Diet-induced obesity blunts the behavioural effects of ghrelin: studies in a mouse-progressive ratio task

Rational 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. Methods 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. Results 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-Lys3)-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. Conclusions 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.