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Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose
metabolism in liver.
Batista TM, Dagdeviren S, Carroll SH, Cai W, Melnik VY, Noh HL, Saengnipanthkul
S, Kim JK, Kahn CR, Lee RT
Submitted Externally on 4/30/2020
Proceedings of the National Academy of Sciences of the United States of America
Volume : Pages
117 : 6733 - 6740
Insulin action in the liver is critical for glucose homeostasis through
regulation of glycogen synthesis and glucose output. Arrestin domain-containing
3 (Arrdc3) is a member of the a-arrestin family previously linked to human
obesity. Here, we show that Arrdc3 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 Arrdc3 messenger RNA, while, conversely, mice with liver-specific KO of
Arrdc3 (L-Arrdc3 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, Arrdc3 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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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
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