Ghrelin signaling in the ventral tegmental area mediates both reward-based feeding and fasting-induced hyperphagia on high-fat diet

•Intra-VTA microinjection of ghrelin stimulates reward-based feeding on HFD and enhances hyperphagia on HFD.•The stimulatory effect of ghrelin could be blocked by pretreatment with D-Lys3-GHRP-6 intra-VTA microinjection.•Intra-VTA microinjection of ghrelin increased 1 h HFD intake when sated but did not stimulate 1 h HFD intake when fasted.•Intra-VTA microinjection of D-Lys3-GHRP-6 inhibited HFD intake when sated but just showed a trend of decrease when fasted.

Ghrelin is a potent orexigenic hormone that acts in the central nervous system to stimulate food intake via the growth hormone secretagogue receptor (GHSR) that is abundantly expressed in the ventral tegmental area (VTA). Not only does ghrelin modulate feeding behavior via a homeostatic mechanism, but numerous studies have identified ghrelin as a key regulator of reward-based hedonic feeding behaviors. Nutritional states influence ghrelin and GHSR expression as well as the behavioral sensitivity to reward-inducing stimuli. In the current study, we examined the role of ghrelin at the VTA level in food intake in two different nutritional states, satiety and hunger, by using a restricted feeding model. In this model, rats were conditioned to a daily 3-h (h) feeding session on standard chow for 10 days and a high-fat diet (HFD) was supplied either in the third hour after 2 h of chow diet intake, or at the beginning of a daily meal on the test day. We found that intra-VTA microinjection of 1, 2, and 4 μg of ghrelin, induced a dose-related increase of 1 h of reward-based feeding on HFD in sated rats, as well as a 24-h body weight gain. The overconsumption stimulated by ghrelin could be attenuated by 10 μg of direct infusion of the ghrelin receptor antagonist D-Lys3-GHRP-6 into the VTA. Moreover, our data showed that the injection of 1, 2, and 4 μg of ghrelin in the VTA, enhanced fasting-induced hyperphagia on HFD in a dose-related manner following a 21-h food restriction as well as a 24-h body weight gain. Conversely, hyperphagia on HFD that is potentiated by ghrelin could be blocked by pretreatment with a 10-μg D-Lys3-GHRP-6 intra-VTA microinjection. Collectively, these data demonstrate that ghrelin signaling at the VTA level mediates both reward-based eating and fasting-induced hyperphagia and provides a primary target for the control of the intake of rewarding food.