Resveratrol ameliorates High-Fat Diet induced ovarian damage by reshaping gut microbiota and reversing aberrant ovarian energy metabolism and gene expression

Resveratrol (RSV) improve gut-ovarian metabolic inflammation, and this effect could be related to the remodeling of the gut microbiota. • RSV reverses the high-fat diet (HFD) induced ovary glycolytic switch and restores its mitochondrial energy homeostasis. • RSV is associated with downregulated expression of Il-6 , Lpl , and Fabbp4 , which helps alleviate the vicious cycle between lipotoxicity and inflammation in the ovaries. • RSV can promote the enrichment of Akkermansia and Lachnospiraceae , a change that may be associated with gut microbiota remodeling. Metabolic stress induced by a high-fat diet (HFD) is one of the key factors leading to ovarian dysfunction. In this study, a multi-omics approach was employed to investigate the protective effects of resveratrol (RSV) against HFD-induced ovarian dysfunction in rats. The results indicate that RSV not only significantly mitigated systemic metabolic imbalances, such as weight gain and dyslipidemia, but also restored ovarian homeostasis, as evidenced by normalized estrous cycles, improved ovarian morphology, and balanced hormone levels. Mechanistically, RSV normalized altered ovarian energy metabolism by enhancing the tricarboxylic acid (TCA) cycle and oxidative phosphorylation while inhibiting glycolysis, thereby increasing ATP production. Transcriptomic analysis further revealed significant upregulation of key pathways, including the PPAR signaling pathway and steroidogenesis, and identified Apob and Lpl as potential core regulatory genes. Notably, RSV intervention modulated the gut microbiota, increasing microbial diversity and enriching beneficial bacterial genera, suggesting a restorative effect on the gut-ovary axis. In summary, our findings demonstrate that RSV alleviates HFD-induced ovarian dysfunction partially alleviates through a multilevel network involving systemic metabolism, ovarian energy metabolism, and gut microbiota regulation. This demonstrates its potential as a functional food ingredient for protecting female reproductive health. Download: Download high-res image (104KB) Download: Download full-size image