Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China; Reproductive Medicine Center, Zhongshan Hospital, Fudan University, Shanghai, China.
Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Key Laboratory of Assisted Reproduction, Ministry of Education, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China.
EBioMedicine. 2023 Mar;89:104492. doi: 10.1016/j.ebiom.2023.104492. Epub 2023 Feb 28.
Polycystic ovary syndrome (PCOS) is one of the most common diseases with the coexistence of reproductive malfunction and metabolic disorders. Previous studies have found increased branched chain amino acid (BCAA) levels in women with PCOS. However, it remains unclear whether BCAA metabolism is causally associated with the risk of PCOS.
The changes of BCAA levels in the plasma and follicular fluids of PCOS women were detected. Mendelian randomization (MR) approaches were used to explore the potential causal association between BCAA levels and the risk of PCOS. The function of the gene coding the protein phosphatase Mg/Mn-dependent 1K (PPM1K) was further explored by using Ppm1k-deficient mouse model and PPM1K down-regulated human ovarian granulosa cells.
BCAA levels were significantly elevated in both plasma and follicular fluids of PCOS women. Based on MR, a potential direct, causal role for BCAA metabolism was revealed in the pathogenesis of PCOS, and PPM1K was detected as a vital driver. Ppm1k-deficient female mice had increased BCAA levels and exhibited PCOS-like traits, including hyperandrogenemia and abnormal follicle development. A reduction in dietary BCAA intake significantly improved the endocrine and ovarian dysfunction of Ppm1k female mice. Knockdown of PPM1K promoted the conversion of glycolysis to pentose phosphate pathway and inhibited mitochondrial oxidative phosphorylation in human granulosa cells.
Ppm1k deficiency-impaired BCAA catabolism causes the occurrence and development of PCOS. PPM1K suppression disturbed energy metabolism homeostasis in the follicular microenvironment, which provided an underlying mechanism of abnormal follicle development.
This study was supported by the National Key Research and Development Program of China (2021YFC2700402, 2019YFA0802503), the National Natural Science Foundation of China (81871139, 82001503, 92057107), the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-001), Key Clinical Projects of Peking University Third Hospital (BYSY2022043), the China Postdoctoral Science Foundation (2021T140600), and the Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01).
多囊卵巢综合征（PCOS）是一种最常见的疾病，其特征是生殖功能障碍和代谢紊乱并存。先前的研究发现，PCOS 患者的支链氨基酸（BCAA）水平升高。然而，BCAA 代谢是否与 PCOS 的发病风险有因果关系尚不清楚。
检测 PCOS 女性血浆和卵泡液中 BCAA 水平的变化。采用孟德尔随机化（MR）方法探讨 BCAA 水平与 PCOS 发病风险之间的潜在因果关系。利用 Ppm1k 基因敲除小鼠模型和下调人卵巢颗粒细胞中 PPM1K 的表达，进一步研究编码蛋白磷酸酶 Mg/Mn 依赖性 1K（PPM1K）的基因的功能。
PCOS 女性的血浆和卵泡液中 BCAA 水平均显著升高。基于 MR，发现 BCAA 代谢在 PCOS 的发病机制中具有直接的、因果关系，而 PPM1K 被检测为关键驱动因素。Ppm1k 基因敲除的雌性小鼠的 BCAA 水平升高，并表现出 PCOS 样特征，包括高雄激素血症和卵泡发育异常。减少饮食中 BCAA 的摄入可显著改善 Ppm1k 雌性小鼠的内分泌和卵巢功能障碍。敲低 PPM1K 可促进人颗粒细胞中糖酵解向磷酸戊糖途径的转化，并抑制线粒体氧化磷酸化。
Ppm1k 缺陷导致的 BCAA 分解代谢受损导致 PCOS 的发生和发展。PPM1K 抑制破坏了卵泡微环境中的能量代谢平衡，为卵泡发育异常提供了潜在的机制。
本研究得到国家重点研发计划（2021YFC2700402、2019YFA0802503）、国家自然科学基金（81871139、82001503、92057107）、中国医学科学院医学与健康科技创新工程（2019-I2M-5-001）、北京大学第三医院临床重点项目（BYSY2022043）、中国博士后科学基金（2021T140600）和上海市卫生健康委员会协同创新项目（2020CXJQ01）的资助。
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