Gut Microbiota and <scp>SCFAs</scp> Mediate the Therapeutic Effects of Canagliflozin in <scp>PCOS</scp> by Promoting White Fat Browning

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women, characterized by hyperandrogenism and frequently accompanied by insulin resistance. Canagliflozin (Cana), a sodium-dependent glucose transporter 2 (SGLT2) inhibitor used to treat diabetes, significantly inhibits renal SGLT2 activity. Clinical studies indicate that SGLT2 inhibitors improve endocrine and reproductive disorders in PCOS patients; however, whether these benefits involve the gut microbiota remains unknown. A PCOS mouse model was established by subcutaneous administration of dehydroepiandrosterone (DHEA). Serum samples were collected for the quantification of sex hormones, insulin, and lipid profiles. Ovarian, adipose tissue, and intestinal samples were harvested for analyses including hematoxylin-eosin staining, immunohistochemistry, reverse transcription polymerase chain reaction, and Western blotting. Gut microbiota composition was assessed via 16S rDNA sequencing, and short-chain fatty acid (SCFA) concentrations in intestinal contents were measured by gas chromatography. Cana improves ovarian function in PCOS mice, addressing disrupted estrous cycles, abnormal ovarian morphology, and hormonal imbalances. Meanwhile, Cana also demonstrated positive effects on glucose tolerance, insulin sensitivity, and gut barrier function. These changes were accompanied by enhanced white fat browning and increased mitochondrial biogenesis. Mechanistically, these beneficial effects were associated with modulation of the gut microbiota and its metabolites SCFAs, and butyric acid add-on treatment could significantly ameliorate insulin resistance and reproductive dysfunction in a PCOS mouse. This study reveals that Cana contributes to WAT browning and gut microbiota homeostasis, indicating that its therapeutic effects on PCOS-related metabolic and reproductive dysfunction are partially driven by modulation of the gut microbiome.