O-GlcNAcylation of orphan nuclear receptor estrogen-related receptorγ promotes hepatic gluconeogenesis

Estrogen-related receptorγ (ERRγ) 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 ERRγis O-GlcNAcylated by O-GlcNAc transferase in the fasted state. This stabilizes the protein by inhibiting proteasome-mediated protein degradation, increasing ERRγrecruitment to gluconeogenic gene promoters. Mass spectrometry identifies two serine residues (S317, S319) present in the ERRγligandbinding domain that are O-GlcNAcylated. Mutation of these residues destabilizes ERRγprotein and blocks the ability of ERRγto 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 ERRγby overexpressing the deglycosylating enzyme O-GlcNAcase decreases ERRgdependent glucose production in fasted mice. We conclude that O-GlcNAcylation of ERRγserves as a major signal to promote hepatic gluconeogenesis.