Kaempferol CounteractsObesity and Impairs Adipogenesisby Suppressing PI3K/AKT/GSK3β-Mediated Mitotic Clonal Expansionand Attenuating Adipose Tissue Fibrosis

Abstract Kaempferol, a widely present dietary flavonoid in numerous fruits and vegetables, possesses antiobesity potential with unclearly defined mechanisms. This study investigated how kaempferol regulates adipogenesis in 3T3-L1 preadipocytes and exerts antiobesity effects in high-fat diet (HFD)-induced obese mice. Kaempferol inhibited preadipocyte differentiation at the early mitotic clonal expansion (MCE) stage by S-phase (18 h) and G2/M-phase (24 h) cell cycle arrest. Mechanistically, this action was mediated through inhibition of the PI3K/AKT/GSK3β pathway. Application of the AKT activator SC79 confirmed that kaempferol suppresses AKT phosphorylation to inhibit terminal adipogenesis. In vivo, kaempferol significantly alleviated HFD-induced body weight gain, adiposity, dyslipidemia, and insulin resistance. Transcriptomic and histological analyses revealed that kaempferol reversed obesity-associated upregulation of cell cycle and metabolic pathways in white adipose tissue and alleviated adipose tissue fibrosis. These findings underscore the potential of kaempferol as a promising functional food ingredient for preventing obesity and related metabolic diseases.