%0 Journal Article
%T Hepatic Gi signaling regulates whole-body glucose homeostasis
%A Ama H. Cohen
%A Hideaki Kaneto
%A Jie Liu
%A J¨¹rgen Wess
%A Lei Wang
%A Lu Zhu
%A Mario Rossi
%A Morris J. Birnbaum
%A Owen P. McGuinness
%A Regina J. Lee
%A Sai Prasad Pydi
%A Sara M. McMillin
%A Shanu Jain
%A Toren Finkel
%A Travis J. Cyphert
%A Yanling Ma
%A Yaron Rotman
%A Yinghong Cui
%J The Journal of Clinical Investigation
%D 2018
%R 10.1172/JCI94505
%X An increase in hepatic glucose production (HGP) is a key feature of type 2 diabetes. Excessive signaling through hepatic Gs¨Clinked glucagon receptors critically contributes to pathologically elevated HGP. Here, we tested the hypothesis that this metabolic impairment can be counteracted by enhancing hepatic Gi signaling. Specifically, we used a chemogenetic approach to selectively activate Gi-type G proteins in mouse hepatocytes in vivo. Unexpectedly, activation of hepatic Gi signaling triggered a pronounced increase in HGP and severely impaired glucose homeostasis. Moreover, increased Gi signaling stimulated glucose release in human hepatocytes. A lack of functional Gi-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 Gi 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 Gi¨Ccoupled GPCRs may prove beneficial as antidiabetic drugs
%U https://www.jci.org/articles/view/94505