HELMUT SIES ognition of the multifaceted effects of brain insulin and its signaling pathways not only in the brain Series Editors and in different brain cell populations but how Oxidative Stress and Disease brain insulin modulates systemic tissue functions. This acquires further relevance in terms of brain viii OXIDATIVE STRESS AND DISEASE Kleinridders PREFACE The discovery of insulin represents a land- of brain insulin resistance is not only a feature mark achievement in medical sciences. Insulin of unhealthy obesity but is also observed in the was discovered by Frederick Grant Banting and brains of patients suffering from Alzheimer’s dis- Charles Herbert Best in the laboratory of John ease. Together, these observations highlight the James Rickard McLeod more than 100 years importance of the precise regulation of insulin ago and saved millions of lives from a formerly action in the central nervous system for a healthy non-curable disease. While type 1 diabetes is metabolism and proper cognitive function. characterized by insulin deficiency, which can be treated by the administration of insulin, the This book will cover the molecular mechanisms majority of patients suffer from type 2 diabetes. of insulin signaling and the establishment of insu- These patients exhibit initially reduced sensitiv- lin resistance. As the brain shows r egion-specific ity to insulin, known as insulin resistance. Insulin differences in terms of function and cell compo- resistance causes reduced glucose uptake in skel- sition, c ell- and r egion-specific effects of insulin etal muscle and adipose tissue. In the liver, insu- action are discussed. Diabetes-associated disorders lin resistance causes deteriorated hepatic glucose including mood disorders and neurodegenerative production, leading to elevated blood glucose lev- diseases will be described and associated with els overall. Although glucose uptake in the brain brain insulin resistance. The complex interac- is mostly independent of insulin, insulin and its tion of peripheral organs with the brain is char- receptor have already been detected in the late acterized to a great extent in this book, as is the 1960s and 1970s in the brain, and research over hormonal crosstalk of insulin with leptin in the the last decades has clearly demonstrated that the central nervous system. Importantly, novel insights brain is an insulin-sensitive organ. about brain insulin signaling in humans will be Insulin in the brain regulates food intake, explained in addition to behavioral and pharma- affects energy metabolism and glucose handling cological treatment options to counteract insulin in peripheral tissues and even modulates fertility. resistance. In summary, this book will provide a In addition, there is ample evidence that insulin comprehensive overview about the physiological exhibits neuroprotective function. The presence consequences of brain insulin action. ix