microRNA介导的白色脂肪棕色化研究

It is estimated that only 50g of brown fat in adult humans could burn about 20% of an average daily caloric intake.Therefore,BAT could be a powerful target organ for treat obesity and related diseases.Recently, it has been shown that microRNA also could trans-differentiate one type of cells to another. In contrast to transcription factor, short length of microRNA can be easily absorbed by cell and organisms. In addition, microRNA is not able to integrate to the host genome, which makes it safer and more efficient from clinical standpoint. However, there are only few reports related to the microRNA mediated BAT trans-differentiation. In the current proposal, we aim to identify BAT specific microRNAs and investigate the potential role of its trans-differentiation ability, explore molecular mechanism of microRNA mediated BAT trans-differentiation, finally establish cell based screening platform for development of new class of anti-obesity drug.

正常人体内大约存在50g的棕色脂肪，消耗的日摄入能量甚至可以达20%之多。因此，棕色脂肪很可能是治疗肥胖以及相关疾病的强有力的靶器官。最近的研究结果表明，microRNA也是能够促进转分化的重要因子。与转录因子相比，microRNA序列较短，细胞和机体能够轻易吸收从而稳定地发挥作用；不仅如此，microRNA还不会整合到机体的基因组，安全高效。但有关microRNA促进白色脂肪棕色化的研究仍不多见。本课题拟利用高通量深度测序对小鼠白色脂肪和棕色脂肪的microRNA的差异表达进行研究，筛选棕色脂肪特异表达的microRNA，探索其潜在的白色脂肪棕色化的功能，揭示microRNA介导的白色脂肪向棕色脂肪转分化的分子机制，从而为开发新型抗肥胖药物建立细胞筛选平台。

白色脂肪中米色脂肪的形成对抗肥胖、其他代谢疾病具有极其重要的作用。而棕色脂肪的特异性microRNA的研究有助于了解其对米色脂肪的形成。本论文研究发现，miRNA 17-92集簇主要富集于棕色脂肪。体外C3H10T1/2细胞系过表达miRNA 17-92显著增强棕色脂肪特异性基因Ucp1的表达。同时，脂肪特异性miRNA 17-92转基因小鼠的表型显示miRNA 17-92显著降低白色脂肪的含量，较对照组具有更强的整体代谢水平。检测发现miRNA 17-92能够增强白色脂肪中多种产热基因的表达量以及线粒体数量。经软件预测并证实miRNA 17-92通过干预白色脂肪特异性基因RB1促进棕色脂肪分化和米色脂肪的形成。我们发现了一种特异性的米色脂肪形成基因参与的白色脂肪功能调控，同时针对白色脂肪靶点基因的药物干预可能是一种全新的研究方向。