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

• Cnot7 and/or Tob deficiencies make mice resistant to diet-induced obesity
• Expression of Cnot7 and Tob is augmented in obese iWAT and inhibits Ucp1 level
• Tob interacts with BRF1 at the AU-rich region in the 3′-UTR of Ucp1 mRNA
• Tob-BRF1 interaction recruits Cnot7 deadenylase to Ucp1 mRNA for its destabilization

SummaryUncoupling 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.

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