N6-methyladenosine (m6A) is one of the most abundant modifications on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex (MTC) containing a key factor methyltransferase-like 3 (Mettl3). However, the functions of Mettl3 and m6A modification in hepatic lipid and glucose metabolism remain unclear. Here, we showed that both Mettl3 expression and m6A level increased in the livers of mice with high fat diet (HFD)-induced metabolic disorders. Overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance. In contrast, hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation, and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated m6A loss caused extended RNA half-lives of metabolism-related genes, which consequently protected mice against HFD-induced metabolic syndrome. Our findings reveal a critical role of Mettl3-mediated m6A in HFD-induced metabolic disorders and hepatogenous diabetes.
N6-甲基腺嘌呤（N6-methyladenosine, m6A）是mRNA上最普遍存在的甲基化修饰之一，由甲基转移酶3（Methyltransferase-like 3, Mettl3)等甲基转移酶复合物（Methyltransferase Complex, MTC）催化形成，参与调控多种RNA代谢过程及生物学功能。然而，Mettl3和m6A修饰在肝脏的脂质和葡萄糖代谢中的作用尚不清楚。本研究报道了在高脂饮食（High Fat Diet, HFD）诱导的代谢紊乱的小鼠肝脏中Mettl3和m6A水平升高，肝脏条件性Mettl3过表达加重了HFD诱导的肝脏代谢紊乱和胰岛素抵抗，肝脏条件性敲除Mettl3则显著减轻了HFD诱导的代谢综合征，主要表现为体重增加减慢、脂质累积减少以及胰岛素敏感性的改善。进一步机制研究表明，Mettl3敲除介导的m6A缺失使得代谢相关基因mRNA的半衰期延长，保护小鼠不受HFD诱导的代谢综合征的影响。该发现揭示了Mettl3介导的m6A在HFD引发的肝脏代谢紊乱和肝源性糖尿病中的重要调控作用。





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