Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1α interaction

Pere Puigserver, James Rhee, Jerry Donovan, Christopher J. Walkey, John Yoon, Francesco Oriente, Yukari Kitamura, Jennifer Altomonte, Hengjiang Dong, Domenico Accili, Bruce M. Spiegelman

Research output: Contribution to journalArticle

1000 Scopus citations

Abstract

Hepatic gluconeogenesis is absolutely required for survival during prolonged fasting or starvation, but is inappropriately activated in diabetes mellitus. Glucocorticoids and glucagon have strong gluconeogenic actions on the liver. In contrast, insulin suppresses hepatic gluconeogenesis1-3. Two components known to have important physiological roles in this process are the forkhead transcription factor FOXO1 (also known as FKHR) and peroxisome proliferative activated receptor-γ co-activator 1 (PGC-1α; also known as PPARGC1), a transcriptional co-activator; whether and how these factors collaborate has not been clear. Using wild-type and mutant alleles of FOXO1, here we show that PGC-1α binds and co-activates FOXO1 in a manner inhibited by Akt-mediated phosphorylation. Furthermore, FOXO1 function is required for the robust activation of gluconeogenic gene expression in hepatic cells and in mouse liver by PGC-1α. Insulin suppresses gluconeogenesis stimulated by PGC-1α but coexpression of a mutant allele of FOXO1 insensitive to insulin completely reverses this suppression in hepatocytes or transgenic mice. We conclude that FOXO1 and PGC-1α interact in the execution of a programme of powerful, insulin-regulated gluconeogenesis.

Original languageEnglish (US)
Pages (from-to)550-555
Number of pages6
JournalNature
Volume423
Issue number6939
DOIs
StatePublished - May 29 2003
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Puigserver, P., Rhee, J., Donovan, J., Walkey, C. J., Yoon, J., Oriente, F., Kitamura, Y., Altomonte, J., Dong, H., Accili, D., & Spiegelman, B. M. (2003). Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1α interaction. Nature, 423(6939), 550-555. https://doi.org/10.1038/nature01667