1781-P: Adipocyte GI Signaling Regulates Whole-Body Glucose Homeostasis and Insulin Sensitivity

Adipocyte dysfunction links obesity to insulin resistance and type 2 diabetes (T2D). Receptor-mediated activation of heterotrimeric G proteins plays a pivotal role in regulating adipocyte function. Little is known about the potential in vivo metabolic roles of G_i-type G proteins expressed by adipocytes, primarily due to the lack of suitable animal models. To address this issue, we generated adipo^cre-ROSA 26^PTXmice in which G_isignaling was selectively disrupted in adipocytes ('adipo-Gi KO mice'). Compared to control mice, adipo-Gi KO mice displayed increased lipolysis and decreased fat mass when maintained on regular chow or a high fat diet (HFD). Moreover, HFD adipo-Gi KO mice showed impaired glucose tolerance and reduced insulin sensitivity. In vitro studies with primary adipocytes prepared from adipo-Gi KO mice indicated that the lack of G_isignaling led to impaired insulin signaling and reduced insulin-stimulated glucose uptake. In parallel, we also used a chemo-genetic approach to generate a mouse line selectively expressing a CNO-sensitive, G_i-coupled DREADD (designer receptor exclusively activated by a designer drug) in adipocytes (adipo-GiD mice). CNO-induced activation of adipocyte G_i signaling in adipo-GiD mice significantly improved glucose tolerance and insulin sensitivity independent of the diet that the mice consumed (regular chow or HFD). In vivo ¹⁴C-2-deoxy-glucose uptake assays demonstrated that activation of adipocyte G_isignaling enhanced insulin-induced glucose uptake in adipose tissues. Stimulation of adipocyte G_isignaling activation also further enhanced insulin signaling in adipose tissues. Taken together, our data clearly demonstrate that adipocyte G_isignaling is a critical regulator of insulin signaling in adipocytes and is critical for the maintenance of glucose homeostasis. A better understanding of the mechanisms through which G_ipromotes adipocyte insulin signaling should stimulate the development of novel antidiabetic drugs.