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
  • 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.
PMID: 36847712 DOI: 10.15252/emmm.202317450
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.
Products
Inhibitors & Agonists
Other Products