title: Ghrelin signaling in the ventral tegmental area mediates both reward-based feeding and fasting-induced hyperphagia on high-fat diet.
abstract: 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 10days and a high-fat diet (HFD) was supplied either in the third hour after 2h 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 4μg of ghrelin, induced a dose-related increase of 1h 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 10μg 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 4μg 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.
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, PR China.
authors.forename: X J
authors.initials: XJ
authors.lastname: Wei
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, PR China.
authors.forename: B
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, PR China.
authors.forename: K
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, PR China.
authors.forename: B
authors.initials: B
authors.lastname: Lv
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, PR China. Electronic address: jqyan810@gmail.com.
authors.forename: J Q
authors.initials: JQ
authors.lastname: Yan
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D005215:Fasting / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D005508:Food Deprivation / Q000502:physiology; D054439:Ghrelin / Q000008:administration & dosage / Q000378:metabolism*; D006728:Hormones / Q000494:pharmacology; D006963:Hyperphagia / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012201:Reward; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
chemical_list: C520836:GHRP-6, Lys(3)-; D054439:Ghrelin; D006728:Hormones; D009842:Oligopeptides; D054440:Receptors, Ghrelin
keywords: fasting-induced hyperphagia; ghrelin; high-fat diet; nutritional state; reward-based feeding; ventral tegmental area