m6A Regulates Liver Metabolic Disorders and Hepatogenous Diabetes

N-6-methyladenosine (m(6)A) is one of the most abundant modifications on mRNAs and plays important roles in various biological processes. The formation of m(6)A is catalyzed by a methyltransferase complex (MTC) containing a key factor methyltransferase-like 3 (Mettl3). However, the functions of Mettl3 and m(6)A modification in hepatic lipid and glucose metabolism remain unclear. Here, we showed that both Mettl3 expression and m(6)A 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 m(6)A 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 m(6)A in HFD-induced metabolic disorders and hepatogenous diabetes.