G proteins of the G(12) 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 G(12/13) in regulating the function of central POMC neurons remains unknown. To address this question, we used a chemogenetic approach to selectively stimulate G(12/13) signaling in POMC neurons. We found that receptor-mediated activation of G(12/13) signaling in POMC neurons caused notable improvements in glucose homeostasis in lean and obese mice. Stimulation of G(12/13) signaling in POMC neurons also enhanced the physiological actions of leptin. Studies with G(12/13) knockout mice showed that G(12/13) signaling in POMC neurons mediated the beneficial metabolic effects of lorcaserin, an appetite-suppressant drug that selectively activates serotonin 5-HT(2C) receptors. These findings indicate that G(12/13)-coupled receptors expressed by POMC neurons represent potential targets for advanced classes of antidiabetic and appetite-suppressant drugs.