Adipocyte Gq signaling is a regulator of glucose and lipid homeostasis in mice

Abstract

Obesity is the major driver of the global epidemic in type 2 diabetes (T2D). In individuals with obesity, impaired insulin action leads to increased lipolysis in adipocytes, resulting in elevated plasma free fatty acid (FFA) levels that promote peripheral insulin resistance, a hallmark of T2D. Here we show, by using a combined genetic/biochemical/pharmacologic approach, that increased adipocyte lipolysis can be prevented by selective activation of adipocyte G_q signaling in vitro and in vivo (in mice). Activation of this pathway by a G_q-coupled designer receptor or by an agonist acting on an endogenous adipocyte G_q-coupled receptor (CysLT₂ receptor) greatly improved glucose and lipid homeostasis in obese mice or in mice with adipocyte insulin receptor deficiency. Our findings identify adipocyte G_q signaling as an essential regulator of whole-body glucose and lipid homeostasis and should inform the development of novel classes of GPCR-based antidiabetic drugs.