Ghrelin O-acyltransferase (GOAT) and energy metabolism

Abstract

Ghrelin O-acyltransferase (GOAT), a member of MBOATs family, is essential for octanoylation of ghrelin, which is required for active ghrelin to bind with and activate its receptor. GOAT is expressed mainly in the stomach, pancreas and hypothalamus. Levels of GOAT are altered by energy status. GOAT contains 11 transmembrane helices and one reentrant loop. Its invariant residue His-338 and conserved Asn-307 are located in the endoplasmic reticulum lumen and cytosol respectively. GOAT contributes to the regulation of food intake and energy expenditure, as well as glucose and lipids homeostasis. Deletion of GOAT blocks the acylation of ghrelin leading to subsequent impairment in energy homeostasis and survival when mice are challenged with high energy diet or severe caloric restriction. GO-CoA-Tat, a peptide GOAT inhibitor, attenuates acyl-ghrelin production and prevents weight gain induced by a medium-chain triglycerides-rich high fat diet. Further, GO-CoA-Tat increases glucose-induced insulin secretion. Overall, inhibition of GOAT is a novel strategy for treatment of obesity and related metabolic disorders.ghrelin O-acyltransferase (GOAT), acyl-ghrelin, enzyme inhibitor, food intake, energy metabolism, obesity Citation:

Effects of ghrelin in energy balance and body weight homeostasis

“…GHSR1a, the ghrelin-specific receptor, binds acylated ghrelin and mainly induces the release of the growth hormone from the somatotropic cells in the anterior pituitary gland. Via the vagus nerve or directly at the central level, ghrelin activates the neurons in the arcuate nucleus (ARC nucleus) secreting orexigenic peptides-neuropeptide Y (NPY) and agouti-related peptide (AgRP) 39 -and inhibits the anorexigenic neurons secreting pro-opiomelanocortin and α-melanocyte-stimulating hormone. Orexigenic signals act via adenosine monophosphate-activated protein kinase (AMPK) and increase the dopaminergic transmission from the ventral tegmental area to the nucleus accumbens, enhancing the reward signals.…”

“…51,52 Interestingly enough, there is also a preferential effect on fat intake that has recently been demonstrated. 28 Additionally, ghrelin would seem to promote adipose tissue deposition, 39 reduced energy expenditure and more efficient storage of lipids. 39,53 It can be said that ghrelin acts to protect the energy resources of the body when these are available (defensive role, protecting against hypoglycaemia that may occur in conditions of prolonged caloric restriction), 54 to redirect the metabolism to storing excess calories for later use in case of food insufficiency.…”

“…28 Additionally, ghrelin would seem to promote adipose tissue deposition, 39 reduced energy expenditure and more efficient storage of lipids. 39,53 It can be said that ghrelin acts to protect the energy resources of the body when these are available (defensive role, protecting against hypoglycaemia that may occur in conditions of prolonged caloric restriction), 54 to redirect the metabolism to storing excess calories for later use in case of food insufficiency. Some authors have suggested that ghrelin is the factor that modulates feeding behaviour towards energy accumulation, 50,55 which is not beneficial to the human body in the current circumstances, as we often witness at the individual level a positive energy balance oriented to excessive caloric intake associated with reduced energy expenditure mainly because of our present-day sedentary lifestyle.…”

“…57 Thus, ghrelin directly stimulates glucagon secretion from pancreatic α cells (via GHS-R), 90 while glucagon stimulates ghrelin secretion under nutrient-deficient conditions. 91 Studies on laboratory animals have revealed that under the action of acyl-ghrelin, fat is stored not only in adipose tissue but also the liver, 39 where an increase in triacylglycerol content and genes involved in hepatic lipogenesis was found. 92 A recent study published by Gagnon et al brought up for discussion a new aspect of ghrelin involvement in glucose regulation, the authors demonstrating that ghrelin increases the secretion of GLP-1 (glucagon like peptide 1), thereby improving glucose tolerance.…”

“…In conclusion, circulating ghrelin level in humans are low under conditions of positive energy balance, Table 1. The main effects of ghrelin that can influence energy metabolism Food intake 1,35 ↑ appetite/↑ food intake ↑ hedonic aspect of eating ↑ motivation to obtain food ↑ food seeking behaviours Gastrointestinal function [47][48][49][50] ↑ gastric motility ↑ gastric acid secretion and digestive enzymes Adipose tissue 26,39,53,58 ↑ lipogenesis ↑ adipogenesis (↑ differentiation and proliferation of preadipocytes) ↓ lipid oxidation Intermediary metabolisms 57,62,79,82,90,92,93 ↓ insulin secretion ↑ hepatic gluconeogenesis ↓ insulin sensitivity ↑ glucagon secretion ↑ hepatic lipogenesis GLP-1 secretagogue Energy expenditure 52,57,94,95 ↓ energy expenditure ↓ thermogenesis in BAT ↓ sympathetic nervous system in BAT either in acute conditions (food intake) or chronic conditions (obesity). Elevated circulating ghrelin levels are found in fasting conditions and in patients with anorexia of various causes.…”