Resveratrol inhibits white adipose deposition by the ESR1-mediated PI3K/AKT signaling pathway

Excessive adipose accumulation is the primary cause of obesity. Resveratrol (RES), a natural polyphenolic compound, has garnered significant attention for its anti-obesity properties. However, the precise mechanisms by which RES influences fat deposition have not yet been explored. In this study, the aim was to identify the target proteins and associated pathways of RES in order to elucidate the mechanisms by which RES reduces fat deposition. In this study, mice were administered 400 mg/kg of RES via gavage for 12 weeks. We found that while 400 mg/kg RES had no impact on the growth of the mice, it significantly reduced the weight of various white adipose tissues, as well as the serum and liver concentrations of total cholesterol and triglycerides. Network pharmacology identified 15 potential targets of RES and highlighted the PI3K/AKT signaling pathway as a key pathway. Molecular docking and dynamic simulations suggested that ESR1 might be the target protein through which RES exerts its anti-fat deposition effects. In vitro experiments revealed that ESR1 promotes the proliferation and inhibits the differentiation of 3 T3-L1 adipocytes, and suppresses the PI3K/AKT signaling pathway. Silencing the ESR1 gene altered the ability of RES to inhibit cell differentiation via the PI3K/AKT pathway. Gene expression results in subcutaneous adipose tissue, epididymal fat tissue, and liver tissue of mice were consistent with observations in cells. In summary, RES reduces white fat deposition by directly targeting the ESR1 protein and inhibiting the PI3K/AKT signaling pathway. Our findings provide new insights into the potential use of RES in the prevention and treatment of obesity.