G q signaling in adipocytes is a key regulator of systemic glucose and lipid homeostasis

Abstract

Objective : Adipocytes play a crucial role in the regulation of whole-body glucose and energy homeostasis. We aimed to investigate the metabolic effects of selective activation of Gq signaling in adipocytes in vivo. Methods : We generated a new mutant mouse strain that expressed a CNO-sensitive, Gq-coupled designer G protein-coupled receptor (Gq DREADD = GqD) selectively in adipocytes (adipo-GqD mice). Notably, DREADDs are activated by an exogenous agent (e.g. CNO) that is otherwise pharmacologically inert. We also created a mouse strain that selectively lacked Galpha-q and -11 in adipocytes (adipo-Gq/11 KO mice). Mice consuming either regular chow or a high-fat diet (HFD) were subjected to a series of metabolic tests. Results : CNO-mediated activation of adipocyte Gq signaling in the adipo-GqD mice significantly improved glucose homeostasis and suppressed lipolysis. In contrast, adipo-Gq/11 KO mice showed the opposite metabolic phenotypes, impaired glucose metabolism and enhanced lipolysis. In vitro studies with cultured adipocytes showed that activation of Gq signaling enhanced glucose uptake and inhibited lipolysis in an AMPK-dependent fashion. We hypothesized that activation of adipocyte Gq signaling might compensate for impaired insulin signaling in adipocytes. To test this hypothesis, we generated adipo-GqD mice that carried only one copy of the insulin receptor (IR) gene in adipocytes (adipo-GqD-IR+/- mice). Interestingly, activation of adipocyte Gq signaling by CNO ameliorated the metabolic deficits displayed by adipo-GqD-IR+/- mice maintained on a HFD. Conclusion : Activation of adipocyte Gq signaling counteracts the metabolic deficits caused by impaired IR signaling in adipocytes. Our data indicate that adipocyte Gq signaling represents an essential regulator of whole-body glucose and lipid homeostasis.