支链氨基酸代谢异常在多囊卵巢综合征胰岛素抵抗发生中的作用及机制研究

Polycystic ovary syndrome (PCOS) is universally recognized as the commonest endocrinopathy of women. The definition and the pathogenesis of PCOS are continuously evolving to accommodate expanding knowledge on the syndrome, which is now known to be more complex than purely a reproductive disorder. At present, alterations in several metabolic pathways have been implicated in the pathophysiology of PCOS, including abnormalities in steroid hormone regulation and insulin signaling pathway. Moreover, there is increasing focus on the complications associated with metabolic disturbances among women with PCOS. This highlights the need of understanding the metabolic dysfunction in PCOS for prevention of long-term complications through appropriate screening, diagnosis and intervention. Some reports have shown that circulating concentrations of branched-chain amino acids contributed to development of obesity-associated insulin resistance.moreover,our previous metabolomics study demenstrated that branched-chain amino acids were significantly elevated in the PCOS samples comparing to the controls,and were positively corelated with the development of insulin resistance. In this study, we further investigate the role and molecular mechanism of branched-chain amino acids-mediated insulin resistance in PCOS.Our findings will be important not only in identifying novel metabolic biomarkers that predict PCOS and its long-term complications, but also in better understanding of the metabolic pathways directly affected during PCOS occurrence, which can provide a rational basis for the development of novel therapeutic targets.

多囊卵巢综合征（PCOS）是生殖功能障碍与糖、脂代谢异常共存的一种异质性疾病，然而目前对其发病机制仍不清楚。PCOS全身及卵巢局部胰岛素抵抗是联系PCOS生殖与代谢紊乱的关键环节，阐明PCOS胰岛素抵抗的发生发展对于理解PCOS的发病机理，拓展临床治疗及预防其并发症具有重要意义。本课题组前期利用代谢组学分析方法发现PCOS患者血浆中支链氨基酸水平明显上升，且与胰岛素抵抗的发生显著正相关，这提示支链氨基酸可能参与PCOS胰岛素抵抗发生的病理过程。此外，一些研究报道，游离支链氨基酸的浓度与肥胖诱导的胰岛素抵抗的发展密切相关。因此，本课题在前期工作基础上，拟探讨支链氨基酸代谢异常在PCOS全身和卵巢局部胰岛素抵抗发生中的作用及其分子机制，为PCOS早期诊断、新药物靶点的开发提供可靠的理论基础及应用依据。

多囊卵巢综合征（PCOS）是生殖功能障碍与糖、脂代谢异常共存的一种异质性疾病，然而目前对其发病机制仍不清楚。PCOS全身及卵巢局部胰岛素抵抗是联系PCOS生殖与代谢紊乱的关键环节，阐明PCOS胰岛素抵抗的发生发展对于理解PCOS的发病机理，拓展临床治疗及预防其并发症具有重要意义。课题组前期利用代谢组学分析方法发现PCOS患者血浆中支链氨基酸水平明显上升，本研究进一步完成PCOS及对照组卵泡液支链氨基酸水平检测分析，明确PCOS患者中其水平显著升高且与代谢紊乱特别是胰岛素抵抗的发生正相关，这表明支链氨基酸可能参与PCOS全身及卵巢局部胰岛素抵抗发生的病理过程。在探索卵巢局部胰岛素抵抗发生机制方面，由于胰岛素抵抗与慢性炎症反应密切相关，而PCOS患者普遍存在慢性炎症状态，我们进一步揭示PCOS卵巢颗粒细胞炎症发生的新机制，阐明了WNT5a分子通过PI3K/AKT/NFKB信号通路调控卵巢颗粒细胞炎症反应。此外，利用DHEA诱导建立PCOS动物模型探索PCOS干预治疗有效措施，发现二甲双胍干预可有效改善PCOS代谢异常和卵母细胞质量。以上研究结果发表SCI论文3篇，为PCOS早期诊断治疗、新药物靶点的开发提供可靠的理论基础及应用依据。