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 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. Methods: 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. Results: 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. Conclusions/interpretation: These results suggest that ERRγ is a major contributor to insulin action in maintaining hepatic glucose homeostasis.
Bibliographical noteFunding Information:
Funding This work was supported by a National Creative Research Initiatives Grant (20110018305) through the National Research Foundation of Korea (NRF) funded by the Korean government (Ministry of Science, ICT & Future Planning) to H-SC; DK094162 (to SBB); and a grant of the Korea Health Technology R&D Project (A111345) funded by the Korean government (Ministry of Health & Welfare) to I-KL.
© 2014, Springer-Verlag Berlin Heidelberg.
- Hepatic gluconeogenesis
- Insulin receptor signalling
- Nuclear hormone receptor
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism