mRNA m6A修饰酶METTL3在棕色脂肪组织能量代谢中的作用机制研究

棕色脂肪组织调节了能量代谢，参与了肥胖和代谢类疾病的发生。以往研究主要集中在转录水平调控，而mRNA m6A修饰是否参与了棕色脂肪组织能量代谢还远不清楚。本项目的科学假设为：mRNA m6A修饰核心酶METTL3在棕色脂肪组织中高表达，促进了m6A修饰PPARγ、PRDM16、PGC1α和UCP1 mRNA，增加其mRNA稳定性，促进BAT发育和产热。本课题组已构建了BAT特异的METTL3基因敲除（BKO）和过表达小鼠，已取得重要研究进展：我们发现METTL3在BAT中高表达，BKO小鼠出现BAT发育异常，脂质异常积累，产热能力降低，对高脂诱导的肥胖更敏感，出现肥胖和代谢综合症表型。本项目拟在前期工作基础上，通过BAT组织特异性METTL3敲除和过表达、能量代谢分析、m6A-RIP-seq、RNA稳定性分析等手段，深入研究METTL3在棕色脂肪组织能量代谢中的作用机制。

Brown adipose tissue regulates energy metabolism, contributing to the development of obesity and metabolic diseases. In the recent years, lots of progress have been made in identifying transcriptional factors and co-factors in the regulation of brown cell differentiation and thermogenesis. However, whether mRNA m6A modification and mRNA processing regulate thermogenesis is largely unknown. Our hypothesis is that METTL3, a key RNA methyltransferase, promotes BAT development and energy expenditure by promoting m6A modification and stability of PRDM16、PGC1α and UCP1 mRNA. Our preliminary data showed that METTL3 is selectively expressed in BAT, and BAT-specific deletion of METTL3 impairs BAT development and reduces energy expenditure. In this proposal, we will further elucidate the mechansims of METTL3 in the regulation of BAT development and energy metabolism. This study will reveal a novel mechanism that METTL3-mediated m6A modification of PRDM16 and PGC1α promotes brown cell differentiation and thermogenesis in mice.