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 S eok 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

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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

ASJC Scopus subject areas

  • Medicine(all)

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    Kim, D. K., Kim, Y. H., Hynx, D., Wang, Y., Yang, K. J., Ryu, D., Kim, K. S. E., Yoo, E. K., Kim, J. S., Koo, S-H., Lee, I. K., Chae, H. Z., Park, J., Lee, C. H., Biddinger, S. B., Hemmings, B. A., & Choi, H. S. (2014). PKB/Akt phosphorylation of ERRγ contributes to insulin-mediated inhibition of hepatic gluconeogenesis. Diabetologia, 57(12), 2576-2585. https://doi.org/10.1007/s00125-014-3366-x