Hepatic [beta]-arrestin 2 is essential for maintaining euglycemia

• Published in: The Journal of clinical investigation Vol. 127; no. 8; pp. 2941 - 2945
• Main Authors: Zhu, Lu, Rossi, Mario, Cui, Yinghong, Lee, Regina J, Sakamoto, Wataru, Perry, Nicole A, Urs, Nikhil M, Caron, Marc G, Gurevich, Vsevolod V, Godlewski, Grzegorz, Kunos, George, Chen, Minyong, Chen, Wei, Wess, Jurgen
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 01.08.2017
• Subjects: Arrestins; Blood glucose; Cellular signal transduction; Hepatocytes; Type 2 diabetes
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI92913

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 [beta]-arrestin 2 in hepatocytes of adult mice results in greatly increased hepatic GCGR signaling, leading to striking deficits in glucose homeostasis. However, hepatocyte-specific [beta]-arrestin 2 deficiency did not affect hepatic insulin sensitivity or p -adrenergic signaling. Adult mice lacking [beta]-arrestin 1 selectively in hepatocytes did not show any changes in glucose homeostasis. Importantly, hepatocyte-specific overexpression of [beta]-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 [beta]-arrestin 2 activity could prove useful for suppressing HGP for therapeutic purposes.