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Interactions of the Growth Hormone Secretory Axis and the Central Melanocortin System

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Interactions of the Growth Hormone Secretory Axis and the Central Melanocortin System INTERACTIONS OF THE GROWTH HORMONE SECRETORY AXIS AND THE CENTRAL MELANOCORTIN SYSTEM By AMANDA MARIE SHAW A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2004 Copyright 2004 by Amanda Marie Shaw This document is dedicated to my wonderful family. ACKNOWLEDGMENTS I would like to thank a number of people who greatly helped me through this long process of earning my Ph.D. First, I would like to thank my husband, Jason Shaw for his unwavering love and support during this time. I would also like to thank my parents, Robert and Rita Crews and my sister, Erin Crews for always standing by me and for their constant support throughout my life. I would also like to thank my extended family including my grandmother, aunts, uncles, in-laws, and cousins as well as friends who have always been tremendously supportive of me. I couldn’t have made it through this process without the support of all of these people. I would also like to thank my advisor, Dr. William Millard, for his guidance and understanding in helping me reach my goal. I truly value the independence I was allowed while working in his lab, and I appreciate the fact that he always knew when I needed help getting through the rough spots. I would also like to thank the other members of my supervisory committee: Dr. Joanna Peris, Dr. Maureen Keller-Wood, Dr. Michael Katovich, Dr. Steve Borst, and Dr. Ed Meyer for their valuable advice and for allowing me to use their laboratories and equipment as needed. I would especially like to thank Dr. Carrie Haskell-Luevano for supplying me with all of the animals used in these studies as well as for her advice in the initial development of my doctoral research project. I would also like to thank many people who shared their technical expertise with me and were there to help me figure out things throughout this entire process: Dr. Robin Picking, Dr. Baerbel Eppler, Dr. Yun-Ju He, Dr. Brenda Pedersen, Boman Irani, Justin iv Grobe, Melanie Powers, Marcella Von Reitzenstein, Zhimin Xiang, Caren Beck, Anthony Smith, and Marcus Moore. Thanks also go to the departmental office staff: Donna Walko, Anastasia Winkel and Paulette Monroe for your help and support. I truly value the support and friendships from so many people who have helped me along the way to earning my Ph.D and to all of you I offer my sincerest appreciation. v TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................................................................................. iv LIST OF TABLES............................................................................................................. ix LIST OF FIGURES .............................................................................................................x ABSTRACT...................................................................................................................... xii CHAPTER 1 LITERATURE REVIEW ................................................................................................1 Introduction...................................................................................................................1 Theories of Food Intake................................................................................................2 Hypothalamic Control of Energy Balance....................................................................5 Animal Models of Obesity............................................................................................6 The Melanocortin System.............................................................................................8 Melanocortin 3 and 4 Receptor Knockout Mice...........................................................9 Growth Hormone and Insulin-Like Growth Factor I..................................................11 Regulation of Growth Hormone Secretion..........................................................13 Growth Hormone Secretion in Obesity ...............................................................16 Growth Hormone Secretion in Aging..................................................................17 Ghrelin ........................................................................................................................19 Ghrelin Receptors................................................................................................21 Regulation of Ghrelin Levels ..............................................................................22 Ghrelin and Growth Hormone Secretion.............................................................24 Ghrelin and Energy Regulation...........................................................................26 Summary and Objectives............................................................................................28 2 GENERAL METHODS.................................................................................................30 Animals.......................................................................................................................30 Age Study ...................................................................................................................30 Genotyping .................................................................................................................31 Radioimmunoassays (RIA).........................................................................................32 GH Iodination......................................................................................................32 GH RIA ...............................................................................................................32 IGF-I Iodination...................................................................................................33 vi IGF-I RIA ............................................................................................................34 GHRH RIA..........................................................................................................34 SRIH Iodination...................................................................................................35 SRIH RIA ............................................................................................................36 Ghrelin RIA.........................................................................................................36 Animals for Feeding and GH Release Studies ...........................................................37 Peptide Preparation.....................................................................................................37 Measurement of Food Intake (Old mice: 14-15 months) ...........................................38 Measurement of Food Intake (Young mice: 3-4 months) ..........................................38 GH Stimulation...........................................................................................................39 Micro BCA Protein Assay..........................................................................................40 RNA Isolation.............................................................................................................40 2-Step Real-Time RT-PCR.........................................................................................41 Statistical Analysis......................................................................................................42 3 CHARACTERIZATION OF THE GROWTH HORMONE SECRETORY AXIS IN MC3R KO AND MC4R KO MICE ...........................................................................44 Introduction.................................................................................................................44 Materials and Methods ...............................................................................................45 Animals................................................................................................................45 Radioimmunoassays (RIA) .................................................................................46 GH RIA ...............................................................................................................46 IGF-I RIA.....................................................................................................46 GHRH RIA...................................................................................................46 SRIH RIA.....................................................................................................47 Statistics...............................................................................................................47 Results.........................................................................................................................47 Mouse Body Weights ..........................................................................................47 Serum GH Levels ................................................................................................48 Serum IGF-I Levels.............................................................................................48 Pituitary GH Content...........................................................................................49 Liver and Skeletal Muscle IGF-I Content ...........................................................50 Hypothalamic GHRH Content ............................................................................52 Hypothalamic SRIH Content...............................................................................53
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