title: PKB/Akt phosphorylation of ERRγ contributes to insulin-mediated inhibition of hepatic gluconeogenesis.
abstract: OBJECTIVE
  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
  These results suggest that ERRγ is a major contributor to insulin action in maintaining hepatic glucose homeostasis.
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, 500-757, Republic of Korea.
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Debby
authors.initials: D
authors.lastname: Hynx
authors.forename: Yanning
authors.initials: Y
authors.lastname: Wang
authors.forename: Keum-Jin
authors.initials: KJ
authors.lastname: Yang
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.forename: Kyung Seok
authors.initials: KS
authors.lastname: Kim
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Yoo
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Kim
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Ho-Zoon
authors.initials: HZ
authors.lastname: Chae
authors.forename: Jongsun
authors.initials: J
authors.lastname: Park
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Sudha B
authors.initials: SB
authors.lastname: Biddinger
authors.forename: Brian A
authors.initials: BA
authors.lastname: Hemmings
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects* / Q000502:physiology; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007328:Insulin; D011960:Receptors, Estrogen; C425824:estrogen receptor gamma; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt