32-OR: Receptor-Mediated Gq Signaling in Adipocytes as a Critical Modulator of Systemic Glucose and Lipid Homeostasis

• Published in: Diabetes (New York, N.Y.) Vol. 70; no. Supplement_1
• Main Authors: KIMURA, TAKEFUMI, PYDI, SAI PRASAD, WANG, LEI, CUI, YINGHONG, GAVRILOVA, OKSANA, WESS, JÜRGEN
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01.06.2021
• Subjects: Adipocytes; Diabetes; Diabetes mellitus (non-insulin dependent); Drug development; Glucose; Glucose metabolism; High fat diet; Homeostasis; Insulin; Insulin resistance; Lipolysis; Metabolic rate; Metabolism; Mutants; Phenotypes; Triglycerides
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db21-32-OR

Objective: In obesity, decreased insulin action leads to the accelerated breakdown of triglycerides stored in adipocytes, causing peripheral insulin resistance, a hallmark of type 2 diabetes. In this study, we investigated whether selective activation of Gq signaling in adipocytes might cause similar metabolic effects as insulin. Methods: We generated a novel mutant mouse strain that expressed a CNO-sensitive, Gq-coupled designer G protein-coupled receptor (Gq DREADD = QGD) selectively in adipocytes (adipo-GqD mice). DREADDs are stimulated by an exogenous agent (e.g., CNO) that is otherwise pharmacologically inactive. We also made another mouse strain that selectively lacked Galpha-q and -11 in adipocytes (adipo-Gq/11 KO mice). Both mutant mouse strains underwent 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. Consistent with these findings, in vitro studies with cultured adipocytes demonstrated that activation of Gq signaling enhanced glucose uptake and inhibited lipolysis in an AMPK-dependent manner. To test the hypothesis that activation of adipocyte Gq signaling might counteract impaired insulin signaling in adipocytes, 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 high-fat diet. Conclusion: Our data indicate that adipocyte Gq signaling represents an essential regulator of whole-body glucose and lipid homeostasis. This finding is likely to stimulate the development of novel drugs that can mimic the actions of insulin in the insulin-resistant state. Disclosure T. Kimura: None. S. Pydi: None. L. Wang: None. Y. Cui: None. O. Gavrilova: None. J. Wess: None.