Cited 33 time in
- PKB/Akt phosphorylation of ERRγ contributes to insulin-mediated inhibition of hepatic gluconeogenesis
- D K Kim; Yong-Hoon Kim; D Hynx; Y Wang; K J Yang; D Ryu; K S Kim; E K Yoo; J S Kim; S H Koo; I K Lee; H Z Chae; J Park; Chul Ho Lee; S B Biddinger; B A Hemmings; H S Choi
- Bibliographic Citation
- Diabetologia, vol. 57, no. 12, pp. 2576-2585
- Publication Year
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 γ (ERRγ) is a major transcriptional regulator of hepatic gluconeogenesis. In this study, we investigated insulin-dependent post-translational modifications (PTMs) altering the transcriptional activity of ERRγ for the regulation of hepatic gluconeogenesis.
We examined insulin-dependent phosphorylation and subcellular localisation of ERRγ 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) β-deficient (Pkbβ (-/-)) mice. To demonstrate the role of ERRγ 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 ERRγ.
We demonstrated that insulin suppressed the transcriptional activity of ERRγ by promoting PKB/Akt-mediated phosphorylation of ERRγ at S179 and by eliciting translocation of ERRγ 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 Pkbβ (-/-) mice displayed enhanced ERRγ transcriptional activity due to a block in PKBβ-mediated ERRγ phosphorylation during refeeding. Finally, the phosphorylation-deficient mutant ERRγ S179A was resistant to the inhibitory action of insulin on HGP.
These results suggest that ERRγ is a major contributor to insulin action in maintaining hepatic glucose homeostasis.
- Akt/PKB; Hepatic gluconeogenesis; Insulin receptor signalling; Nuclear hormone receptor; Phosphorylation
- Appears in Collections:
- Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
- Files in This Item:
Items in OpenAccess@KRIBB are protected by copyright, with all rights reserved, unless otherwise indicated.