Ingested Medium-Chain Fatty Acids Are Directly Utilized for the Acyl Modification of Ghrelin

Abstract

Ghrelin, an acylated brain and gut peptide, is primarily produced by endocrine cells of the gastric mucosa for secretion into the circulation. The major active form of ghrelin is a 28-amino-acid peptide containing an n-octanoyl modification at serine that is essential for activity. Studies have identified multiple physiological functions for ghrelin, including GH release, appetite stimulation, and metabolic fuel preference. Until now, there has not been any report detailing the mechanism of ghrelin acyl modification. Here we report that ingestion of either medium-chain fatty acids (MCFAs) or medium-chain triacylglycerols (MCTs) increased the stomach concentrations of acylated ghrelin without changing the total (acyl- and des-acyl-) ghrelin amounts. After ingestion of either MCFAs or MCTs, the carbon chain lengths of the acyl groups attached to nascent ghrelin molecules corresponded to that of the ingested MCFAs or MCTs. Ghrelin peptides modified with n-butyryl or n-palmitoyl groups, however, could not be detected after ingestion of the corresponding short-chain or long-chain fatty acids, respectively. Moreover, n-heptanoyl ghrelin, an unnatural form of ghrelin, could be detected in the stomach of mice after ingestion of either n-heptanoic acid or glyceryl triheptanoate. These findings indicate that ingested medium-chain fatty acids are directly used for the acylation of ghrelin.

Ghrelin secretion stimulated by β 1 -adrenergic receptors in cultured ghrelinoma cells and in fasted mice

“…2). These findings are consistent with previous whole-animal data indicating that ghrelin secretion is dependent on an exogenous source of octanoate (25). It appears that the ghrelin-secreting cells cannot synthesize octanoate de novo, nor can they shorten longchain fatty acids.…”

Analysis of plasma ghrelin in patients with medium-chain acyl-CoA dehydrogenase deficiency and glutaric aciduria type II

“…BMIs of these patients were comparable to those of normal Japanese female children (23). These findings support the hypothesis that octanoyl-CoA is a primary substrate for ghrelin, although medium-chain triglyceride dietary lipids are a direct source for ghrelin acylation (7,16,24). Moreover, GOAT is a membrane-bound molecule in the endoplasmic reticulum (ER).…”

“…The eluate was evaporated and separated by RP-HPLC. All HPLC fractions were quantified using RIAs for ghrelin (4,14,15,16). RIAs for a ghrelin C-terminal region (C-RIA) and a ghrelin N-terminal region (N-RIA) measure des-acyl ghrelin and octanoyl-ghrelin respectively (15).…”

“…RIAs for a ghrelin C-terminal region (C-RIA) and a ghrelin N-terminal region (N-RIA) measure des-acyl ghrelin and octanoyl-ghrelin respectively (15). A RIA for N-terminal ghrelin showed w20-25% cross-reactivity values for the n-decanoylated and n-decenoylated forms (16). Authentic human ghrelin-(1-28) was chromatographed with the same HPLC system.…”

Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes

“…The factors regulating ghrelin acylation have been largely unknown, although increased availability of the FFA has been proposed to enhance the hormone acylation in mice. 43 Interestingly, Yang et al 44 have recently identified a novel enzyme implicated in the n-octanoylation of ghrelin, namely GOAT (Ghelin O-Acyltransferase), that is expressed in the major ghrelin-secreting tissues, such as the stomach and intestine. It seems plausible that obesity influences the expression and/or activity of this acyltranferase, leading to elevated plasma concentrations of acylated ghrelin.…”