Department of Psychiatry, Metabolic Diseases Institute, University of Cincinnati, OH, USA.
Horm Behav. 2012 Nov;62(5):598-604. doi: 10.1016/j.yhbeh.2012.08.009. Epub 2012 Sep 8.
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.
胃饥饿素是一种促进食欲的激素，调节稳态和与奖励相关的进食行为。最近的证据表明，肠道酶胃饥饿素 O-酰基转移酶 (GOAT) 对胃饥饿素的酰化是使胃饥饿素在其靶组织中最大限度地发挥活性所必需的。在这里，我们使用行为药理学和缺乏 GOAT 和胃饥饿素受体 (GHSR) 的突变小鼠来测试 GOAT 活性是否调节食物动机和食物快感的假设。我们评估了酰基胃饥饿素给药后的操作性反应，并评估了内源性 GOAT 活性对 GOAT 和 GHSR 缺失小鼠操作性反应的必要性。我们还使用“甜点效应”方案在 GOAT-KO 和 GHSR 缺失小鼠中检查了快感为基础的进食行为，该方案评估了在热量饱和的小鼠中摄入美味高脂肪饮食“甜点”的情况。酰基胃饥饿素的药理学给药增强了操作性反应；值得注意的是，这种作用依赖于完整的 GHSR 信号。GOAT-KO 小鼠表现出操作性反应减弱和快感进食减少，与对照组相比。这些行为结果与 GOAT-KO 小鼠奖励相关脑区的食欲素-1 受体表达减少相关。总之，胃饥饿素刺激食物动机的能力依赖于完整的 GHSR 信号，并受内源性 GOAT 活性的调节。此外，GOAT 活性对于快感进食行为是必需的，这种作用可能由大脑前叶食欲素信号介导。这些数据强调了 GOAT-ghrelin 系统在调节食物动机和快感进食中的重要性。
