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

Don Kyu Kim, Yong Hoon Kim, Debby Hynx, Yanning Wang, Keum Jin Yang, Dongryeol Ryu, Kyung Seok Kim, Eun Kyung Yoo, Jeong Sun Kim, Seung Hoi Koo, In Kyu Lee, Ho Zoon Chae, Jongsun Park, Chul Ho Lee, Sudha B. Biddinger, Brian A. Hemmings, Hueng Sik Choi

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2576-2585
Number of pages10
JournalDiabetologia
Volume57
Issue number12
DOIs
Publication statusPublished - 2014 Dec 1

Keywords

  • Akt/PKB
  • Hepatic gluconeogenesis
  • Insulin receptor signalling
  • Nuclear hormone receptor
  • Phosphorylation

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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