Yinghong Cui

Impaired insulin secretion represents a key feature of type 2 diabetes (T2D), a major global health burden. Insulin release from pancreatic β cells is regulated by G protein–coupled receptors linked to different functional classes of G proteins. The potential metabolic role of β cell G _12/13 (G ₁₂ hereafter) signaling remains unexplored. Thus, we studied the potential metabolic outcomes of β cell G ₁₂ activation by using a combination of mouse gene knockout technology and β cell–specific chemogenetic approaches. We found that selective activation of β cell G ₁₂ signaling strongly promoted insulin secretion, thus protecting mice against obesity-associated metabolic deficits and improving glycemic control in a mouse model of T2D. Mechanistic studies with perifused pancreatic mouse islets identified ROCK as a key downstream effector of G ₁₂ signaling and potent trigger of insulin secretion. Collectively, these findings suggest that G protein–coupled receptors linked to G ₁₂ in β cells represent potential targets for antidiabetic drugs.

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.

Agents able to enhance the activity or levels of β-arrestin-1 in brown fat may prove useful as antidiabetic drugs.

This study suggests that agents able to enhance the activity of β-arrestin-1 in AgRP neurons may be useful as antidiabetic drugs.