Hepatic β-arrestin 2 is essential for maintaining euglycemia

• Published in: The Journal of clinical investigation 2017-08, Vol.127 (8), p.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, Jürgen
• Format: Article
• Language: English
• Subjects: Animals; Arrestin; beta-Arrestin 1 - genetics; beta-Arrestin 2 - metabolism; Biomedical research; Blood Glucose - metabolism; Brief Report; Cercopithecus aethiops; COS Cells; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - metabolism; Diet, High-Fat; Experiments; G protein-coupled receptors; Gene Deletion; Gene expression; Gene Expression Regulation; Glucagon; Glucagon - metabolism; Glucose; Hepatocytes; Hepatocytes - metabolism; High fat diet; Homeostasis; Homeostasis - physiology; Insulin; Insulin - metabolism; Insulin resistance; Liver; Liver - metabolism; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Proteins; Receptors, Glucagon - metabolism; Rodents; Signal Transduction; Studies; Therapeutic applications
• 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 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.