Alexandre Moura-Assis, Kaja Plucińska, David Meseguer, Aiste Baleisyte, Bandy Chen, Kyle Pellegrino, Luca Parolari, Jordan T. Shaked, Keith J. Page, Douglas W. Barrows, Thomas S. Carroll, Jose G. Grajales-Reyes, Daxiang Na, Amanda Rodríguez-Díaz, Jessica Furtado, Juan Uribe Isaza, Hans H. Schiffer, Yun Chen, Huikai Sun, Nidhi Kaushal, Holger Monenschein, Daniel F. Barker, María José Ortuño, Nicolas Renier, Paul Cohen, Mark Carlton, Nathaniel Heintz, Nicola Brice, Jeffrey M. Friedman, Marc Schneeberger
Obesity emerges from a complex interplay of factors, including imbalanced interoception, genetic predisposition, and environmental cues, which ultimately disrupt body weight homeostasis1. While much research has concentrated on strategies to suppress appetite for sustained weight loss, insufficient attention has been given to counterregulatory mechanisms that promote energy expenditure. Here, we show that chronic inhibition of GABAergic neurons in the dorsal raphe nucleus and ventrolateral periaqueductal gray (DRN/vlPAGVGAT) reduces body weight in diet-induced obese (DIO) male mice. In this study, molecular profiling and in-situ hybridization in rodent and human brains revealed that the constitutively activated orphan receptor GPR6 is selectively enriched in DRN/vlPAGVGAT neurons. We next developed and administered a potent and highly selective GPR6 inverse agonist, which significantly prevented weight gain in male mice exposed to a high-fat diet by stimulating brown adipose tissue thermogenesis without affecting appetite. Altogether, this study integrates transcriptomic profiling, high-throughput drug screening and metabolic phenotyping to successfully identify a candidate to treat obesity. Targeting neurons that regulate energy balance may offer new approaches for obesity treatment. Here, authors show that chemogenetic and pharmacological manipulation of GABAergic neurons in the DRN/vlPAG increases adaptive thermogenesis and reduces weight gain in mice fed a highfat diet.