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Potential Role of Melanocortin 4 Receptor in Physical

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Potential Role of Melanocortin 4 Receptor in Physical POTENTIAL ROLE OF MELANOCORTIN 4 RECEPTOR IN PHYSICAL ACTIVITY ENERGY EXPENDITURE IN RATS: EFFECT OF CALORIE RESTRICTION A dissertation submitted to Kent State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy By Tariq Almundarij December 2015 © Copyright All rights reserved Except for previously published materials B.Sc., Al qassim University, Saudi Arabia 2005 M.A., Kent State University, USA, 2012 Ph.D. Kent State University, USA,2015 Approved by Dr. Colleen Novak, Chair, Doctoral Dissertation Committee Dr. Eric Mintz, Member, Doctoral Dissertation Committee Dr. Gary Koski Member, Doctoral Dissertation Committee Dr. Jacob Barkley, Member, Doctoral Dissertation Committee Dr. John Gunstad, Member, Doctoral Dissertation Committee Accepted By, Dr Laura Leff Chair, Department of Biological Science Dr. James L. Blank Dean, College of Arts and Science ii Abstract Tariq, Almundarij, PhD, December 2015 Physiology POTENTIAL ROLE OF MELANOCORTIN 4 RECEPTOR IN PHYSICAL ACTIVITY ENERGY EXPENDITURE IN RATS: EFFECT OF CALORIE RESTRICTION (173 PP) The prevalence of obesity around the world has increased in recent years. Obesity results from imbalance between calories in and energy expenditure. Total daily energy expenditure (EE), including resting energy expenditure and non-resting energy expenditure, are critical factors that contribute for individual differences in body weight, and are affected by genetic predisposition. The brain serves to regulate energy balance homeostasis via number of neuroendocrine regulators; one of these is the brain melanocortin system, which includes the melanocortin 4 receptor (MC4R). Melanocortin 4 receptor mutation is one of the few known monogenic causes of obesity in humans. MC4R is also the target of numerous genetic variants that contribute to human obesity. Central MC4R plays a critical role in controlling energy homeostasis, increasing energy expenditure, and decreasing food intake. Here, I investigate the contribution of physical activity and EE to obesity in rats lacking functional MC4R, and test the hypothesis that MC4R signaling underlies differential weight loss during calorie restriction. Although rats lacking functional MC4R did not show lower EE under free-fed conditions, they lost significantly less weight during calorie restriction. During weight loss, adaptive iii thermogenesis occurs where EE is suppressed beyond what is predicted for the smaller body size. Prolonged food restriction in rats resulted in reduced in daily EE, including resting and non-resting EE. These decreases in EE were significant even when the reductions in body weight and lean mass were taken into account. Similarly, the caloric need for moderate-level treadmill activity was decreased by 50% calorie restriction, as were baseline and activity-related muscle thermogenesis, though the ability to increase muscle thermogenesis above baseline levels was not compromised. When sympathetic nervous system drive was measured by assessing norepinephrine turnover (NETO), 50% calorie restriction was found to decrease NETO in three of the four muscle groups examined, while increasing NETO in white adipose tissue. Central activation of MC4R in the ventromedial hypothalamus stimulated this brain-muscle pathway, enhancing activity EE, and this was not compromised by 50% calorie restriction. These data suggest that suppressed activity EE contributes to adaptive thermogenesis during energy restriction; this may stem from decreased SNS drive to skeletal muscle, increasing locomotor efficiency and reducing skeletal muscle thermogenesis. The capacity to increase activity EE in response to central MC4R activation is retained, however, presenting a potential target for pharmacotherapy intervention. iv TABLE OF CONTENTS Page Appendix 1: List of Figures………………………………...…….…………………….viii Appendix 2: List of Tables…………………………………...…………………..………x Appendix 3: List of Abbreviations ………………………………………………….…...xi Acknowledgements……………………………………...………………………………xiv : Introduction ................................................................................................ 1 Obesity ................................................................................................................... 1 Energy expenditure and adaptive thermogenesis .................................................. 3 Melanocortin system .............................................................................................. 6 Melanocortin receptors .......................................................................................... 7 POMC and AgRP neuron regulation ................................................................... 11 MC-hypothalamic regulation of energy balance ................................................. 12 Arcuate nucleus (ARC) ................................................................................. 14 Ventromedial hypothalamus (VMH) ............................................................ 15 Other hypothalamic regions .......................................................................... 18 Melanocortin 4 receptors ..................................................................................... 20 Melanocortin-4 receptor (MC4R) deficiency in human obesity ................... 23 Autonomic nervous system and energy balance .................................................. 26 Sympathetic nervous system-MC4R regulation ........................................... 28 v Rat model ............................................................................................................. 30 Aims ..................................................................................................................... 30 : MC4R loss of function in rats................................................................... 32 Study 1: MC4R loss-of-function affects body weight, lean and fat mass, food intake, physical activity, respiratory exchange ratio (RER), and EE. .......................... 35 Methods......................................................................................................... 35 Results ........................................................................................................... 38 Study 2: Calorie restriction in MC4R loss-of-function rats................................. 43 Methods......................................................................................................... 43 Results ........................................................................................................... 44 Study 3: The effect of MC4R loss-of-function on molecular pathways supporting metabolism in skeletal muscle and brown adipose tissue (BAT) ................................. 49 Experimental Methods .................................................................................. 52 Results ........................................................................................................... 54 Discussion ............................................................................................................ 56 : Long-term calorie restriction induces adaptive thermogenesis in different components of energy expenditure ................................................................................... 63 Methods ............................................................................................................... 65 Results ................................................................................................................. 71 Discussion ............................................................................................................ 79 : Long-term calorie restriction reduces sympathetic nervous system outflow to skeletal muscle .............................................................................................................. 82 vi Experimental design ............................................................................................ 85 Results ................................................................................................................. 89 Discussion ............................................................................................................ 91 : The ability of VMH-MC4R signaling to increase activity EE with long- term calorie restriction ...................................................................................................... 94 Methods ............................................................................................................... 96 Results ................................................................................................................. 99 Discussion .......................................................................................................... 103 : General discussion .................................................................................. 107 Future perspectives ............................................................................................ 112 References ................................................................................................................... 115 vii Appendix 1: List of Figures Figure 1: Components of total daily energy expenditure (TDEE) in humans and rats. ..... 5 Figure 2: The leptin-melanocortin system and regulation of food intake and energy expenditure. ............................................................................................................... 13 Figure 3 : Illustration of a coronal section of a rat brain.. ...............................................
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