司美格鲁肽通过 AMPK/SIRT1/NF-κB 信号通路缓解多囊卵巢综合征小鼠的卵巢炎症。

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

机构信息

Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China.

Department of Ultrasound Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People's Republic of China.

出版信息

Drug Des Devel Ther. 2024 Sep 4;18:3925-3938. doi: 10.2147/DDDT.S484531. eCollection 2024.

BACKGROUND

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.

背景

GLP-1 受体激动剂（GLP-1RA）已被证明可治疗多种代谢疾病，但 GLP-1RA 对多囊卵巢综合征（PCOS）的影响尚不清楚。在这里，我们旨在研究新型 GLP-1RA 司美格鲁肽是否可以减轻 PCOS 小鼠的卵巢炎症。

方法

雌性 C57BL/6J 小鼠皮下注射脱氢表雄酮 21 天以建立 PCOS 模型。然后，将小鼠随机分为三组：PCOS 组（n=6）、S-0.42 组（司美格鲁肽 0.42mg/kg/w，n=6）和 S-0.84 组（司美格鲁肽 0.84mg/kg/w，n=6）。其余六只小鼠作为对照组（NC）。干预 28 天后，测量血清性激素和炎症细胞因子水平。苏木精和伊红染色观察卵巢形态。免疫组织化学染色检测卵巢中 CYP19A1、TNF-α、IL-6、IL-1β和 NF-κB 的相对表达。使用免疫荧光染色检测 CYP17A1 和 StAR。最后，使用 Western 印迹法检测 AMPK、pAMPK、SIRT1、NF-κB、IκBα、pIκBα、TNF-α、IL-6 和 IL-1β的相对表达。

结果

首先，司美格鲁肽干预后，小鼠体重减轻，胰岛素抵抗改善，发情周期恢复正常。血清睾酮和 IL-1β水平显著降低，而雌二醇和孕酮水平显著升高。卵泡囊性扩张明显改善。卵巢中 TNF-α、IL-6、IL-1β、NF-κB、CYP17A1 和 StAR 的表达显著下调，而 CYP19A1 的表达上调。最后，我们证实司美格鲁肽通过 AMPK/SIRT1/NF-κB 信号通路缓解卵巢组织炎症，改善 PCOS。