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.

N ⁶ -甲基腺苷 (m ⁶ A) 是 mRNA 上最丰富的修饰之一，在各种生物过程中起着重要作用。m ⁶ A的形成由包含关键因子甲基转移酶样 3 ( Mettl3 )的甲基转移酶复合物 (MTC) 催化。然而，Mettl3 和 m ⁶ A 修饰在肝脏脂质和葡萄糖代谢中的功能仍不清楚。在这里，我们发现高脂肪饮食(HFD) 诱导的代谢紊乱小鼠肝脏中的Mettl3 表达和 m ⁶ A 水平均增加。Mettl3的过表达加重HFD诱导的肝脏代谢紊乱和胰岛素抵抗. 相比之下，Mettl3 的肝细胞特异性敲除通过减缓体重增加、减少脂质积累和提高胰岛素敏感性显着缓解了 HFD 诱导的代谢紊乱。从机制上讲，Mettl3 耗竭介导的 m ⁶ A 损失导致代谢相关基因的 RNA 半衰期延长，从而保护小鼠免受 HFD 诱导的代谢综合征。我们的研究结果揭示了 Mettl3 介导的 m ⁶ A 在 HFD 诱导的代谢紊乱和肝源性糖尿病中的关键作用。