Food for Health Ireland, University College Cork, Cork, Ireland.
Psychopharmacology (Berl). 2012 Mar;220(1):173-81. doi: 10.1007/s00213-011-2468-0. Epub 2011 Sep 3.
The ghrelinergic system is implicated in the development of obesity and in modulating central reward systems. It has been reported that diet-induced obesity causes blunted responding on food intake to ghrelin administration, associated with central ghrelin resistance. Here we investigate whether the stimulatory effects of ghrelin on the reward system are altered in diet-induced obese mice.
Obesity was induced in C57BL/6J mice by feeding high-fat diet for 13 weeks. Mice were trained in an operant fixed and exponential progressive ratio task to respond for sucrose rewards. In an ad libitum fed state, ghrelin and a ghrelin receptor antagonist were administered in the progressive ratio. Alterations in the central ghrelin system in diet-induced obese mice were assessed.
Obese mice showed attenuated acquisition and performance in the fixed and progressive ratio paradigm. Most importantly, diet-induced obesity inhibited the stimulatory effects of ghrelin (2 nmol, 3 nmol/10 g) on progressive ratio responding whereas lean animals presented with increased responding. Administration of the ghrelin-receptor antagonist (D-Lys(3))-GHRP-6 (66.6 nmol/10 g) decreased performance in lean but not obese mice. This insensitivity to ghrelin receptor ligands in mice on high-fat diet was further supported by decreased mRNA expression of the ghrelin receptor in the hypothalamus and the nucleus accumbens in obese mice.
This study demonstrates that the modulatory effects of ghrelin receptor ligands are blunted in a mouse model of diet-induced obesity in a progressive ratio task. Thereby, our data extend the previously described ghrelin resistance in these mice from food intake to reward-associated behaviours.
胃饥饿素能系统参与肥胖的发展，并调节中枢奖励系统。有报道称，饮食诱导肥胖导致食物摄入对胃饥饿素给药的反应迟钝，与中枢胃饥饿素抵抗有关。在这里，我们研究饮食诱导肥胖的小鼠中胃饥饿素对奖励系统的刺激作用是否发生改变。
用高脂肪饮食喂养 C57BL/6J 小鼠 13 周诱导肥胖。用蔗糖奖赏操作条件反射程序训练小鼠。在自由进食状态下，给予胃饥饿素和胃饥饿素受体拮抗剂进行递增比率实验。评估饮食诱导肥胖小鼠中中枢胃饥饿素系统的变化。
肥胖小鼠在固定和递增比率范式中表现出习得和表现能力下降。最重要的是，饮食诱导的肥胖抑制了胃饥饿素（2 nmol，3 nmol/10 g）对递增比率反应的刺激作用，而瘦鼠则表现出反应增强。给予胃饥饿素受体拮抗剂（D-Lys(3))-GHRP-6（66.6 nmol/10 g）降低了瘦鼠但不影响肥胖鼠的表现。在高脂肪饮食的肥胖小鼠中，胃饥饿素受体配体的这种不敏感性进一步得到支持，因为下丘脑和伏隔核中胃饥饿素受体的 mRNA 表达减少。
本研究表明，在递增比率任务中，肥胖小鼠模型中胃饥饿素受体配体的调节作用减弱。因此，我们的数据将以前描述的这些肥胖小鼠的胃饥饿素抵抗从食物摄入扩展到与奖励相关的行为。
