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Hepatic β-arrestin 2 is essential for maintaining euglycemia
Lu Zhu, … , Wei Chen, Jürgen Wess
Lu Zhu, … , Wei Chen, Jürgen Wess
Published June 26, 2017
Citation Information: J Clin Invest. 2017;127(8):2941-2945. https://doi.org/10.1172/JCI92913.
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Brief Report Endocrinology Metabolism

Hepatic β-arrestin 2 is essential for maintaining euglycemia

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Abstract

An increase in hepatic glucose production (HGP) represents a key feature of type 2 diabetes. This deficiency in metabolic control of glucose production critically depends on enhanced signaling through hepatic glucagon receptors (GCGRs). Here, we have demonstrated that selective inactivation of the GPCR-associated protein β-arrestin 2 in hepatocytes of adult mice results in greatly increased hepatic GCGR signaling, leading to striking deficits in glucose homeostasis. However, hepatocyte-specific β-arrestin 2 deficiency did not affect hepatic insulin sensitivity or β-adrenergic signaling. Adult mice lacking β-arrestin 1 selectively in hepatocytes did not show any changes in glucose homeostasis. Importantly, hepatocyte-specific overexpression of β-arrestin 2 greatly reduced hepatic GCGR signaling and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Our data support the concept that strategies aimed at enhancing hepatic β-arrestin 2 activity could prove useful for suppressing HGP for therapeutic purposes.

Authors

Lu Zhu, Mario Rossi, Yinghong Cui, Regina J. Lee, Wataru Sakamoto, Nicole A. Perry, Nikhil M. Urs, Marc G. Caron, Vsevolod V. Gurevich, Grzegorz Godlewski, George Kunos, Minyong Chen, Wei Chen, Jürgen Wess

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Figure 2

Metabolic phenotyping and GCGR internalization studies.

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Metabolic phenotyping and GCGR internalization studies.
(A and B) i.p. G...
(A and B) i.p. Glucose tolerance tests (IGTT). (C and D) i.p. pyruvate tolerance tests (PTT). In B and D, an anti-GCGR Ab (10 mg/kg i.p) was administered approximately 24 hours prior to glucose or pyruvate injections, respectively. (E) i.p. glucagon challenge test (GCT). (F–I) In vitro studies with primary mouse hepatocytes. The ability of glucagon to stimulate intracellular cAMP accumulation (F), glucose production (G), and the expression of the G6Pase (H) and Pepck (I) genes was studied using primary hepatocytes prepared from hep-barr2–KO mice and their control littermates. Gene expression data were normalized relative to the expression of β-actin (quantitative reverse-transcriptase PCR [qRT-PCR] analysis). Hepatocyte data are shown as mean ± SEM of at least 3 independent experiments. (J and K) Hepatic glycogen and triglyceride content. All studies were carried out with male mice consuming RC (mouse age, 11–20 weeks). Data represent mean ± SEM (n = 7–10 mice per group) (A–K). *P < 0.05; **P < 0.01, versus control (Student’s t test). (L and M) GCGR internalization assays. Primary hepatocytes prepared from hep-barr2–KO (L) or hep-barr1–KO (M) mice and their control littermates were stimulated with glucagon (100 nM) for 30 minutes at 37 °C. Cell surface GCGRs were labeled with I125-glucagon. Data represent the mean ± SEM of 3 independent experiments, each carried out in triplicate. **P < 0.01, versus cells not exposed to glucagon (Student’s t test).
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