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- Title
Hepatic Gi signaling regulates whole-body glucose homeostasis.
- Authors
Rossi, Mario; Zhu, Lu; McMillin, Sara M; Pydi, Sai Prasad; Jain, Shanu; Wang, Lei; Cui, Yinghong; Lee, Regina J; Cohen, Amanda H; Kaneto, Hideaki; Birnbaum, Morris J; Ma, Yanling; Rotman, Yaron; Liu, Jie; Cyphert, Travis J; Finkel, Toren; McGuinness, Owen P; Wess, Jürgen
- Abstract
An increase in hepatic glucose production (HGP) is a key feature of type 2 diabetes. Excessive signaling through hepatic Gs-linked 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-coupled GPCRs may prove beneficial as antidiabetic drugs.
- Publication
Journal of Clinical Investigation, 2018, Vol 128, Issue 2, p746
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI94505