Esculetin improves lipid metabolism disorders induced by a high-fat diet by regulating the P13K-AKT signaling pathway and taurocholic acid metabolism.

High-fat diet (HFD)-induced lipid metabolism disorders are significant pathogenic factors in the development of various chronic diseases associated with metabolic dysfunction, posing a serious threat to public health. Esculetin (EL) is characterized by its relatively low toxicity and has potential applications in agriculture and the food industry. However, there is a paucity of research regarding its intervention effects and mechanisms in lipid metabolism disorders induced by HFD in obese mice. Through transcriptomic, network pharmacological, and metabolomic analyses of the livers from HFD-fed obese mice, we found that the PI3K-AKT signaling pathway was significantly enriched, indicating that EL could influence lipid metabolism disorders by regulating this pathway. Metabolomic analysis of the serum from EL-treated obese mice revealed a significant increase in taurocholic acid content, which is regulated by the gut microbiota. Both in vivo and in vitro experiments further demonstrated that EL intervention could affect the expression of proteins involved in lipid metabolism, oxidative stress, and inflammation, thereby increasing insulin sensitivity. Overall, EL intervention can improve lipid metabolism in obese mice by regulating the PI3K-AKT signaling pathway and taurocholic acid metabolism.