PKB/Akt phosphorylation of ERRγ contributes to insulin-mediated inhibition of hepatic gluconeogenesis

Insulin resistance, a major contributor to the pathogenesis of type 2 diabetes, leads to increased hepatic glucose production (HGP) owing to an impaired ability of insulin to suppress hepatic gluconeogenesis. Nuclear receptor oestrogen-related receptor gamma (ERR gamma) is a major transcriptional regulator of hepatic gluconeogenesis. In this study, we investigated insulin-dependent post-translational modifications (PTMs) altering the transcriptional activity of ERR gamma for the regulation of hepatic gluconeogenesis. We examined insulin-dependent phosphorylation and subcellular localisation of ERR gamma in cultured cells and in the liver of C57/BL6, leptin receptor-deficient (db/db), liver-specific insulin receptor knockout (LIRKO) and protein kinase B (PKB) beta-deficient (Pkb beta (-/-)) mice. To demonstrate the role of ERR gamma in the inhibitory action of insulin on hepatic gluconeogenesis, we carried out an insulin tolerance test in C57/BL6 mice expressing wild-type or phosphorylation-deficient mutant ERR gamma. We demonstrated that insulin suppressed the transcriptional activity of ERR gamma by promoting PKB/Akt-mediated phosphorylation of ERR gamma at S179 and by eliciting translocation of ERR gamma from the nucleus to the cytoplasm through interaction with 14-3-3, impairing its ability to promote hepatic gluconeogenesis. In addition, db/db, LIRKO and Pkb beta (-/-) mice displayed enhanced ERR gamma transcriptional activity due to a block in PKB beta-mediated ERR gamma phosphorylation during refeeding. Finally, the phosphorylation-deficient mutant ERR gamma S179A was resistant to the inhibitory action of insulin on HGP. These results suggest that ERR gamma is a major contributor to insulin action in maintaining hepatic glucose homeostasis.