Gut-restricted farnesoid X receptor agonist fexaramine improves abnormal metabolic and reproductive phenotypes in PCOS-model mice

Objective: Although farnesoid X receptor (FXR) signaling has been implicated in obesity and inflammatory disorders, its mechanistic role in polycystic ovary syndrome (PCOS) remains unclear. Here, we investigated whether the gut-restricted FXR agonist fexaramine (Fex) could ameliorate metabolic and reproductive abnormalities in a mouse model of PCOS. Methods: Female C57BL/6J mice were randomly assigned to four groups: Control, Fex, PCOS, and PCOS + Fex. In parallel experiments, the PCOS phenotype was induced using either dehydroepiandrosterone combined with a high-fat diet (discovery model) or letrozole (validation model). Fex was administered via oral gavage to achieve gut-restricted FXR activation. During the intervention period, body weight, glucose metabolism, insulin sensitivity, and estrous cyclicity were monitored. At the end of the intervention, adipocyte size, reproductive hormone levels, follicular development, and ovarian transcriptomic changes were assessed. Results: Fex intervention significantly improved multiple metabolic parameters in PCOS mice, including attenuated body weight gain (5.08 ± 0.32 g vs. 7.72 ± 0.43 g, P < 0.0001), enhanced glucose tolerance (OGTT-AUC: 749.4 ± 131.9 vs. 972.4 ± 49.88, P = 0.022), increased insulin sensitivity (ITT-AUC: 530.60 ± 59.11 vs. 950.30 ± 148.30, P < 0.001), and reduced mean adipocyte size (3720 ± 676.3 vs. 11,863 ± 845.3 pixels, P < 0.0001). Fex also ameliorated reproductive abnormalities, as evidenced by restoration of estrous cyclicity (3.0 ± 0.8 vs. 0 cycles, P < 0.001), reduced relative ovarian weight (0.13 ± 0.04 vs. 0.19 ± 0.02 mg/g, P = 0.004), fewer antral follicles (8.5 ± 1.7 vs. 18.0 ± 2.1, P < 0.001), and increased corpus luteum counts (13.2 ± 2.6 vs. 7.0 ± 0.8, P = 0.029). In addition, Fex alleviated hyperandrogenemia, reflected by lower testosterone (37.39 ± 8.52 vs. 52.54 ± 7.97 ng/mL, P = 0.002) and androstenedione levels (7.94 ± 2.6 vs. 12.27 ± 0.99 ng/mL, P < 0.001), as well as reduced luteinizing hormone (37.22 ± 5.91 vs. 52.67 ± 3.37 mIU/mL, P < 0.001) and anti-Müllerian hormone levels (1.23 ± 0.24 vs. 2.05 ± 0.17 ng/mL, P < 0.001). Ovarian transcriptomic analysis further supported these findings, revealing that Fex modulated pathways associated with follicular development, steroidogenesis, and glycolipid metabolism. Conclusion: Fex ameliorated both metabolic and reproductive abnormalities in PCOS-model mice. These findings highlight gut-restricted FXR activation as a potential therapeutic strategy for PCOS, although further mechanistic studies are needed to establish causality.