G proteins of the G12 family expressed by POMC neurons regulate key metabolic functions.

Proopiomelanocortin (POMC) neurons play a key role in maintaining glucose and energy homeostasis. POMC neurons express many heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors that are linked to different functional classes of G proteins. The potential role of G12/13 in regulating the function of central POMC neurons remains unknown. To address this question, we used a chemogenetic approach to selectively stimulate G12/13 signaling in POMC neurons. We found that receptor-mediated activation of G12/13 signaling in POMC neurons caused notable improvements in glucose homeostasis in lean and obese mice. Stimulation of G12/13 signaling in POMC neurons also enhanced the physiological actions of leptin. Studies with G12/13 knockout mice showed that G12/13 signaling in POMC neurons mediated the beneficial metabolic effects of lorcaserin, an appetite-suppressant drug that selectively activates serotonin 5-HT2C receptors. These findings indicate that G12/13-coupled receptors expressed by POMC neurons represent potential targets for advanced classes of antidiabetic and appetite-suppressant drugs.