Gut microbiota-derived 4-hydroxyphenylacetic acid from resveratrol supplementation prevents obesity through SIRT1 signaling activation

Resveratrol (RSV), a natural polyphenol, has been suggested to influence glucose and lipid metabolism. However, the underlying molecular mechanism of its action remains largely unknown due to its multiple biological targets and low bioavailability. In this study, we demonstrate that RSV supplementation ameliorates high-fat-diet (HFD)-induced gut microbiota dysbiosis, enhancing the abundance of anti-obesity bacterial strains such as <i>Akkermansia, Bacteroides</i> and <i>Blautia</i>. The critical role of gut microbiota in RSV-mediated anti-obesity effects was confirmed through antibiotic-induced microbiome depletion and fecal microbiota transplantation (FMT), which showed that RSV treatment effectively mitigates body weight, histopathological damage, glucose dysregulation and systematic inflammation associated with HFD. Metabolomics analysis revealed that RSV supplementation significantly increases the levels of the gut microbial flavonoid catabolite 4-hydroxyphenylacetic acid (4-HPA). Notably, 4-HPA was sufficient to reverse obesity and glucose intolerance in HFD-fed mice. Mechanistically,4-HPA treatment markedly regulates SIRT1 signaling pathways and induces the expression of beige fat and thermogenesis-specific markers in white adipose tissue (WAT). These beneficial effects of 4-HPA are partially abolished by EX527, a known SIRT1 inhibitor. Collectively, our findings indicate that RSV improve obesity through a gut microbiota-derived 4-HPA-SIRT1 axis, highlighting gut microbiota metabolites as a promising target for obesity prevention.