| First Author | Kim DK | Year | 2014 |
| Journal | Diabetologia | Volume | 57 |
| Issue | 12 | Pages | 2576-85 |
| PubMed ID | 25205222 | Mgi Jnum | J:219690 |
| Mgi Id | MGI:5629496 | Doi | 10.1007/s00125-014-3366-x |
| Citation | Kim DK, et al. (2014) PKB/Akt phosphorylation of ERRgamma contributes to insulin-mediated inhibition of hepatic gluconeogenesis. Diabetologia 57(12):2576-85 |
| abstractText | AIMS/HYPOTHESIS: 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 (ERRgamma) is a major transcriptional regulator of hepatic gluconeogenesis. In this study, we investigated insulin-dependent post-translational modifications (PTMs) altering the transcriptional activity of ERRgamma for the regulation of hepatic gluconeogenesis. METHODS: We examined insulin-dependent phosphorylation and subcellular localisation of ERRgamma 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 (Pkbbeta (-/-)) mice. To demonstrate the role of ERRgamma 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 ERRgamma. RESULTS: We demonstrated that insulin suppressed the transcriptional activity of ERRgamma by promoting PKB/Akt-mediated phosphorylation of ERRgamma at S179 and by eliciting translocation of ERRgamma 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 Pkbbeta (-/-) mice displayed enhanced ERRgamma transcriptional activity due to a block in PKBbeta-mediated ERRgamma phosphorylation during refeeding. Finally, the phosphorylation-deficient mutant ERRgamma S179A was resistant to the inhibitory action of insulin on HGP. CONCLUSIONS/INTERPRETATION: These results suggest that ERRgamma is a major contributor to insulin action in maintaining hepatic glucose homeostasis. |
