Hepatic ?-arrestin 2 is essential for maintaining euglycemia.

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

SUBMITTER: Zhu L 

PROVIDER: S-EPMC5531395 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature