1. Academic Validation
  2. BCAA insufficiency leads to premature ovarian insufficiency via ceramide-induced elevation of ROS

BCAA insufficiency leads to premature ovarian insufficiency via ceramide-induced elevation of ROS

  • EMBO Mol Med. 2023 Feb 27;e17450. doi: 10.15252/emmm.202317450.
Xiao Guo # 1 Yuemeng Zhu # 1 2 Lu Guo # 1 2 Yiwen Qi # 1 2 3 Xiaocheng Liu 1 2 Jinhui Wang 1 Jiangtao Zhang 4 5 Linlin Cui 4 5 Yueyang Shi 6 Qichu Wang 1 Cenxi Liu 1 Guangxing Lu 1 Yilian Liu 1 Tao Li 6 Shangyu Hong 1 Yingying Qin 3 4 Xuelian Xiong 1 Hao Wu 1 Lin Huang 1 He Huang 1 Chao Gu 1 2 Bin Li 1 2 Jin Li # 1
Affiliations

Affiliations

  • 1 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.
  • 2 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
  • 3 Shanghai First Maternity and Infant Hospital, Shanghai, China.
  • 4 Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 5 Key Laboratory of Reproductive Endocrinology of Ministry of Education, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, China.
  • 6 Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • # Contributed equally.
Abstract

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.

Keywords

ROS; ceramide; infertility; low BCAA diet; premature ovarian insufficiency.

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