State Key Laboratory of Cancer Biology, Department of Pathology, The First Affiliated Hospital, Air Force Medical University, Xi'an, 710032, China; China-Nepal Friendship Medical Research Center of Prof. Rajiv Kumar Jha, Xi'an Medical University, Xi'an, 710021, China.
State Key Laboratory of Cancer Biology, Department of Pathology, The First Affiliated Hospital, Air Force Medical University, Xi'an, 710032, China.
Biochem Biophys Res Commun. 2018 Jun 18;501(1):9-15. doi: 10.1016/j.bbrc.2018.04.073. Epub 2018 May 3.
A close relationship between epigenetic regulation and obesity has been demonstrated in several recent studies. Histone methyltransferase enhancer of Zeste homolog 2 (Ezh2), which mainly catalyzes trimethylation of histone H3K27 to form H3K27me3 was found to be required for the differentiation of white and brown adipocytes in vitro. Here, we investigated the effects of the Ezh2-specific inhibitor GSK126 in a mouse model of obesity induced by a high-fat diet (HFD). We found that GSK126 treatment reduced body fat, improved glucose tolerance, increased lipolysis and improved cold tolerance in mice by promoting the differentiation of thermogenic beige adipocytes. Moreover, we discovered that GSK126 inhibited the differentiation of white adipocytes, and the decrease of Ezh2 enzymatic activity and H3K27me3 also changed the morphology of brown adipocytes but did not alter the expression of thermogenic genes in these cells. Our results indicated that GSK126 was a novel chemical inducer of beige adipocytes and may be a potential therapeutic agent for the management of obesity. Furthermore, they also prompted that Ezh2 and H3K27me3 play different roles in the differentiation of the white, brown, and beige adipocytes in vivo.
近年来的几项研究表明，表观遗传调控与肥胖之间存在密切关系。组蛋白甲基转移酶增强子的锌指蛋白 2（Ezh2）主要催化组蛋白 H3K27 的三甲基化，形成 H3K27me3，被发现是体外白色和棕色脂肪细胞分化所必需的。在这里，我们研究了 Ezh2 特异性抑制剂 GSK126 在高脂肪饮食（HFD）诱导肥胖的小鼠模型中的作用。我们发现，GSK126 通过促进产热米色脂肪细胞的分化，降低了肥胖小鼠的体脂肪含量，改善了葡萄糖耐量，增加了脂肪分解，提高了耐寒性。此外，我们发现 GSK126 抑制了白色脂肪细胞的分化，Ezh2 酶活性和 H3K27me3 的减少也改变了棕色脂肪细胞的形态，但没有改变这些细胞中产热基因的表达。我们的结果表明，GSK126 是一种新型米色脂肪细胞化学诱导剂，可能是肥胖管理的潜在治疗药物。此外，这些结果还提示 Ezh2 和 H3K27me3 在体内白色、棕色和米色脂肪细胞的分化中发挥不同的作用。
