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

Sep 9, 2024Drug design, development and therapy

Semaglutide reduces ovary inflammation through energy-regulating signals in mice with polycystic ovary syndrome

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Abstract

Semaglutide treatment resulted in significant changes in ovarian inflammation and hormone levels in mice.

Mice receiving semaglutide showed decreased weight and improved insulin resistance.
Serum testosterone and IL-1β levels decreased, while estradiol and progestin levels increased after treatment.
Follicular cystic dilation in the ovaries significantly improved with semaglutide intervention.
Expression levels of inflammatory markers TNF-α, IL-6, IL-1β, and NF-κB were significantly reduced in ovarian tissue.
Semaglutide upregulated CYP19A1 expression, which is associated with improved ovarian function.
The effects of semaglutide may be mediated through the AMPK/SIRT1/NF-κB signaling pathway.

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BACKGROUND: GLP-1 receptor agonists (GLP-1 RA) have been proven to treat several metabolic diseases; however, the effects of GLP-1 RA on (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.

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n = 6 per group

Decrease in Serum Level

Comparison of serum levels in group vs. -treated groups.

n = 6 per group

Decrease in IL-1β Level

Comparison of serum IL-1β levels in group vs. -treated groups.

n = 6 per group

Weight Loss

Weight measurements of mice after treatment.

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

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