Curcumin prevents obesity by targeting TRAF4-induced ubiquitylation in m⁶ A-dependent manner

Obesity has become a major health problem that has rapidly prevailed over the past several decades worldwide. Curcumin, a natural polyphenolic compound present in turmeric, has been shown to have a protective effect on against obesity and metabolic diseases. However, its underlying mechanism remains largely unknown. Here, we show that the administration of curcumin significantly prevents HFD-induced obesity and decreases the fat mass of the subcutaneous inguinal WAT (iWAT) and visceral epididymal WAT (eWAT) in mice. Mechanistically, curcumin inhibits adipogenesis by reducing the expression of AlkB homolog 5 (ALKHB5), an m⁶ A demethylase, which leads to higher m⁶ A-modified TNF receptor-associated factor 4 (TRAF4) mRNA. TRAF4 mRNA with higher m⁶ A level is recognized and bound by YTHDF1, leading to enhanced translation of TRAF4. TRAF4, acting as an E3 RING ubiquitin ligase, promotes degradation of adipocyte differentiation regulator PPARγ by a ubiquitin-proteasome pathway thereby inhibiting adipogenesis. Thus, m⁶ A-dependent TRAF4 expression upregulation by ALKBH5 and YTHDF1 contributes to curcumin-induced obesity prevention. Our findings provide mechanistic insights into how m⁶ A is involved in the anti-obesity effect of curcumin.