Intermittent fasting attenuates ovarian chronic inflammation in obese mice by inhibiting the CXCL12-CXCR4 axis.

AIM: Obesity disrupts ovarian function in female via chronic inflammation. Intermittent fasting (IF) prevents obesity and exerts protective effects against inflammation. However, the underlying mechanisms remain poorly understood. This study aimed to elucidate the effects and putative mechanisms of action of IF on obesity-induced ovarian dysfunction.

METHODS

Ovarian samples were collected from mice fed a normal diet (ND), high-fat diet (HFD), HFD + IF, ND + AMD3100, and HFD + AMD3100. Ovarian function was evaluated using HE staining, ELISA, TUNEL assay, and Ki67 staining. Mitochondrial function in oocytes and granulosa cells was assessed using TEM and western blotting. ROS levels were determined by dihydroethidium staining. Macrophage activation and immune cell infiltration in ovarian tissue were analyzed using immunofluorescence and flow cytometry. Transcriptomic analysis, qPCR, and western blotting were performed to delineate the regulatory networks underlying the effects of IF.

RESULTS

HFD-induced obesity triggered ovarian chronic inflammation and various ovarian dysfunctions, including depleted follicular reserves, dysregulated hormone levels, disrupted estrous cycles, abnormal mitochondrial morphology, exacerbated oxidative stress, and increased apoptosis of granulosa cells. Importantly, IF intervention significantly alleviated chronic inflammation and reversed ovarian impairment. Mechanistically, IF suppressed the CXCL12-CXCR4 signaling axis in the ovaries of obese mice, thereby reducing the recruitment of peripheral neutrophils and inhibiting the activation of proinflammatory resident macrophages, which collectively contributed to the resolution of chronic inflammation. Inhibition of CXCR4 by AMD3100 exerted significant protective effects, effectively mitigating ovarian inflammation and preserving ovarian function in HFD-fed mice.

CONCLUSION

Our results revealed that IF alleviated ovarian chronic inflammation in obese mice by inhibiting the CXCL12-CXCR4 axis, thereby preserving ovarian function. These findings suggest that IF and pharmacological CXCR4 blockade are potential strategies for mitigating obesity-associated female reproductive dysfunction.