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Central Regulation of Energy Homeostasis and the Reproductive Axis

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Central Regulation of Energy Homeostasis and the Reproductive Axis CENTRAL REGULATION OF ENERGY HOMEOSTASIS AND THE REPRODUCTIVE AXIS A thesis submitted for the degree of Doctor of Philosophy, Imperial College London. 2010 Charlotte Katie Boughton Section of Investigative Medicine Division of Diabetes, Endocrinology and Metabolism Department of Medicine Imperial College London ABSTRACT Alarin is a recently discovered splice variant of the galanin-like peptide (GALP) gene. Alarin is a highly conserved 25 amino acid peptide which shares its first 5 amino acids with GALP, but lacks the galanin receptor binding domain, suggesting that it mediates its biological effects through alternative receptors. Alarin has been detected in the rodent hypothalamus. GALP has a well-characterised role in the integration of energy and reproductive homeostasis. Intracerebroventricular (ICV) alarin increases food intake and plasma luteinising hormone (LH) levels in rats. Alarin stimulates the release of the orexigenic neuropeptide Y (NPY) and gonadotrophin releasing hormone (GnRH) from hypothalamic explants, and GnRH release from an immortalised GnRH releasing cell line. Pre-treatment with a GnRH antagonist blocked the alarin-induced increase in plasma LH levels in vivo. These results suggest that ICV alarin activates the HPG axis via hypothalamic GnRH release. My data also suggests that alarin does not bind to the known galanin receptors. The ventral tegmental area (VTA) is the origin of the mesolimbic dopamine pathway, which mediates the rewarding properties of palatable food. Recent work suggests that the VTA reward pathway is regulated by appetite-regulating signals including leptin and ghrelin. I have shown that intra-VTA melanocortin receptor agonist administration inhibits food intake and administration of an antagonist stimulates food intake in rats, suggesting that the melanocortin system may be involved in hedonic regulation of appetite, in addition to its role in homeostatic regulation of appetite. These studies have elucidated the biological effects of alarin in the regulation of appetite and the HPG axis, and identified a role for the melanocortin system in regulating the central reward circuitry modulating food intake. Further work is required to determine the receptor by which alarin mediates its effect and its precise physiological function, and the physiological importance of the VTA melanocortin system. 2 DECLARATION OF CONTRIBUTORS The majority of the work described in thesis was performed by the author. Any collaboration and assistance is described below. All radioimmunoassays were carried out under the supervision of Professor M.A. Ghatei (Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London). Chapters 2 and 3 - In vivo ICV injection studies were carried out with the assistance of the ‘hypothalamic group’. Chapter 5 - The competent bacteria used for generation of probes was produced by Dr J.V. Gardiner (Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London). The GAD67 probe utilised for in situ hybridisation was generated by Dr T. Ambepitiya. In vivo iVTA injection studies were carried out with the assistance of Dr J. Cooke and Miss K. Beale. Immunocytochemistry and in situ hybridisation was carried out with the guidance of Mr J.A.Tadross. 3 ACKNOWLEDGEMENTS I would first like to thank my supervisors: Dr. Kevin Murphy for his unfailing scientific guidance and support, and for his positivity and sense of humour throughout. Dr. Gavin Bewick for his practical advice and help. I am grateful to Professor Stephen Bloom for giving me the opportunity to work in his department. Many thanks to all members of the ‘hypothalamic group’ for help with in vivo studies. Thanks to all of those in the lab who made my time so enjoyable. Finally, I would like to thank my family and friends for all their support and ‘enthusiasm’ for my work. 4 TABLE OF CONTENTS ABSTRACT .................................................................................................................................. 2 DECLARATION OF CONTRIBUTORS .................................................................................. 3 ACKNOWLEDGEMENTS ......................................................................................................... 4 ABBREVIATIONS .................................................................................................................... 23 CHAPTER 1: GENERAL INTRODUCTION ........................................................................ 27 1.1 The Neuroendocrine system .............................................................................................. 28 1.2 The Hypothalamus ............................................................................................................. 29 1.3. Food Intake ....................................................................................................................... 31 1.3.1. Hypothalamic control of food intake ......................................................................... 31 1.3.1.1. Hypothalamic nuclei involved in the control of energy homeostasis ................ 32 1.3.1.1.1. Arcuate nucleus .......................................................................................... 32 1.3.1.1.1.1. The melanocortin system ..................................................................... 33 1.3.1.1.1.2. Neuropeptide Y .................................................................................... 34 1.3.1.1.1.3. Cocaine and amphetamine regulated transcript ................................... 35 1.3.1.1.2. Dorsomedial nucleus ................................................................................... 36 1.3.1.1.2.1. Cholecystokinin ................................................................................... 36 1.3.1.1.3. Ventromedial nucleus ................................................................................. 37 1.3.1.1.4. Lateral hypothalamic area ........................................................................... 38 1.3.1.1.4.1. Orexins ................................................................................................. 39 1.3.1.1.4.2. Melanin concentrating hormone .......................................................... 39 1.3.1.1.5. Paraventricular nucleus ............................................................................... 40 1.3.1.1.5.1. Corticotrophin releasing hormone ....................................................... 41 1.3.1.1.5.1. Glucagon-like peptide 1 ....................................................................... 41 1.3.1.1.6. Tuberomammillary nucleus ........................................................................ 42 1.3.2. Brainstem regulation of energy homeostasis ............................................................. 43 1.3.3. Peripheral regulators of energy homeostasis ............................................................. 44 1.3.3.1. Leptin ................................................................................................................. 44 5 1.3.3.2. Insulin ................................................................................................................ 46 1.3.3.3. Gut hormones ..................................................................................................... 47 1.3.3.3.1. Ghrelin ........................................................................................................ 47 1.3.3.3.2. Cholecystokinin .......................................................................................... 48 1.3.3.3.3. Peptide YY ................................................................................................. 49 1.3.3.3.4. Pancreatic polypeptide ................................................................................ 49 1.3.3.3.5. Preproglucagon products ............................................................................ 50 1.3.4. Non-homeostatic regulation of feeding ..................................................................... 51 1.3.4.1. The mesolimbic dopaminergic pathway ............................................................ 51 1.3.4.2. Dopamine and food intake ................................................................................. 53 1.4.The Neuroendocrine axes .................................................................................................. 54 1.4.1. Hypothalamic releasing factors ................................................................................. 54 1.4.2. The median eminence ................................................................................................ 54 1.4.3. The pituitary gland .................................................................................................... 55 1.4.3.1. The posterior pituitary ........................................................................................ 55 1.4.3.2. The anterior pituitary ......................................................................................... 56 1.4.3.2.1. The growth hormone axis .......................................................................... 57 1.4.3.2.1.1. Hypothalamic control of the GH axis .................................................. 57 1.4.3.2.1.2. Pituitary control of the GH axis ........................................................... 58 1.4.3.2.2. The hypothalamo-pituitary-thyroid axes .................................................... 59 1.4.3.2.2.1. Hypothalamic control of the HPT axis ...............................................
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