GOAT links dietary lipids with the endocrine control of energy balance

Abstract

CNS nutrient sensing and afferent endocrine signalling are established as parallel systems communicating metabolic status and energy availability in vertebrates. The only afferent endocrine signal known to require modification with a fatty acid side chain is the orexigenic hormone ghrelin. We find that the ghrelin O-acyl transferase (GOAT) which is essential for ghrelin acylation, is regulated by nutrient availability, depends on specific dietary lipids as acylation substrates and modulates body fat mass in mice.Two discoveries have softened the traditional differentiation between the classic model of nutrient sensing 1 and the concept of endocrine signals controlling energy status 2 and drawn attention to the regulation of energy homeostasis by circulating long chain fatty acids (LCFAs). Hotamisligil and colleagues recently reported that one specific adipocyte derived long chain fatty acid (C16:1n7), the lipokine palmitoleate, functions as a hormone regulating systemic insulin sensitivity 3. A recent study followed with the discovery that a gastrointestinal lipid metabolite, N-acylphosphatidylethanolamine (NAPE), can function as an endocrine signal which targets hypothalamic energy balance centers to control food intake, particularly when the acyl NAPE species is C16:0 4. Ten years after the discovery of the only orexigenic gut hormone ghrelin 5,6, this unique medium-chain fatty acid (MCFA)-peptide chimera is now revealing itself as yet another nutrient-hormone hybrid with the specific role of linking macronutrient composition with CNS energy balance regulation. It is further intriguing that the only peptide hormone known to require a fatty acid modification 5 is also the only known afferent endocrine factor which depends on intra-neuronal fatty acid metabolism 7. Unique characteristics of the predominantly stomach derived ghrelin include Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use

Proghrelin peptides: Desacyl ghrelin is a powerful inhibitor of acylated ghrelin, likely to impair physiological effects of acyl ghrelin but not of obestatin

“…their effects on PP release from islets) will reflect not only the receptor make-up of the target cells but also the circulating concentration of all three peptides, acyl ghrelin, desacyl ghrelin and obestatin. Plasma desacyl ghrelin levels are typically 5-10-fold higher than acyl ghrelin in rat, mouse and man (desacyl ghrelin levels in rodents ranging between 150-600 pmol/l while acyl ghrelin levels range between 10-50 pmol/l) (8,10). Obestatin levels are also higher than acyl ghrelin levels, ranging between 100-800 pmol/l (9,21,56).…”

“…Hatched areas in the Fig. show the range of reported blood concentrations of obestatin, acyl ghrelin and desacyl ghrelin in fasted or fed mice and rats (1,4,(7)(8)(9)(10)21). From the concentrationresponse curves it seems that the circulating concentrations of both obestatin and acyl ghrelin will cause 80-90 % suppression of spontaneous PP release.…”

“…During processing, a fraction of desacyl ghrelin is acylated in position 3 (serine) to form variants of acylated ghrelin (1,2,5-7), which are considered to be biologically active. It is noteworthy that desacyl ghrelin is more abundant than acyl ghrelin in both stomach (5) and circulation (5,(8)(9)(10). Conceivably, desacyl ghrelin is being produced in the ghrelin cells as well as in the circulation by deacylation of acylated ghrelin.…”

“…Acyl ghrelin is thought to be a "hunger hormone" because circulating ghrelin concentrations increase as a result of food deprivation and decrease following food intake (1,4,(8)(9)(10)(11)(12)(13)(14)(15). Numerous reports have suggested that ghrelin affects energy balance; causing body weight increase and adiposity (see e.g.…”

Ghrelin neutralization during fasting-refeeding cycle impairs the recuperation of body weight and alters hepatic energy metabolism

“…2001bNakazato et al 2001) and its acylation is considered necessary for its actions via GHSR1a (the functional variant of GHSR) (Howard et al 1996; Kojima et al 1999). Recently, several groups identified ghrelin O-Acyltransferase (GOAT), a membrane-bound enzyme that transfers octanoate from octanoyl CoA to serine-3 of ghrelin, forming an acyl ester (Gutierrez et al 2008;Yang et al 2008) and a recent study observed that GOAT links dietary lipids with the endocrine control of energy balance (Kirchner et al 2009). …”