Project Summary The Arrestin superfamily of proteins controls the trafficking, turnover and signaling of trans- membrane receptors, as well as other intracellular signaling functions. Several members of the family, including ARRDC3 and TXNIP, are now known to have important roles in metabolism. ARRDC4 is an understudied protein that has been shown to inhibit glucose uptake in vitro, interact with ubiquitin ligases and plays a role in membrane receptor trafficking. The in vivo functions and the molecular mechanisms of ARRDC4 are unknown. My preliminary experiments reveal that mice with systemic deletion of ARRDC4 are glucagon resistant compared to wildtype controls. Decreased hepatic gluconeogenesis and glucagon signaling and defects in hepatic glucose production suppression were also observed in the liver tissues of ARRDC4KO mice. I have now generated a new conditional deletion ARRDC4 mouse model for this project. The glucagon receptor is a GPCR, and therefore a potential target to interact with arrestin family proteins. As ARRDC4 interacts with membrane proteins and 7TM receptors, an important goal of my research is to answer if ARRDC4 controls glucagon signaling by interacting with glucagon receptors or its downstream mediators. The specific aims of this project will focus on unraveling the functions of ARRDC4 in hepatic glucose metabolism in vivo and the mechanism of ARRDC4 regulation at the molecular level. Because ARRDC4 is itself regulated by glucose and insulin, defining the metabolic functions of ARRDC4 has the potential to reveal a metabolic feedback loop in glucose metabolism that interfaces with glucagon signaling.