State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Beijing, People's Republic of China.
University of Chinese Academy of Sciences, Beijing, People's Republic of China.
Diabetes. 2019 Jul;68(7):1449-1461. doi: 10.2337/db18-1103. Epub 2019 Apr 22.
The unique thermogenic capacity of brown adipocyte makes it an attractive target for antiobesity treatments. Several epigenetic regulators can control brown adipocyte development. In this study, we show that SIRT5, a member of the sirtuins, is required for brown adipocyte differentiation and essential for brown adipogenic gene activation in vitro. Furthermore, we find out that knockdown of SIRT5 reduces intracellular α-ketoglutarate concentration, which leads to elevated H3K9me2 and H3K9me3 levels at promoter regions of and loci. Finally, we discover that SIRT5 knockout mice on the Sv129 background exhibit less browning capacity in subcutaneous white adipose tissue compared with controls and show apparent cold intolerance, suggesting that SIRT5 can modulate the browning process in vivo. Thus, our study uncovers a new biological function of SIRT5 in brown adipocyte differentiation and a mechanism by which SIRT5 regulates brown adipogenic gene activation at least partly through an indirect effect on histone modifications. Our study extends the linkage between epigenetics and cell differentiation.
棕色脂肪细胞独特的产热能力使其成为抗肥胖治疗的一个有吸引力的靶点。几种表观遗传调节剂可以控制棕色脂肪细胞的发育。在这项研究中，我们表明，SIRT5，一种 sirtuins 家族的成员，是棕色脂肪细胞分化所必需的，并且对于体外棕色脂肪生成基因的激活也是必不可少的。此外，我们发现 SIRT5 的敲低会降低细胞内α-酮戊二酸的浓度，从而导致 和 基因座启动子区域的 H3K9me2 和 H3K9me3 水平升高。最后，我们发现 Sv129 背景下的 SIRT5 基因敲除小鼠的皮下白色脂肪组织的棕色化能力明显低于对照组，并且表现出明显的不耐冷，表明 SIRT5 可以在体内调节棕色化过程。因此，我们的研究揭示了 SIRT5 在棕色脂肪细胞分化中的一个新的生物学功能，以及 SIRT5 通过间接影响组蛋白修饰来调节棕色脂肪生成基因激活的机制。我们的研究扩展了表观遗传学和细胞分化之间的联系。
