Cell Signal Unit, Okinawa Institute of Science and Technology, Kunigami, Okinawa 904-0412, Japan.
Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan.
Cell Rep. 2015 Dec 29;13(12):2756-67. doi: 10.1016/j.celrep.2015.11.056. Epub 2015 Dec 17.
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.
解偶联蛋白 1（Ucp1）有助于产热，其表达受转录水平调控。在这里，我们表明 Ucp1 的表达也受到转录后调控。在高脂肪饮食（HFD）喂养的小鼠腹股沟白色脂肪组织（iWAT）中，Ucp1 水平随着 Cnot7 及其相互作用伙伴 Tob 的增加而降低。缺乏 Cnot7 和 Tob 的 HFD 喂养小鼠在 iWAT 中表达升高的 Ucp1 mRNA，并且对饮食诱导的肥胖具有抗性。Ucp1 mRNA 具有长的 poly(A)尾巴，并且在 Cnot7(-/-)和/或 Tob(-/-)小鼠的 HFD 上持续存在于 iWAT 中。在表达无法与 Cnot7 结合的突变型 Tob 的细胞中，含有 Ucp1 3'-UTR 的 mRNA 比在 WT Tob 表达细胞中更稳定。Tob 与 BRF1 相互作用，BRF1 结合到 Ucp1 3'-UTR 中的富含 AU 的元件上。BRF1 敲低部分恢复了含有 Ucp1 3'-UTR 的 mRNA 的稳定性。因此，Cnot7-Tob-BRF1 轴抑制 Ucp1 的表达并导致肥胖。
