Direct conversion of human fibroblasts to brown adipocytes by small chemical compounds.
Direct conversion of human fibroblasts to brown adipocytes by small chemical compounds.
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DOI：
10.1038/s41598-017-04665-x
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发表时间：
2017-06-27
影响因子：
4.6
通讯作者：
Dai P
中科院分区：
文献类型：
--
作者：
Takeda Y;Harada Y;Yoshikawa T;Dai P
棕色脂肪细胞在人体能量代谢以及预防肥胖和糖尿病方面发挥着重要作用。诱导多能干细胞（iPSCs）是棕色脂肪细胞的一个有前景的来源；然而，iPSCs的产生通常需要外源性基因诱导，这可能会产生不良影响，特别是在移植后的长期治疗中。我们之前曾报道过一种由六种小分子化合物组成的混合物，它能将人成纤维细胞转化为化合物诱导的神经元细胞（CiNCs）。在此，我们报道这些化合物与罗格列酮（一种过氧化物酶体增殖物激活受体γ激动剂）的改良组合可将人成纤维细胞直接转化为棕色脂肪细胞。化合物诱导的棕色脂肪细胞（ciBAs）表现出对人棕色脂肪细胞特异性基因如解偶联蛋白1（Ucp1）、肌酸激酶线粒体1（Ckmt1）、Cited1以及其他脂肪细胞特异性基因如脂肪酸结合蛋白4（Fabp4）、脂联素（AdipoQ）和过氧化物酶体增殖物激活受体γ（Pparγ）的诱导。用异丙肾上腺素或毛喉素处理进一步诱导了Ucp1的表达，这表明ciBAs中的β肾上腺素能受体信号传导可能对产热基因的诱导起作用。此外，ciBAs的耗氧率随着细胞线粒体的增加而升高。我们的研究结果可能为从成纤维细胞生成人棕色脂肪细胞提供一种简便易行的方法，并为肥胖、糖尿病及相关代谢紊乱的治疗提供潜在方法。
Brown adipocytes play an important role in human energy metabolism and prevention of obesity and diabetes. Induced pluripotent stem cells (iPSCs) represent a promising source for brown adipocytes; however, exogenous gene induction is generally required for iPSCs generation, which might cause undesired effects particularly in long-term treatment after transplantation. We have previously reported a cocktail of six small chemical compounds that enables a conversion of human fibroblasts into chemical compound-induced neuronal cells (CiNCs). Here, we report that modified combinations of the chemical compounds and rosiglitazone, a PPARγ agonist, afforded direct conversion of human fibroblasts into brown adipocytes. The chemical compound-induced brown adipocytes (ciBAs) exhibit induction of human brown adipocyte-specific genes such as Ucp1, Ckmt1, Cited1 and other adipocyte-specific genes such as Fabp4, AdipoQ, and Pparγ. Treatment with either isoproterenol or Forskolin further induced the expression of Ucp1, suggesting that β adrenergic receptor signalling in ciBAs could be functional for induction of thermogenic genes. Moreover, oxygen consumption rates were elevated in ciBAs along with increase of cellular mitochondria. Our findings might provide an easily accessible approach for generating human brown adipocytes from fibroblasts and offer therapeutic potential for the management of obesity, diabetes, and related metabolic disorders.