Post-transcriptional Stabilization of Ucp1 mRNA Protects Mice from Diet-Induced Obesity

Cell Rep. 2015 Dec 29;13(12):2756-67. doi: 10.1016/j.celrep.2015.11.056. Epub 2015 Dec 17.

Abstract

Uncoupling protein 1 (Ucp1) contributes to thermogenesis, and its expression is regulated at the transcriptional level. Here, we show that Ucp1 expression is also regulated post-transcriptionally. In inguinal white adipose tissue (iWAT) of mice fed a high-fat diet (HFD), Ucp1 level decreases concomitantly with increases in Cnot7 and its interacting partner Tob. HFD-fed mice lacking Cnot7 and Tob express elevated levels of Ucp1 mRNA in iWAT and are resistant to diet-induced obesity. Ucp1 mRNA has an elongated poly(A) tail and persists in iWAT of Cnot7(-/-) and/or Tob(-/-) mice on a HFD. Ucp1 3'-UTR-containing mRNA is more stable in cells expressing mutant Tob that is unable to bind Cnot7 than in WT Tob-expressing cells. Tob interacts with BRF1, which binds to an AU-rich element in the Ucp1 3'-UTR. BRF1 knockdown partially restores the stability of Ucp1 3'-UTR-containing mRNA. Thus, the Cnot7-Tob-BRF1 axis inhibits Ucp1 expression and contributes to obesity.

Keywords: Cnot7; Tob; Ucp1; deadenylation; obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, White / metabolism
  • Animals
  • Butyrate Response Factor 1
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Diet, High-Fat
  • Exoribonucleases
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Ion Channels / genetics*
  • Ion Channels / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Obesity / genetics*
  • Obesity / metabolism*
  • Protein Stability
  • Proteins / genetics
  • Proteins / metabolism
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Repressor Proteins
  • Ribonucleases
  • TATA-Binding Protein Associated Factors / genetics
  • TATA-Binding Protein Associated Factors / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Uncoupling Protein 1

Substances

  • BRF1 protein, human
  • Butyrate Response Factor 1
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ion Channels
  • Mitochondrial Proteins
  • Nuclear Proteins
  • Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Repressor Proteins
  • TATA-Binding Protein Associated Factors
  • TOB1 protein, human
  • Tob1 protein, mouse
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Uncoupling Protein 1
  • Zfp36l1 protein, mouse
  • CNOT7 protein, human
  • Cnot7 protein, mouse
  • Exoribonucleases
  • Ribonucleases