Figure 2.

Spatiotemporal regulation of fasting response by O-GlcNAcylation. (Left) During short-term fasting, glucagon stimulates gluconeogenesis by enhancing the activity of CREB. Phosphorylation of CREB by PKA directly promotes gluconeogenic gene expression. Additionally, OGT can induce gluconeogenesis by O-GlcNAcylating CRTC2, the co-activator of CREB. When CRTC2 is dephosphorylated and then O-GlcNAcylated at the same site, it translocates into the nucleus and binds to CREB to induce gluconeogenesis. (Right) In prolonged fasting, OGT targets PGC-1α via a complex with HCF-1. Both PGC-1α and HCF-1 can be O-GlcNAcylated. O-GlcNAcylated PGC-1α helps recruit OGT to glycosylate and activate FOXO1, which further promotes hepatic glucose production.