Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital and Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
EMBO Mol Med. 2023 Apr 11;15(4):e17450. doi: 10.15252/emmm.202317450. Epub 2023 Feb 27.
Premature ovarian insufficiency (POI) is a disease featured by early menopause before 40 years of age, accompanied by an elevation of follicle-stimulating hormone. Though POI affects many aspects of women's health, its major causes remain unknown. Many clinical studies have shown that POI patients are generally underweight, indicating a potential correlation between POI and metabolic disorders. To understand the pathogenesis of POI, we performed metabolomics analysis on serum and identified branch-chain amino acid (BCAA) insufficiency-related metabolic disorders in two independent cohorts from two clinics. A low BCAA diet phenotypically reproduced the metabolic, endocrine, ovarian, and reproductive changes of POI in young C57BL/6J mice. A mechanism study revealed that the BCAA insufficiency-induced POI is associated with abnormal activation of the ceramide-reactive oxygen species (ROS) axis and consequent impairment of ovarian granulosa cell function. Significantly, the dietary supplement of BCAA prevented the development of ROS-induced POI in female mice. The results of this pathogenic study will lead to the development of specific therapies for POI.
卵巢早衰（POI）是一种 40 岁以前绝经的疾病，伴有卵泡刺激素升高。虽然 POI 影响女性健康的许多方面，但主要原因仍不清楚。许多临床研究表明，POI 患者通常体重偏轻，这表明 POI 与代谢紊乱之间存在潜在的相关性。为了了解 POI 的发病机制，我们对血清进行了代谢组学分析，并在两个来自两个诊所的独立队列中鉴定出支链氨基酸（BCAA）不足相关的代谢紊乱。低 BCAA 饮食在年轻的 C57BL/6J 小鼠中表型重现了 POI 的代谢、内分泌、卵巢和生殖变化。机制研究表明，BCAA 不足引起的 POI 与鞘氨醇-活性氧（ROS）轴的异常激活有关，进而导致卵巢颗粒细胞功能障碍。值得注意的是，BCAA 的饮食补充可预防 ROS 诱导的雌性小鼠 POI 的发展。这项发病机制研究的结果将导致针对 POI 的特定治疗方法的发展。
