1971-P: Activation of Adipocyte Gq Signaling Causes Improved Whole-Body Glucose Homeostasis

Abstract

Objective: Obesity and type 2 diabetes have emerged as severe threats to human health worldwide. Adipocytes play a key role in the regulation of whole-body glucose and energy homeostasis. The aim of this study was to examine the metabolic effects of selective activation of Gq signaling in adipocytes in vivo. Methods: We generated a novel mutant mouse strain that expressed a CNO-sensitive designer G protein-coupled receptor (Gq DREADD = GqD) which couples to Gq selectively in adipocytes (adipo-GqD mice). Notably, DREADDs can only be activated by an exogenous agent (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 were subjected to a series of metabolic tests. Results: CNO-mediated activation of GqD in adipo-GqD mice caused significant improvements in glucose homeostasis and suppressed lipolysis, while adipo-Gq/11 KO mice showed opposite metabolic phenotypes (impaired glucose metabolism and enhanced lipolysis). In agreement with these findings, CNO treatment of GqD-expressing 3T3-F442A adipocytes resulted in enhanced glucose uptake and inhibited CL316,243-induced lipolysis. Conclusion: Studies with newly generated mouse models allowed us to evaluate the metabolic relevance of adipocyte Gq signaling in vivo. Most strikingly, Gq activation in adipocytes led to improved glucose homeostasis and reduced lipolysis in mice. These findings are of considerable relevance for the development of novel antidiabetic drugs. Disclosure T. Kimura: None. S. Pydi: None. L. Wang: None. Y. Cui: None. O. Gavrilova: None. J. Wess: None. Funding Japan Society for the Promotion of Science