GOAT induced ghrelin acylation regulates hedonic feeding

Abstract

Ghrelin is an orexigenic hormone that regulates homeostatic and reward-related feeding behavior. Recent evidence indicates that acylation of ghrelin by the gut enzyme ghrelin O-acyl transferase (GOAT) is necessary to render ghrelin maximally active within its target tissues. Here we tested the hypothesis that GOAT activity modulates food motivation and food hedonics using behavioral pharmacology and mutant mice deficient for GOAT and the ghrelin receptor (GHSR). We evaluated operant responding following pharmacological administration of acyl-ghrelin and assessed the necessity of endogenous GOAT activity for operant responding in GOAT and GHSR-null mice. Hedonic-based feeding behavior also was examined in GOAT-KO and GHSR-null mice using a “Dessert Effect” protocol in which the intake of a palatable high fat diet “dessert” was assessed in calorically-sated mice. Pharmacological administration of acyl-ghrelin augmented operant responding; notably, this effect was dependent on intact GHSR signaling. GOAT-KO mice displayed attenuated operant responding and decreased hedonic feeding relative to controls. These behavioral results correlated with decreased expression of the orexin-1 receptor in reward-related brain regions in GOAT-KO mice. In summary, the ability of ghrelin to stimulate food motivation is dependent on intact GHSR signaling and modified by endogenous GOAT activity. Furthermore, GOAT activity is required for hedonic feeding behavior, an effect potentially mediated by forebrain orexin signaling. These data highlight the significance of the GOAT-ghrelin system for the mediation of food motivation and hedonic feeding.

A link between FTO, ghrelin, and impaired brain food-cue responsivity

“…Ghrelin, the only known orexigenic peptide hormone, regulates both homeostatic and reward-related feeding (37,38,(49)(50)(51). Posttranslational addition of an acyl group to serine-3 by GOAT, resulting in the generation of acyl-ghrelin, is essential for the appetite-stimulatory and reward-related effects of ghrelin, which are mediated via GHSR (52,53). The effects of ghrelin on appetite and food intake are well established; acyl-ghrelin stimulates hunger and increases food intake (34,49), and chronic administration increases adiposity (54).…”

“…**P < 0.01. Difference between normalized TT unbound and normalized AA unbound; ### P < 0.001. ade of ghrelin signaling on feeding or body weight (55,56), other studies suggest that intact ghrelin signaling is required for normal eating behavior and body-weight responses, especially to rewarding high-fat diets (38,51,53,57,58). Not only does acyl-ghrelin increase the intake of freely available food, but it also shifts food preference toward diets rich in fat, enhances operant responding for food rewards, and induces conditioned place preference for food rewards (38,51).…”

Physiological significance of ghrelin revealed by studies using genetically engineered mouse models with modifications in the ghrelin system [Review]

“…Furthermore, administration of ghrelin increased the consumption of rewarding food and alcohol in WT mice, but not in ghrelin receptor-null mice [72,73]. Moreover, GOAT-null mice exhibit a decreased hedonic feeding [74]. These reports suggest that the ghrelin system is required for hedonic feeding.…”

The future role of gut hormones in the treatment of obesity

“…By neutralizing active ghrelin, they demonstrated a reduction in food intake, and body weight loss in mice [Shearman et al 2006]. Knockout of the GOAT enzyme that activates ghrelin in vivo has been demonstrated to reduce hedonic feeding behaviour in mice [Davis et al 2012], and therefore opened up a further possible avenue for ghrelin therapeutics. Other groups have subsequently manipulated GOAT, demonstrating end-product inhibition of GOAT activity [Yang et al 2008], and it remains a potential target for obesity treatment [Gualillo et al 2008].…”