Hyperinsulinemia impairs decidualization via AKT-NR4A1 signaling: new insight into polycystic ovary syndrome (PCOS)-related infertility

Investigating the underlying molecular mechanisms responsible for endometrial dysfunction in women with PCOS is essential, particularly focusing on the role of hyperinsulinemia. We explored the role of insulin in the decidualization process using a synthetic decidualization assay. To dissect the eff...

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Veröffentlicht in:Journal of ovarian research 2024-02, Vol.17 (1), p.31-31, Article 31
Hauptverfasser: Jiang, Nan-Xing, Zhao, Wei-Jie, Shen, Hao-Ran, Du, Dan-Feng, Li, Xue-Lian
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Sprache:eng
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Zusammenfassung:Investigating the underlying molecular mechanisms responsible for endometrial dysfunction in women with PCOS is essential, particularly focusing on the role of hyperinsulinemia. We explored the role of insulin in the decidualization process using a synthetic decidualization assay. To dissect the effects of PI3K/AKT-NR4A signaling, we employed small interfering RNAs (siRNAs) targeting the NR4A genes and inhibitors of the PI3K/AKT pathway. We also investigated the disruption of AKT-NR4A1 signaling in the endometrium of PCOS female rats induced with dehydroepiandrosterone (DHEA). Quantitative real-time PCR (qRT-PCR) and Western blot (WB) analyses were utilized to evaluate gene expression regulation. Insulin was found to suppress the expression of decidualization markers in human endometrial stromal cells (hESC) in a dose-dependent manner, concurrently triggering an inappropriate activation of the PI3K/AKT pathway. Members of the NR4A family, as downstream effectors in the PI3K/AKT pathway, were implicated in the insulin-induced disruptions during the decidualization process. Moreover, the endometrium of PCOS models showed significantly elevated levels of phosphorylated (Ser473) AKT, with a corresponding reduction in Nr4a1 protein. Our research demonstrates that insulin negatively regulates decidualization in hESC via the PI3K/AKT-NR4A pathway. In vivo analysis revealed a significant dysregulation of the AKT-NR4A1 pathway in the endometrium of PCOS rats. These findings offer novel insights into the pathogenesis of infertility and endometrial disorders associated with hyperinsulinemia in PCOS.
ISSN:1757-2215
1757-2215
DOI:10.1186/s13048-023-01334-8