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.

Figure 1

Illustrates acyl-ghrelin levels following A) a twenty-four hour fast. This figure also depicts break point responding under a progressive ratio of reinforcement expressed as active nose pokes in B) wild-type, C) GOAT-KO or D) GHSR-null mice under ad lib and fasting conditions. Ad libidum (Ad lib), Deprivation (Dep) * indicates p<0.05.

Figure 2

Depicts break point responding expressed as active nose pokes in A) wild-type or B) GHSR-null mice following acute administration of acyl-ghrelin and hedonic feeding behavior in C) GOAT or D) GHSR-null mice. This figure also illustrates E) blood glucose following an overnight fast and F) body weight gain from a medium chain triglyceride diet in wild-type and GOAT-KO mice. Preload refers to feeding from chow following fasting* indicates p<0.05.

Figure 3

Indicates expression of prepro-orexin, orexin-1 receptor (Orx1R) and orexin-2 receptor (OrxR2) in the hypothalamus A–C and nucleus accumbens (NAcc) D–E in wild-type and GOAT-KO mice following an overnight fast. * indicates p<0.05.