Betulin Activates Hepatic PPARα-FGF21 Signaling to Combat Obesity

Betulin, a natural pentacyclic triterpenoid, demonstrates potential in combating obesity and metabolic disorders, yet its mechanisms remain incompletely understood. Here, we found that dietary betulin supplementation significantly attenuated body weight gain, improved glucose tolerance, and reduced ectopic lipid accumulation in the liver in mice fed a high-fat diet. Hepatic transcriptomics revealed enrichment of the peroxisome proliferator-activated receptor-α (PPARα) signaling pathway and identified fibroblast growth factor 21 (FGF21) as a key upregulated hepatokine. We found that betulin can regulate liver FGF21 expression via the PPARα signaling pathway both <i>in vivo</i> and <i>in vitro</i>. Our findings were further corroborated by the observation that liver-specific FGF21 knockout abolished betulin's metabolic benefits. Mechanistically, combining molecular dynamics simulations and experimental validation, we demonstrated that betulin acts as a PPARα agonist to induce FGF21 expression. These findings establish betulin as a PPARα agonist and elucidate a hepatokine-dependent pathway underlying betulin's metabolic benefits.