Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver
Thiago M. Batista, Sezin Dağdeviren, Shannon H. Carroll, Weikang Cai, Veronika Melnik, Hye Lim Noh, Suchaorn Saengnipanthkul, Jason K. Kim, C. Ronald Kahn, Richard Lee
Abstract
Significance Insulin resistance in liver is a key component in the pathogenesis of type 2 diabetes, obesity-associated nonalcoholic fatty liver disease, and metabolic syndrome. Here we demonstrate that hepatic expression of Arrdc3 , a molecular adaptor previously linked to human obesity, is potently induced by physiological insulin and obesity-related hyperinsulinemia. Liver-specific deletion of Arrdc3 increases hepatic insulin sensitivity. This is mechanistically linked to a direct interaction between the insulin receptor (IR) and ARRDC3 proteins controlling IR levels in the plasma membrane and downstream insulin signaling involving the transcription factor FOXO1 and expression of the rate-limiting enzymes in the glycolysis and gluconeogenesis pathways. Thus, Arrdc3 may provide a therapeutic target for diseases associated with hepatic insulin resistance.