GOAT and the Regulation of Energy and Glucose Homeostasis

Abstract

Ghrelin is the only known circulating hormone that potently stimulates food intake and adipogenesis in rodents and humans. Through a unique posttranslational modification, the premature ghrelin peptide is acyl-modified with a medium-chain fatty acid at the serine-3 position by ghrelin-O-acyl transferase (GOAT) to form acyl ghrelin. This step is necessary to activate ghrelin’s only known receptor, the growth hormone secretagogue receptor 1a, also known as the ghrelin receptor. GOAT activity is highly influenced by the availability of dietary lipids; dietary lipids serve as a direct GOAT substrate for ghrelin acylation. Further, GOAT gene expression and circulating acyl ghrelin levels are decreased after long-term starvation when dietary lipids are absent. These findings suggest that the ghrelin-GOAT system plays an important role in linking nutrient availability with endogenous regulation of energy homeostasis, especially adipogenesis. Recent data further suggest that GOAT is a significant factor in the regulation of glucose homeostasis as specific pharmacological GOAT inhibition improves glucose tolerance and insulin secretion. During caloric restriction, the ghrelin-GOAT system may play an important role for the maintenance of physiological range glucose levels by stimulating the secretion of growth hormone.