Obesity resistance and increased hepatic expression of catabolism-related mRNAs in Cnot3 +/- mice

Masahiro Morita, Yuichi Oike, Takeshi Nagashima, Tsuyoshi Kadomatsu, Mitsuhisa Tabata, Toru Suzuki, Takahisa Nakamura, Nobuaki Yoshida, Mariko Okada, Tadashi Yamamoto

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Obesity is a life-threatening factor and is often associated with dysregulation of gene expression. Here, we show that the CNOT3 subunit of the CCR4-NOT deadenylase complex is critical to metabolic regulation. Cnot3 +/- mice are lean with hepatic and adipose tissues containing reduced levels of lipids, and show increased metabolic rates and enhanced glucose tolerance. Cnot3 +/- mice remain lean and sensitive to insulin even on a high-fat diet. Furthermore, introduction of Cnot3 haplodeficiency in ob/ob mice ameliorated the obese phenotype. Hepatic expression of most mRNAs is not altered in Cnot3 +/- vis-à-vis wild-type mice. However, the levels of specific mRNAs, such as those coding for energy metabolism-related PDK4 and IGFBP1, are increased in Cnot3 +/- hepatocytes, having poly(A) tails that are longer than those seen in control cells. We provide evidence that CNOT3 is involved in recruitment of the CCR4-NOT deadenylase to the 3-2 end of specific mRNAs. Finally, as CNOT3 levels in the liver and white adipose tissues decrease upon fasting, we propose that CNOT3 responds to feeding conditions to regulate deadenylation-specific mRNAs and energy metabolism.

Original languageEnglish (US)
Pages (from-to)4678-4691
Number of pages14
JournalEMBO Journal
Volume30
Issue number22
DOIs
StatePublished - Nov 16 2011
Externally publishedYes

Keywords

  • deadenylase
  • energy metabolism
  • insulin resistance
  • mRNA decay
  • obesity

ASJC Scopus subject areas

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

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    Morita, M., Oike, Y., Nagashima, T., Kadomatsu, T., Tabata, M., Suzuki, T., Nakamura, T., Yoshida, N., Okada, M., & Yamamoto, T. (2011). Obesity resistance and increased hepatic expression of catabolism-related mRNAs in Cnot3 +/- mice. EMBO Journal, 30(22), 4678-4691. https://doi.org/10.1038/emboj.2011.320