FTO regulates adipogenesis by controlling cell cycle progression via mA-YTHDF2 dependent mechanism.

N-methyladenosine (mA) is the most prevalent internal mRNA modification in eukaryotes. Loss of mA demethylase FTO increases mA levels and inhibits adipogenesis of preadipocytes. However, its underlying mechanism remains elusive. Here, we demonstrated that silencing FTO inhibited adipogenesis of preadipocytes through impairing cell cycle progression at the early stage of adipogenesis. FTO knockdown markedly decreased the expression of CCNA2 and CDK2, crucial cell cycle regulators, leading to delayed entry of MDI-induced cells into G2 phase. Furthermore, the mA levels of CCNA2 and CDK2 mRNA were significantly upregulated following FTO knockdown. mA-binding protein YTHDF2 recognized and decayed methylated mRNAs of CCNA2 and CDK2, leading to decreased protein expression, thereby prolonging cell cycle progression and suppressing adipogenesis. Our work unravels that FTO regulates adipogenesis by controlling cell cycle progression in an mA-YTHDF2 dependent manner, which provides insights into critical roles of mA methylation in adipogenesis.