Branched-chain amino acids prevent obesity by inhibiting the cell cycle in an NADPH-FTO-m⁶A coordinated manner

Obesity has become a major health crisis in the past decades. Branched-chain amino acids (BCAA), a class of essential amino acids, exerted beneficial health effects with regard to obesity and its related metabolic dysfunction, although the underlying reason is unknown. Here, we show that BCAA supplementation alleviates high-fat diet (HFD)-induced obesity and insulin resistance in mice and inhibits adipogenesis in 3T3-L1 cells. Further, we find that BCAA prevent the mitotic clonal expansion (MCE) of preadipocytes by reducing cyclin A2 (CCNA2) and cyclin-dependent kinase 2 (CDK2) expression. Mechanistically, BCAA decrease the concentration of nicotinamide adenine dinucleotide phosphate (NADPH) in adipose tissue and 3T3-L1 cells by reducing glucose-6-phosphate dehydrogenase (G6PD) expression. The reduced NADPH attenuates the expression of fat mass and obesity-associated (FTO) protein, a well-known m⁶A demethylase, to increase the N⁶-methyladenosine (m⁶A) levels of Ccna2 and Cdk2 mRNA. Meanwhile, the high m⁶A levels of Ccna2 and Cdk2 mRNA are recognized by YTH N⁶-methyladenosine RNA binding protein 2 (YTHDF2), which results in mRNA decay and reduction of their protein expressions. Overall, our data demonstrate that BCAA inhibit obesity and adipogenesis by reducing CDK2 and CCNA2 expression via an NADPH-FTO-m⁶A coordinated manner in vivo and in vitro, which raises a new perspective on the role of m⁶A in the BCAA regulation of obesity and adipogenesis.