m <b>6</b> A Regulates Liver Metabolic Disorders and Hepatogenous Diabetes

Abstract

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.