Novel repressor regulates insulin sensitivity through interaction with Foxo1

Jun Nakae, Yongheng Cao, Fumihiko Hakuno, Hiroshi Takemori, Yoshinaga Kawano, Risa Sekioka, Takaya Abe, Hiroshi Kiyonari, Toshiya Tanaka, Juro Sakai, Shin Ichiro Takahashi, Hiroshi Itoh

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Forkhead box-containing protein o (Foxo) 1 is a key transcription factor in insulin and glucose metabolism. We identified a Foxo1-CoRepressor (FCoR) protein in mouse adipose tissue that inhibits Foxo1's activity by enhancing acetylation via impairment of the interaction between Foxo1 and the deacetylase Sirt1 and via direct acetylation. FCoR is phosphorylated at Threonine 93 by catalytic subunit of protein kinase A and is translocated into nucleus, making it possible to bind to Foxo1 in both cytosol and nucleus. Knockdown of FCoR in 3T3-F442A cells enhanced expression of Foxo target and inhibited adipocyte differentiation. Overexpression of FCoR in white adipose tissue decreased expression of Foxo-target genes and adipocyte size and increased insulin sensitivity in Lepr db/db mice and in mice fed a high-fat diet. In contrast, Fcor knockout mice were lean, glucose intolerant, and had decreased insulin sensitivity that was accompanied by increased expression levels of Foxo-target genes and enlarged adipocytes. Taken together, these data suggest that FCoR is a novel repressor that regulates insulin sensitivity and energy metabolism in adipose tissue by acting to fine-tune Foxo1 activity.

Original languageEnglish
Pages (from-to)2275-2295
Number of pages21
JournalEMBO Journal
Volume31
Issue number10
DOIs
Publication statusPublished - 2012 May 16

Keywords

  • FCoR
  • Foxo1
  • Sirt1
  • cellular metabolism Keywords: acetylation
  • signal transduction

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Nakae, J., Cao, Y., Hakuno, F., Takemori, H., Kawano, Y., Sekioka, R., Abe, T., Kiyonari, H., Tanaka, T., Sakai, J., Takahashi, S. I., & Itoh, H. (2012). Novel repressor regulates insulin sensitivity through interaction with Foxo1. EMBO Journal, 31(10), 2275-2295. https://doi.org/10.1038/emboj.2012.97