m6A阅读蛋白YTHDF1调节白色脂肪米色化的作用机制研究

白色脂肪米色化可增加脂肪组织产热、促进能量消耗，被认为是防治肥胖等代谢性疾病的潜在策略。新近研究表明，m6A修饰影响mRNA表达而调控脂肪组织产热，然而介导该过程的关键因子有待鉴定。我们前期研究发现，m6A阅读蛋白YTHDF1在小鼠米色脂肪组织产生过程中表达上调；脂肪组织中敲除Ythdf1基因抑制米色化进程，并促进高脂饮食诱导的肥胖；敲除Ythdf1在翻译层面影响一批脂肪分化、产热基因的表达。基于此，本项目将进一步研究小鼠体内高表达YTHDF1对米色化过程和肥胖发生的影响；阐明YTHDF1调控的靶mRNA及分子机制；在人体样本中分析YTHDF1表达与肥胖的关联性。本项目将明确YTHDF1在转录后层面对基因表达进行重编程以促进白色脂肪米色化，丰富我们对m6A表观修饰生物学功能的认识，拓宽脂肪代谢研究思路。

The induction of beige adipocytes in white adipose tissue (WAT beiging) increases heat production and promotes glucose utilization, which is one of the most potential therapeutic strategies for obesity and obesity-related metabolic diseases. Studies have shown that m6A modifications in mRNA act as cis-elements to regulate the expression of thermogenic genes, leading to adipose tissue thermogenesis. However, the key proteins (trans-factors) that mediate the thermogenic function of m6A remain to be identified. Our previous studies revealed that the expression of YTHDF1, one of the m6A “reader” proteins, is dramatically induced during WAT beiging in mice. Knockout of Ythdf1 gene in adipose tissue inhibits the beiging process and promotes obesity induced by high-fat diet. Moreover, knockout of Ythdf1 mainly affects the expression of a subset of fat differentiation genes and thermogenic genes at the translational level. These preliminary data led to the central hypothesis that YTHDF1 reprograms gene expression at the translational level to mediate m6A-promoted WAT beiging. To test this hypothesis, we will first study the effect of YTHDF1 overexpression on WAT beiging and obesity. Second, we will explore the molecular mechanism of YTHDF1-regulated mRNA translation in the beiging process. Finally, we will study the relationship between YTHDF1 expression and obesity in human samples. This project will not only expand our understanding of the biological function of m6A modification, but also open up new avenues of research on adipose tissue metabolism.