Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 8, Pages 2941-2945Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI92913
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Funding
- Intramural Research Program of the NIDDK
- National Institute on Alcohol Abuse and Alcoholism
- NIH [5R37-MH-073853, R01-CA172570, RO1 GM109955, EY011500]
- Clinical Oncology Research Center Development grant [5K12-CA100639-08]
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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 beta-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.
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