Author: Daniel Cervone

Publisher:

Published: 2020

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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 isoforms reach their 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 appeared to protect insulin signalling, only unacylated ghrelin (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, the effects of UnAG 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.