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The Regulation of Adipose Tissue and Skeletal Muscle Substrate Metabolism by Ghrelin

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The Regulation of Adipose Tissue and Skeletal Muscle Substrate Metabolism by Ghrelin The Regulation of Adipose Tissue and Skeletal Muscle Substrate Metabolism by Ghrelin by Daniel Thomas Cervone A Thesis presented to The University of Guelph In partial fulfilment of requirements for the degree of Doctor of Philosophy in Human Health and Nutritional Sciences Guelph, Ontario, Canada © Daniel Thomas Cervone, May 2020 ABSTRACT THE REGULATION OF ADIPOSE TISSUE AND SKELETAL MUSCLE SUBSTRATE METABOLISM BY GHRELIN Daniel Thomas Cervone Advisor: University of Guelph, 2020 Dr. David J. Dyck Research examining a potential role for ghrelin, the “hunger hormone”, in regulating substrate metabolism beyond its classical role in regulating appetite is relatively sparse. This is surprising given that ghrelin reaches its peak circulating concentration just prior to the consumption of macronutrients. Here, we demonstrate a role for ghrelin in the direct regulation of glucose and fatty acid metabolism in isolated skeletal muscle and adipose tissue. Experiments were primarily ex vivo to eliminate confounding factors, such as growth hormone release following ghrelin administration in vivo. Metabolic measurements were coupled with cellular signalling analyses to give insight into ghrelin’s cellular action. In study one, we investigated whether ghrelin could influence the mobilization of fatty acids from adipose tissue. We speculated, in theory, that the pre-prandial rise in ghrelin would downregulate adipose tissue lipolysis in preparation for a meal. We indeed found that ghrelin inhibited the adrenergic stimulation of lipolysis, although it remains uncertain whether this has physiological mealtime implications, in vivo. In the second study of this thesis, the purported role in the literature for ghrelin as a regulator of glucose uptake in skeletal muscle is challenged. Ghrelin was unable to alter skeletal muscle insulin signalling or glucose uptake either independently, or in combination with insulin in isolated muscle. Finally, the third study expanded on previous work from our lab demonstrating that ghrelin stimulates skeletal muscle fatty acid oxidation. We sought to determine whether ghrelin could protect muscle against reductions to insulin-stimulated glucose uptake and insulin signalling activation acutely caused by saturated fatty acids. While both isoforms of ghrelin appeared to protect insulin signalling, only UnAG was able to preserve insulin-stimulated glucose uptake. UnAG also stimulated palmitate oxidation more effectively than AG. To that end, the preservation of insulin action by UnAG was abolished when fatty acid oxidation was pharmacologically inhibited. Finally, ghrelin’s effects on glucose uptake and palmitate oxidation were no longer evident in muscle isolated from high-fat fed rats, implying a resistance to ghrelin. Taken together, the findings in this thesis highlight important new roles for ghrelin in regulating substrate metabolism in adipose tissue and skeletal muscle. ACKNOWLEDGEMENTS I am eternally grateful for the endless waves of support that I have received from my parents throughout life. Every day is made a little easier when you know that your family is always going to be in your corner, no matter what. Your open-mindedness and early teachings instilled a sense of curiosity, critical thinking and work ethic that have remained with me throughout my research endeavours and continue to push me forward when met with new life challenges. Your generosity has afforded me the opportunity to carve my own path in science. To HHNS peers, you are all a daily reminder that research is a collective effort and I have been lucky enough to interact with such a hard-working, well-rounded and welcoming group of individuals over the last several years. To Andy, Diana, Andra, Ann and Anne, I cannot thank you all enough for your continued resilience in keeping the animal wing and departmental cogs turning. Without your dedication, my research experiences would not have gone so smoothly. To members of my advisory, thesis examination and qualifying examination committees, I thank you for all the stimulating, speculative and productive scientific discussions even as I ventured towards the unknown in terms of both questions and answers. You are all brilliant minds and have had a pivotal hand in shaping the way I approach and evaluate the literature. Dave, I cannot thank you enough for the countless and diverse opportunities you have provided me over the years. It was a pleasure coming into “work” every day and building this ghrelin research from the ground-up in your lab. I wish you nothing but the best moving forward in lab and in life. To my partner Kate, you are a constant reminder of what can be achieved with a good mindset and persistence. It has been a pleasure watching you (and Nyla) grow over the past few years as well as bearing witness to my own development by your side. iv Table of Contents ABSTRACT .................................................................................................................................. II ACKNOWLEDGEMENTS ....................................................................................................... IV TABLE OF CONTENTS ............................................................................................................ V LIST OF FIGURES ..................................................................................................................... X ABBREVIATIONS ................................................................................................................... XII INTRODUCTION TO LITERATURE REVIEW ..................................................................... 1 CHAPTER 1: LITERATURE REVIEW ................................................................................... 3 1.0 STOMACH HORMONE: GHRELIN ............................................................................ 3 1.1 DISCOVERY OF GHRELIN .................................................................................................. 3 1.2 SOURCE OF GHRELIN AND GHRELIN RECEPTOR (GHS-R) DISTRIBUTION ........................ 4 1.3 POST-TRANSLATIONAL MODIFICATION OF GHRELIN ......................................................... 4 1.4 REGULATION OF CIRCULATING GHRELIN ISOFORM CONCENTRATIONS ............................. 5 1.4.1 Acute and chronic conditions affecting ghrelin concentrations ................................. 6 1.4.2 Fasted ghrelin release................................................................................................. 6 1.4.3 Postprandial decline – macronutrients and energy intake ......................................... 7 1.4.4 GOAT, acylation and deacylation............................................................................... 7 1.5 GROWTH HORMONE SECRETION ....................................................................................... 8 1.5.1 Signalling for growth hormone release ...................................................................... 8 1.6 CENTRAL NERVOUS SYSTEM EFFECTS .............................................................................. 9 2.0 HORMONAL REGULATION OF GLUCOSE AND LIPID METABOLISM: A ROLE FOR GHRELIN .............................................................................................................. 10 2.1 GLUCOSE HOMEOSTASIS ................................................................................................ 10 2.1.1 Insulin secretion ........................................................................................................ 11 2.1.2 Regulation of insulin secretion by ghrelin ................................................................ 11 2.2 SKELETAL MUSCLE GLUCOSE METABOLISM ................................................................. 12 2.2.1 Insulin signalling ...................................................................................................... 12 2.2.2 Regulation of insulin signalling by ghrelin ............................................................... 13 2.2.3 Insulin-stimulated glucose uptake............................................................................. 14 2.2.4 Regulation of glucose uptake by ghrelin ................................................................... 15 v 2.3 SKELETAL MUSCLE FATTY ACID METABOLISM ............................................................. 17 2.3.1 Fatty acid transport and oxidation ........................................................................... 17 2.3.2 Lipid metabolites and insulin action ......................................................................... 18 2.3.3 Regulation of fatty acid metabolism in muscle by ghrelin ........................................ 19 2.3.4 High fatty acid availability, lipid intermediates and ghrelin .................................... 20 2.3.5 Cellular signalling .................................................................................................... 21 2.4 ADIPOSE TISSUE METABOLISM ...................................................................................... 21 2.4.1 Fatty acid mobilization (lipolysis) ............................................................................ 21 2.4.2 Adrenergic receptors and lipolytic enzymes ............................................................. 22 2.4.3 Insulin inhibition of lipolysis .................................................................................... 23 2.4.4 Depots ....................................................................................................................... 23 2.4.5 Regulation
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