Adipocyte Gi signaling is essential for maintaining whole-body glucose homeostasis and insulin sensitivity

Adipocyte dysfunction links obesity to insulin resistance and type 2 diabetes. Adipocyte function is regulated by receptor-mediated activation of heterotrimeric G proteins. 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 question, we generated mice lacking functional G(i) proteins selectively in adipocytes. Here we report that these mutant mice displayed significantly impaired glucose tolerance and reduced insulin sensitivity when maintained on an obesogenic diet. In contrast, using a chemogenetic strategy, we demonstrated that activation of G(i) signaling selectively in adipocytes greatly improved glucose homeostasis and insulin signaling. We also elucidated the cellular mechanisms underlying the observed metabolic phenotypes. Our data support the concept that adipocyte G(i) signaling is essential for maintaining euglycemia. Drug-mediated activation of adipocyte G(i) signaling may prove beneficial for restoring proper glucose homeostasis in type 2 diabetes. Gs-coupled receptor signaling is well known to modulate adipocyte metabolism, but the role of Gi-coupled receptors in adipose tissue is less well understood. Here the authors show that signaling via Gi-type G proteins expressed by adipocytes is essential for maintaining proper blood glucose homeostasis.