Batista TM, Dagdeviren S, Carroll SH, Cai W, Melnik VY, Noh HL, Saengnipanthkul S, Kim JK, Kahn CR, Lee RT. 2020. Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver. Proceedings of the National Academy of Sciences of the United States of America. 117(12):6733-6740. Pubmed: 32156724 DOI:10.1073/pnas.1922370117


Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 () is a member of the α-arrestin family previously linked to human obesity. Here, we show that is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction in messenger RNA, while, conversely, mice with liver-specific KO of (L- KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus, is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.

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Rich Lee seeks to understand heart failure and metabolic diseases that accompany human aging, and translate that understanding into therapies. Lee is an active clinician, regularly treating patients at Brigham and Women’s Hospital.

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