Semaglutide Alleviates Ovary Inflammation via the AMPK/SIRT1/NF‑κB Signaling Pathway in Polycystic Ovary Syndrome Mice

Mei Liu,1,* Sili Guo,1,* Xiaohan Li,1,* Yang Tian,1 Yanjie Yu,2 Lili Tang,1 Qimei Sun,1 Ting Zhang,1 Mingwei Fan,3 Lili Zhang,1 Yingjiang Xu,4 Jiajia An,5 Xiangqian Gao,6 Lei Han,7 Lei Zhang1 1Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 2Department of Ultrasound Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 3Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 4Department of Interventional Vascular Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 5Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 6Department of Pathology, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 7Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei Zhang, Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China, Email [email protected]: GLP-1 receptor agonists (GLP-1 RA) have been proven to treat several metabolic diseases; however, the effects of GLP-1 RA on polycystic ovary syndrome (PCOS) remain unclear. Here, we aimed to investigate whether semaglutide, a novel GLP-1 RA, could alleviate ovarian inflammation in PCOS mice.Methods: Female C57BL/6J mice were subcutaneously injected with dehydroepiandrosterone for 21 days to establish the PCOS model. Then the mice were randomly divided into three groups: PCOS group (n = 6), S-0.42 group (semaglutide 0.42 mg/kg/w, n = 6), and S-0.84 group (semaglutide 0.84 mg/kg/w, n = 6). The remaining six mice were used as controls (NC). After 28 days of intervention, serum sex hormones and inflammatory cytokine levels were measured. Hematoxylin and eosin staining was used to observe the ovarian morphology. Immunohistochemical staining was used to detect the relative expression of CYP19A1, TNF-α, IL-6, IL-1β, and NF-κB in ovaries. CYP17A1 and StAR were detected using immunofluorescence staining. Finally, the relative expressions of AMPK, pAMPK, SIRT1, NF-κB, IκBα, pIκBα, TNF-α, IL-6, and IL-1β were measured using Western blotting.Results: First, after intervention with semaglutide, the weight of the mice decreased, insulin resistance improved, and the estrous cycle returned to normal. Serum testosterone and IL-1β levels decreased significantly, whereas estradiol and progestin levels increased significantly. Follicular cystic dilation significantly improved. The expression of TNF-α, IL-6, IL-1β, NF-κB, CYP17A1, and StAR in the ovary was significantly downregulated, whereas CYP19A1 expression was upregulated after the intervention. Finally, we confirmed that semaglutide alleviates ovarian tissue inflammation and improves PCOS through the AMPK/SIRT1/NF-κB signaling pathway.Conclusion: Semaglutide alleviates ovarian inflammation via the AMPK/SIRT1/NF‑κB signaling pathway in PCOS mice.Keywords: GLP-1 receptor agonist, polycystic ovary syndrome, semaglutide, inflammation