Ventral pallidal GABAergic neurons control hedonic feeding and obesity

Abstract

Food intake is governed by two interacting drives. The homeostatic hunger drive regulates food intake to fulfill caloric needs while the hedonic drive promotes intake of palatable foods outside of caloric need. It is unclear which neural substrates can control the hedonic drive and thereby reduce overeating of palatable foods and associated obesity. Here, we show that ventral pallidal GABAergic neurons (VPGABA) preferentially control hedonic feeding and are necessary for diet-induced obesity in mice. Stimulating VPGABA neurons drove robust consumption of high-fat diet and liquids, but not regular laboratory chow. Despite driving intake of palatable foods, VPGABA neurons are relatively insensitive to homeostatic signals - they express few hunger-hormone receptors and are not activated by ghrelin administration or fasting. Single-cell calcium imaging revealed stronger engagement of VPGABA neurons during long vs short feeding bouts, suggesting control over bout duration, which has been linked to palatability. This was confirmed with closed-loop optogenetic stimulation. Finally, taCasp3-mediated ablation of VPGABA neurons reduced intake of palatable liquids and blocked high-fat diet-induced obesity without impacting homeostatic feeding. Together, these findings establish VPGABA neurons as a neural population that preferentially controls hedonic over homeostatic feeding and can be leveraged to block obesity in mice.