Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides (TGs) in hepatocytes. Obesity is a major risk factor for developing fatty liver, although the intracellular molecular basis remains largely unclear. N⁶‐methyladenosine (m⁶A) RNA methylation is the most common internal modification in eukaryotic mRNA.

In the present study, by m⁶A sequencing and RNA sequencing, we found that both m⁶A enrichment and mRNA expression of lipogenic genes were significantly increased in leptin‐receptor–deficient db/db mice. Importantly, our results showed that YT521‐B homology domain‐containing 2 (Ythdc2), an m⁶A reader, was markedly down‐regulated in livers of obese mice and NAFLD patients. Suppression of Ythdc2 in livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in livers of obese mice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element‐binding protein 1c, fatty acid synthase, stearoyl‐CoA desaturase 1, and acetyl‐CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression.

Our findings describe an important role of the m⁶A reader, Ythdc2, for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity‐related NAFLD.