Hepatic Gi signaling regulates whole-body glucose homeostasis.

An increase in hepatic glucose production (HGP) is a key feature of type 2 diabetes. Excessive signaling through hepatic G(s)-linked glucagon receptors critically contributes to pathologically elevated HGP. Here, we tested the hypothesis that this metabolic impairment can be counteracted by enhancing hepatic G(i) signaling. Specifically, we used a chemogenetic approach to selectively activate G(i)-type G proteins in mouse hepatocytes in vivo. Unexpectedly, activation of hepatic G(i) signaling triggered a pronounced increase in HGP and severely impaired glucose homeostasis. Moreover, increased G(i) signaling stimulated glucose release in human hepatocytes. A lack of functional G(i)-type G proteins in hepatocytes reduced blood glucose levels and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Additionally, we delineated a signaling cascade that links hepatic G(i) signaling to ROS production, JNK activation, and a subsequent increase in HGP. Taken together, our data support the concept that drugs able to block hepatic G(i)-coupled GPCRs may prove beneficial as antidiabetic drugs.