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

Research output: Contribution to journalArticle

19 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

Fingerprint

Proto-Oncogene Proteins c-akt
Gluconeogenesis
Phosphorylation
Insulin
Liver
Insulin Receptor
Glucose
Leptin Receptors
Post Translational Protein Processing
Cytoplasmic and Nuclear Receptors
Estrogen Receptors
Type 2 Diabetes Mellitus
Insulin Resistance
Cultured Cells
Cytoplasm
Homeostasis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kim, D. K., Kim, Y. H., Hynx, D., Wang, Y., Yang, K. J., Ryu, D., ... 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

PKB/Akt phosphorylation of ERRγ contributes to insulin-mediated inhibition of hepatic gluconeogenesis. / Kim, Don Kyu; Kim, Yong Hoon; Hynx, Debby; Wang, Yanning; Yang, Keum Jin; Ryu, Dongryeol; Kim, Kyung S eok; 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.

In: Diabetologia, Vol. 57, No. 12, 01.12.2014, p. 2576-2585.

Research output: Contribution to journalArticle

Kim, DK, Kim, YH, Hynx, D, Wang, Y, Yang, KJ, Ryu, D, Kim, KSE, Yoo, EK, Kim, JS, Koo, S-H, Lee, IK, Chae, HZ, Park, J, Lee, CH, Biddinger, SB, Hemmings, BA & Choi, HS 2014, 'PKB/Akt phosphorylation of ERRγ contributes to insulin-mediated inhibition of hepatic gluconeogenesis', Diabetologia, vol. 57, no. 12, pp. 2576-2585. https://doi.org/10.1007/s00125-014-3366-x
Kim, Don Kyu ; Kim, Yong Hoon ; Hynx, Debby ; Wang, Yanning ; Yang, Keum Jin ; Ryu, Dongryeol ; Kim, Kyung S eok ; 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. / PKB/Akt phosphorylation of ERRγ contributes to insulin-mediated inhibition of hepatic gluconeogenesis. In: Diabetologia. 2014 ; Vol. 57, No. 12. pp. 2576-2585.
@article{e5d7cb0d2f154bf79f2d5012b5177496,
title = "PKB/Akt phosphorylation of ERRγ contributes to insulin-mediated inhibition of hepatic gluconeogenesis",
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.",
author = "Kim, {Don Kyu} and Kim, {Yong Hoon} and Debby Hynx and Yanning Wang and Yang, {Keum Jin} and Dongryeol Ryu and Kim, {Kyung S eok} and Yoo, {Eun Kyung} and Kim, {Jeong Sun} and Seung-Hoi Koo and Lee, {In Kyu} and Chae, {Ho Zoon} and Jongsun Park and Lee, {Chul Ho} and Biddinger, {Sudha B.} and Hemmings, {Brian A.} and Choi, {Hueng Sik}",
year = "2014",
month = "12",
day = "1",
doi = "10.1007/s00125-014-3366-x",
language = "English",
volume = "57",
pages = "2576--2585",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "12",

}

TY - JOUR

T1 - PKB/Akt phosphorylation of ERRγ contributes to insulin-mediated inhibition of hepatic gluconeogenesis

AU - Kim, Don Kyu

AU - Kim, Yong Hoon

AU - Hynx, Debby

AU - Wang, Yanning

AU - Yang, Keum Jin

AU - Ryu, Dongryeol

AU - Kim, Kyung S eok

AU - Yoo, Eun Kyung

AU - Kim, Jeong Sun

AU - Koo, Seung-Hoi

AU - Lee, In Kyu

AU - Chae, Ho Zoon

AU - Park, Jongsun

AU - Lee, Chul Ho

AU - Biddinger, Sudha B.

AU - Hemmings, Brian A.

AU - Choi, Hueng Sik

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84926656626&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926656626&partnerID=8YFLogxK

U2 - 10.1007/s00125-014-3366-x

DO - 10.1007/s00125-014-3366-x

M3 - Article

C2 - 25205222

AN - SCOPUS:84926656626

VL - 57

SP - 2576

EP - 2585

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 12

ER -