Beta-arrestin-2 acts as a negative regulator of hepatic hepatic glucose production in vivo

Monday, September 22, 2014 — Poster Session II
4:00 p.m. – 6:00 p.m.	FAES Academic Center	NIDDK	MOLBIO-25

* FARE Award Winner

Authors

• L. Zhu
• M. Rossi
• Y. Cui
• W. Sakamoto
• N.M. Urs
• M.G. Caron
• J.H. Wess

Abstract

Type 2 diabetes (T2D) has emerged as one of the major threats to human health in this century. Typically, hepatic glucose production (HGP) is unphysiologically high in T2D. HGP is modulated by G protein-coupled receptors (GPCRs) and downstream signaling networks. For example, activation of hepatic glucagon receptors, which are coupled to the stimulatory G protein Gs, leads to a pronounced increase in HGP. GPCR signaling can be regulated by the activity of arrestins. To explore the role of beta-arrestin-2 (barr2) in hepatocyte function, we first generated conditional barr2 knockout mice which specifically lack barr2 in hepatocytes (hep-barr2-KO mice). Hep-barr2-KO mice showed impaired glucose tolerance, associated with enhanced signaling through hepatic glucagon receptors in vivo and in vitro. The hepatic expression levels of the key gluconeogenic enzymes, PEPCK and G-6-Pase, were significantly increased in hep-barr2-KO mice. Moreover, overexpression of barr2 in mouse hepatocytes inhibited glucagon-induced increases of blood glucose levels, further confirming that barr2 acts represents an important negative regulator of hepatic glucagon receptor signaling. We speculate that strategies aimed at enhancing the activity of barr2 in hepatocytes could prove useful to suppress HGP in T2D.

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