State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Diabetes. 2021 Jun;70(6):1317-1333. doi: 10.2337/db20-1110. Epub 2021 Apr 1.
Brown and beige adipocytes are characterized as thermogenic adipocytes and have great potential for treating obesity and associated metabolic diseases. In this article, we identify a conserved mammalian lysine 79 of histone H3 (H3K79) methyltransferase, disruptor of telomeric silencing-1 like (DOT1L), as a new epigenetic regulator that controls thermogenic adipocyte differentiation and function. We show that deletion of DOT1L in thermogenic adipocytes potently protects mice from diet-induced obesity, improves glucose homeostasis, alleviates hepatic steatosis, and facilitates adaptive thermogenesis in vivo. Loss of DOT1L in primary preadipocytes significantly promotes brown and beige adipogenesis and thermogenesis in vitro. Mechanistically, DOT1L epigenetically regulates the brown adipose tissue-selective gene program by modulating H3K79 methylation, in particular H3K79me2 modification. Thus, our study demonstrates that DOT1L exerts an important role in energy homeostasis by regulating thermogenic adipocyte differentiation and function.
棕色和米色脂肪细胞的特征是产热脂肪细胞，具有治疗肥胖症和相关代谢性疾病的巨大潜力。在本文中，我们鉴定出一种保守的哺乳动物组蛋白 H3 赖氨酸 79（H3K79）甲基转移酶，端粒沉默 1 样蛋白（DOT1L），作为一种新的表观遗传调节剂，控制产热脂肪细胞分化和功能。我们表明，在产热脂肪细胞中敲除 DOT1L 可强力保护小鼠免受饮食诱导的肥胖、改善葡萄糖稳态、减轻肝脂肪变性，并促进体内适应性产热。在原代前体细胞中敲除 DOT1L 可显著促进棕色和米色脂肪生成和体外产热。在机制上，DOT1L 通过调节 H3K79 甲基化，特别是 H3K79me2 修饰，来调节棕色脂肪组织选择性基因程序。因此，我们的研究表明，DOT1L 通过调节产热脂肪细胞的分化和功能在能量平衡中发挥重要作用。
