Ghrelin - The Defender of Fat in the Face of Stress: Implications in Obesity Treatment

Abstract

Chronic activation of the stress response can lead to a number of metabolic disturbances such as obesity, metabolic syndrome, Type II diabetes and car- diovascular disease. The exact mechanisms underlying these metabolic changes are currently uncharacterized. Traditionally, many of these effects have been at- tributed to the increased levels of circulating glucocorticoids (cortisol in humans and corticosterone in rodents) as a function of hypothalamic pituitary adrenal (HPA) axis hyperactivity. However, recent evidence suggests that the gut de- rived hormone ghrelin may be a key contributor to the physiological changes generated in response to chronic stress. Ghrelin is a gut-brain peptide that promotes appetite and the accumulation of adipose tissue by encouraging the utilization of carbohydrates as a fuel source, while sparing fat tissue. Inter- estingly, plasma ghrelin concentrations increase in response to stressful stimuli, and remain elevated following cessation of the stressor. The present thesis was aimed at investigating the role of ghrelin in mediating stress-induced metabolic changes. In addition, this thesis explores the efficacy of potential therapeutic treatments of stress-induced metabolic disorders. Overall, the data presented in this thesis suggests that ghrelin elicits an increase in caloric intake in response to stress while promoting the utilization of carbohydrates as a fuel source. Central ghrelin signalling is required to elicit the metabolic consequences of a chronic social defeat stress. Increased ghrelin secretion in response to stress caused a significant increase in visceral adipose tissue and produced a hormonal profile indicative of obesity and metabolic syndrome. Animals lacking a functional ghrelin signalling system do not show these metabolic changes. Pharmacologi- cal blockade of ghrelin with a putative GOAT inhibitor was sufficient to reduce stress-induced ghrelin secretion and subsequent caloric intake, thereby improv- ing the metabolic outcome of a chronic social defeat stress paradigm.