THE PHYSIOLOGICAL ACTIONS OF ADIPONECTIN IN CENTRAL AUTONOMIC NUCLEI: IMPLICATIONS FOR THE INTEGRATIVE CONTROL OF ENERGY HOMEOSTASIS

-----------------------------------------------------------------------------------------------ii CO-AUTHORSHIP --------------------------------------------------------------------------------------iv ACKNOWLEDGEMENTS ------------------------------------------------------------------------------v TABLE OF CONTENTS -------------------------------------------------------------------------------------vi LIST OF FIGURES --------------------------------------------------------------------------------------------ix LIST OF TABLES ----------------------------------------------------------------------------------------------xi LIST OF ABBREVIATIONS -------------------------------------------------------------------------------xii Chapter 1 : GENERAL INTRODUCTION ----------------------------------------------------------1 ADIPOSE TISSUE AS AN ENDOCRINE ORGAN -------------------------------------------------3 ADIPONECTIN: STRUCTURE AND FUNCTION -------------------------------------------------3 The generation of adiponectin knockout mice 5 The insulin sensitizing effects of adiponectin 7 ADIPONECTIN RECEPTORS: DISCOVERY ---------------------------------------------------8 The generation of adiponectin receptor knockout mice 12 SIGNAL TRANSDUCTION PATHWAYS OF THE ADIPONECTIN RECEPTORS ---13 ADIPONECTIN ACTIONS IN THE CENTRAL NERVOUS SYSTEM --------------------14 Effects on sympathetic nervous system activity and autonomic function 16 THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS -------------------17 Neural inputs to the PVN 18 Projections of the PVN 19 Neuronal Subtypes in the PVN: Morphological and Electrical Characteristics 20 Type 1: Magnocellular Neurons 20 Type II: Pre-autonomic Parvocellular neurons 21 Type III: Parvocellular Neuroendocrine 22 Neurochemical cell phenotypes in the PVN 23 Oxytocin 23 Vasopressin 24 vii Thyrotropin releasing hormone 26 Corticotropin releasing hormone 27 THE NUCLEUS OF THE SOLITARY TRACT -------------------------------------------------28 Afferent projections to the NTS 28 Efferent projections of the NTS 29 Electrophysiology of the NTS 29 Neurochemical expression in the NTS 30 Neuropeptide Y 31 STATEMENT OF PROBLEM ----------------------------------------------------------------------33 Chapter 2 : ADIPONECTIN SELECTIVELY INHIBITS OXYTOCIN NEURONS OF THE PARAVENCTRICULAR NUCLEUS OF THE HYPOTHALAMUS -------------------34 ABSTRACT 35 INTRODUCTION 37 MATERIALS AND METHODS 38 RESULTS 44 DISCUSSION 51 ACKNOWLEDGEMENTS 58 Chapter 3 : ADIPONECTIN DEPOLARIZES PARVOCELLULAR PARAVENTRICULAR NUCLEUS NEURONS CONTROLLING NEUROENDOCRINE AND AUTONOMIC FUNCTION ---------------------------------------------------------------------59 ABSTRACT 60 INTRODUCTION 61 MATERIALS AND METHODS 62 RESULTS 68 DISCUSSION 77 ACKNOWLEDGEMENTS 81 Chapter 4 : ADIPONECTIN ACTS IN THE NUCLEUS OF THE SOLITARY TRACT TO DECREASE BLOOD PRESSURE BY MODULATING THE EXCITABILITY OF NEUROPEPTIDE Y NEURONS ----------------------------------------------------------------------82 ABSTRACT 83 INTRODUCTION 85 MATERIALS AND METHODS 86 RESULTS 93 DISCUSSION 99 ACKNOWLEDGEMENTS 103 Chapter 5 : IONIC MECHANISMS RESPONSIBLE FOR ADIPONECTIN INDUCED CHANGES TO THE EXCITABILITY OF PARVOCELLULAR PVN NEURONS ------104 viii ABSTRACT 105 INTRODUCTION 106 MATERIALS AND METHODS 108 RESULTS 111 DISCUSSION 121 ACKNOWLEDGEMENTS 125 Chapter 6 : GENERAL DISCUSSION -------------------------------------------------------------126 REFERENCES ------------------------------------------------------------------------------------------146