PRKAA2 and fatty liver disease: These in vivo and in vitro studies characterize that (1) AMPK is an upstream kinase of Insig; (2) AMPK-dependent phosphorylation of Insig ablates its interaction with E3 ubiquitin ligase gp78; (3) Thr222 phosphorylation of Insig-1 is essential for AMPK to enhance Insig-1 activity and inhibit SREBP-1c proteolytic cleavage and target lipogenic gene expression; (4) Metformin attenuates hepatic steatosis in part through activation of Insig.