RNA Biology Group, Institute for Genomics and Bioinformatics, Graz University of Technology, Austria.
Stem Cells. 2014 Jun;32(6):1578-90. doi: 10.1002/stem.1603.
Adipose tissue contains thermogenic adipocytes (i.e., brown and brite/beige) that oxidize nutrients at exceptionally high rates via nonshivering thermogenesis. Its recent discovery in adult humans has opened up new avenues to fight obesity and related disorders such as diabetes. Here, we identified miR-26a and -26b as key regulators of human white and brite adipocyte differentiation. Both microRNAs are upregulated in early adipogenesis, and their inhibition prevented lipid accumulation while their overexpression accelerated it. Intriguingly, miR-26a significantly induced pathways related to energy dissipation, shifted mitochondrial morphology toward that seen in brown adipocytes, and promoted uncoupled respiration by markedly increasing the hallmark protein of brown fat, uncoupling protein 1. By combining in silico target prediction, transcriptomics, and an RNA interference screen, we identified the sheddase ADAM metallopeptidase domain 17 (ADAM17) as a direct target of miR-26 that mediated the observed effects on white and brite adipogenesis. These results point to a novel, critical role for the miR-26 family and its downstream effector ADAM17 in human adipocyte differentiation by promoting characteristics of energy-dissipating thermogenic adipocytes.
脂肪组织包含产热脂肪细胞（即棕色和米色/ beige），它们通过非颤抖产热以极高的速率氧化营养物质。最近在成年人体内发现的这一物质为对抗肥胖和相关疾病（如糖尿病）开辟了新的途径。在这里，我们确定了 miR-26a 和 miR-26b 是人类白色和米色脂肪细胞分化的关键调节因子。这两种 microRNA 在早期脂肪生成中上调，其抑制阻止了脂质积累，而其过表达加速了脂质积累。有趣的是，miR-26a 显著诱导了与能量耗散相关的途径，将线粒体形态向棕色脂肪细胞中的形态转变，并通过显著增加棕色脂肪的标志性蛋白解偶联蛋白 1 来促进解偶联呼吸。通过结合计算机预测、转录组学和 RNA 干扰筛选，我们确定了金属肽酶结构域 17（ADAM17）是 miR-26 的直接靶标，它介导了对白色和米色脂肪生成的观察到的影响。这些结果表明，miR-26 家族及其下游效应物 ADAM17 通过促进耗能产热脂肪细胞的特征，在人类脂肪细胞分化中发挥着新的、关键的作用。
