Kavli Affiliate: Jeffrey M. Friedman and Nathaniel Heintz
| Authors: Alexandre Moura-Assis, Kaja Plucinska, Aiste Baleisyte, David David, Kyle Pellegrino, Luca Parolari, Parolari T Shaked, Keith J Page, Douglas W Douglas, Thomas S Carrol, Jose G Grajales-Reyes, Daxiang Na, Hans H Schiffer, Yun Chen, Huikai Sun, Nidhi Cohen, Holger Monenschein, Daniel F Barker, Maria J Ortuno, Nicolas Renier, Paul Cohen, Mark Carlton, Nathaniel Heintz, Nicola L Brice, Jeffrey M Friedman and Marc Schneeberger
| Summary:
Obesity emerges from a complex interplay of factors, including imbalanced interoception, genetic predisposition, and environmental cues, ultimately disrupting body weight homeostasis. 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 (DRNVGAT) reduces body weight in diet-induced obese (DIO) 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 DRNVGAT neurons. We next developed and administered a potent and highly selective GPR6 inverse agonist, which significantly reduced weight gain in DIO mice by stimulating brown adipose tissue thermogenesis without affecting appetite. Altogether, this study transitions from transcriptomic profiling, high-throughput drug screening and metabolic phenotyping to successfully identify a novel candidate to treat obesity.