An Insulin-regulated Arrestin Domain Protein Controls Hepatic Glucagon Action

Glucagon signaling is essential for maintaining normoglycemia in mammals. The arrestin fold superfamily of proteins controls the trafficking, turnover, and signaling of transmembrane receptors, as well as other intracellular signaling functions. Further investigation is needed to understand the in vivo functions of the Arrestin Domain Containing 4 (ARRDC4) protein family member and whether it is involved in mammalian glucose metabolism. Here we show that mice with a global deletion of the ARRDC4protein have impaired glucagon responses and gluconeogenesis at a systemic and molecular level. Mice lacking ARRDC4 exhibited lower glucose levels after fasting and could not suppress gluconeogenesis at the refed state. We also show that ARRDC4 co-immunoprecipitates with the glucagon receptor and ARRDC4 expression is suppressed by insulin. These results define ARRDC4 as a critical regulator of glucagon signaling and glucose homeostasis and reveal a novel intersection of insulin and glucagon pathways in the liver.