Obesity-induced reproductive dysfunction is driven by chronic low-grade inflammation and metabolic dysregulation. The potential modulatory effect of GLP-1RAs on the interplay mechanisms of inflammation and metabolic dysregulation in obesity-induced reproductive dysfunction remains unclear. Hence, we investigated the effect of semaglutide on reproductive function via the SIRT-associated pathway in obese female mice. Female mice were divided into three groups: control-normal diet (NC), obesity-high fat diet (HFD), and intervention-high fat diet + semaglutide (HS). Mice body weight, composition and metabolic response to glucose, insulin, and pyruvate were evaluated. Systemic and ovarian inflammatory cytokines (IL-1β, NF-κB, IL-6, TNF-α), reproductive hormones (P4, E2, FSH, LH), and ovarian expression of SIRT1, SIRT6, FOXO1, FOXO3a, NRF1, IRS1, iNOS, eNOS, p27 KIP1, and PTEN were evaluated. The ovarian tissues were analyzed for structural changes, lipid accumulation, oxidative stress, and follicular development. Oocyte's mitochondrial function, DNA damage, lipid and ROS levels, and fertility tests were assessed. Adiposity and metabolic dysregulation, mainly insulin resistance and IRS1 disruption, were observed in the obese group. The HFD group showed higher NF-κB-associated pro-inflammatory cytokine expressions, oxidative stress, FOXO1 and iNOS expression, reduced SIRT1, SIRT6, FOXO3a, NRF1, eNOS levels, and dysregulated p27 KIP1/PTEN colocalization. These observed changes were accompanied by reduced P4 and E2, elevated FSH and LH, disrupted ovarian morphology, ovarian and oocyte lipid accumulation, oocyte DNA damage, and reduced fertility outcomes in the HFD group. Semaglutide treatment alleviated the dysfunctions observed in the obese group. Our findings demonstrated that GLP-1RAs (semaglutide) have potential therapeutic effects on obesity-induced reproductive dysfunctions by modulating the interplay mechanisms of inflammation and metabolic dysregulation via the SIRT-associated pathway.
