PKB/Akt phosphorylation of ERR gamma contributes to insulin-mediated inhibition of hepatic gluconeogenesis
- Authors
- Kim, Don-Kyu; Kim, Yong-Hoon; Hynx, Debby; Wang, Yanning; Yang, Keum-Jin; Ryu, Dongryeol; Kim, Kyung Seok; Yoo, Eun-Kyung; Kim, Jeong-Sun; Koo, Seung-Hoi; Lee, In-Kyu; Chae, Ho-Zoon; Park, Jongsun; Lee, Chul-Ho; Biddinger, Sudha B.; Hemmings, Brian A.; Choi, Hueng-Sik
- Issue Date
- Dec-2014
- Publisher
- SPRINGER
- Keywords
- Akt/PKB; Hepatic gluconeogenesis; Insulin receptor signalling; Nuclear hormone receptor; Phosphorylation
- Citation
- DIABETOLOGIA, v.57, no.12, pp.2576 - 2585
- Indexed
- SCIE
SCOPUS
- Journal Title
- DIABETOLOGIA
- Volume
- 57
- Number
- 12
- Start Page
- 2576
- End Page
- 2585
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/96670
- DOI
- 10.1007/s00125-014-3366-x
- ISSN
- 0012-186X
- Abstract
- 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 (ERR gamma) is a major transcriptional regulator of hepatic gluconeogenesis. In this study, we investigated insulin-dependent post-translational modifications (PTMs) altering the transcriptional activity of ERR gamma for the regulation of hepatic gluconeogenesis. We examined insulin-dependent phosphorylation and subcellular localisation of ERR gamma 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 (Pkb beta (-/-)) mice. To demonstrate the role of ERR gamma 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 ERR gamma. We demonstrated that insulin suppressed the transcriptional activity of ERR gamma by promoting PKB/Akt-mediated phosphorylation of ERR gamma at S179 and by eliciting translocation of ERR gamma 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 Pkb beta (-/-) mice displayed enhanced ERR gamma transcriptional activity due to a block in PKB beta-mediated ERR gamma phosphorylation during refeeding. Finally, the phosphorylation-deficient mutant ERR gamma S179A was resistant to the inhibitory action of insulin on HGP. These results suggest that ERR gamma is a major contributor to insulin action in maintaining hepatic glucose homeostasis.
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Collections - Graduate School > Department of Life Sciences > 1. Journal Articles
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