Hepatic Gi signaling regulates whole-body glucose homeostasis
Mario Rossi, … , Owen P. McGuinness, Jürgen Wess
Mario Rossi, … , Owen P. McGuinness, Jürgen Wess
Published January 16, 2018
Citation Information: J Clin Invest. 2018;128(2):746-759. https://doi.org/10.1172/JCI94505.
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Research Article Endocrinology

Hepatic Gi signaling regulates whole-body glucose homeostasis

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.

Authors

Mario Rossi, Lu Zhu, Sara M. McMillin, Sai Prasad Pydi, Shanu Jain, Lei Wang, Yinghong Cui, Regina J. Lee, Amanda H. Cohen, Hideaki Kaneto, Morris J. Birnbaum, Yanling Ma, Yaron Rotman, Jie Liu, Travis J. Cyphert, Toren Finkel, Owen P. McGuinness, Jürgen Wess

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Figure 1

In vivo metabolic studies in Hep-Di mice, which selectively express the Di designer receptor in hepatocytes.

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In vivo metabolic studies in Hep-Di mice, which selectively express the ...
(A–F) In vivo metabolic tests performed using Hep-Di mice and control littermates (CTR) treated with the AAV-TBG-EGFP control virus. (A and B) CNO challenge tests. Mice that had free access to food (fed) (A) or had been fasted overnight for approximately 12 hours (fasted) (B) were injected with CNO (10 mg/kg i.p.) or vehicle, followed by monitoring of blood glucose levels. (C) IGTTS (2 g glucose/kg i.p.). (D) PTT (2 g sodium pyruvate/kg i.p.). (E) ITTS (0.75 U insulin/kg i.p.). (F) Glucagon challenge test (16 μg glucagon/kg i.p). (G–J) Effect of CNO on hepatic glucose fluxes in conscious Hep-Di mice in vivo. (G) Changes in arterial blood glucose levels and rates of (H) glucose appearance (endogenous glucose production [Endo-Ra]), (I) hepatic glycogenolysis, and (J) gluconeogenesis following CNO (10 mg/kg i.v.) treatment of Hep-Di and control mice. All experiments were carried out with chronically catheterized, conscious mice, as described in detail in Methods. After a 5-hour fast, mice were injected with CNO (10 mg/kg) at t0. Mice were maintained on regular chow. All studies were performed using 11- to 16-week-old male mice. Data represent the mean ± SEM (n = 6–8 mice/group). *P < 0.05, **P < 0.01, and ***P < 0.001 versus the corresponding control value. Significance was determined by (A–F) 2-way ANOVA followed by Bonferroni’s post-hoc test and (G–J) 2-tailed Student’s t test.