O-GlcNAcylation of Orphan Nuclear Receptor Estrogen-Related Receptor γ Promotes Hepatic Gluconeogenesis

Estrogen-related receptor gamma (ERR gamma) is a major positive regulator of hepatic gluconeogenesis. Its transcriptional activity is suppressed by phosphorylation signaled by insulin in the fed state, but whether posttranslational modification alters its gluconeogenic activity in the fasted state is not known. Metabolically active hepatocytes direct a small amount of glucose into the hexosamine biosynthetic pathway, leading to protein O-GlcNAcylation. In this study, we demonstrate that ERR gamma is O-GlcNAcylated by O-GlcNAc transferase in the fasted state. This stabilizes the protein by inhibiting proteasome-mediated protein degradation, increasing ERR gamma recruitment to gluconeogenic gene promoters. Mass spectrometry identifies two serine residues (S317, S319) present in the ERR gamma ligand-binding domain that are O-GlcNAcylated. Mutation of these residues destabilizes ERR gamma protein and blocks the ability of ERR gamma to induce gluconeogenesis in vivo. The impact of this pathway on gluconeogenesis in vivo was confirmed by the observation that decreasing the amount of O-GlcNAcylated ERR gamma by overexpressing the deglycosylating enzyme O-GlcNAcase decreases ERR gamma-dependent glucose production in fasted mice. We conclude that O-GlcNAcylation of ERR gamma serves as a major signal to promote hepatic gluconeogenesis.