State Key Laboratory of Cancer Biology, Department of Pathology, First Affiliated Hospital and School of Basic Medicine, Air Force Medical University, Xi'an, Shaanxi 710032, China; Institute of Obesity and Metabolic Diseases, Clinical Medical School, Xi'an Medical University, Xi'an, Shaanxi 710021, China.
Cadets of Air Force Medical University, Xi'an, Shaanxi 710032, China.
Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Jun;1866(6):158901. doi: 10.1016/j.bbalip.2021.158901. Epub 2021 Feb 9.
Obesity is a disease characterized by imbalance between energy intake and expenditure, excessive energy store in white adipocytes, but brown and beige adipocytes consume energy to relieve obesity. In this study, we want to explore the role of the histone H3 methyltransferase Ezh2 in the differentiation of white, brown and beige adipocytes with Ezh2 conditional knockout mice (Ezh2Prx1-cre) and mouse embryonic fibroblasts (MEFs). The results showed that Ezh2-deficient mice have a leaner phenotype and less white adipose tissues. The morphological changes in the adipose tissue included smaller white adipose tissue depots, white adipocytes with smaller diameter, smaller lipid droplets inside the brown adipocytes and more beige adipocytes in the Ezh2-deficient mice compared with the control. The differentiation markers of white adipocytes in Ezh2 knockout mice decreased; Ucp1 and other browning markers increased in brown and beige adipocytes. The Ezh2 knockout mice could better tolerate cold stimulation, and they can also resist obesity and insulin resistance induced by a high-fat diet. The Ezh2 inhibitor GSK126 could inhibit the differentiation of MEFs into white adipocytes but promote their differentiation into brown/beige adipocytes. The H3K27me3 demethylase Jmjd3/UTX inhibitor GSKJ4 inhibited MEFs' differentiation into brown/beige adipocytes. These results showed that Ezh2 promotes the differentiation of white adipocytes and inhibits the differentiation of brown and beige adipocytes in vivo and in vitro through its methylase activity and this may represent new knowledge for obesity therapeutic strategy.
肥胖是一种能量摄入和支出失衡的疾病，过多的能量储存在白色脂肪细胞中，但棕色和米色脂肪细胞会消耗能量来缓解肥胖。在这项研究中，我们想用 Ezh2 条件性敲除小鼠（Ezh2Prx1-cre）和小鼠胚胎成纤维细胞（MEFs）来探索组蛋白 H3 甲基转移酶 Ezh2 在白色、棕色和米色脂肪细胞分化中的作用。结果表明，Ezh2 缺失的小鼠表现出更瘦的表型和更少的白色脂肪组织。脂肪组织的形态变化包括较小的白色脂肪组织储存，白色脂肪细胞直径较小，棕色脂肪细胞内的脂质滴较小，以及 Ezh2 缺失的小鼠中更多的米色脂肪细胞。白色脂肪细胞的分化标志物在 Ezh2 敲除小鼠中减少；Ucp1 和其他褐色标记物在棕色和米色脂肪细胞中增加。Ezh2 敲除小鼠对冷刺激的耐受性更好，也能抵抗高脂肪饮食引起的肥胖和胰岛素抵抗。Ezh2 抑制剂 GSK126 可抑制 MEFs 分化为白色脂肪细胞，但促进其分化为棕色/米色脂肪细胞。H3K27me3 去甲基酶 Jmjd3/UTX 抑制剂 GSKJ4 抑制 MEFs 分化为棕色/米色脂肪细胞。这些结果表明，Ezh2 通过其甲基转移酶活性促进体内和体外白色脂肪细胞的分化，抑制棕色和米色脂肪细胞的分化，这可能为肥胖的治疗策略提供新的知识。
