PPM1K-regulated impaired catabolism of branched-chain amino acids orchestrates polycystic ovary syndromeResearch in context
Liangshan Mu,
Zhenhong Ye,
Junhao Hu,
Yurong Zhang,
Kai Chen,
Haipeng Sun,
Rong Li,
Weian Mao,
Xiaoyu Long,
Chunmei Zhang,
Yuchen Lai,
Jun Liu,
Yue Zhao,
Jie Qiao
Affiliations
Liangshan Mu
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
Zhenhong Ye
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
Junhao Hu
Transplantation Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Yurong Zhang
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
Kai Chen
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
Haipeng Sun
NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Center for Cardiovascular Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
Rong Li
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
Weian Mao
The First School of Medicine, Wenzhou Medical University, Wenzhou, China
Xiaoyu Long
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
Chunmei Zhang
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
Yuchen Lai
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
Jun Liu
Nuffield Department of Population Health, University of Oxford, Oxford, UK; Corresponding author. Nuffield Department of Population Health, University of Oxford, Oxford, OX37LF, UK.
Yue Zhao
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; Research Units of Comprehensive Diagnosis and Treatment of Oocyte Maturation Arrest, Chinese Academy of Medical Sciences, Beijing, China; Corresponding author. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, No. 49 North HuaYuan Road, HaiDian District, Beijing, 100191, China.
Jie Qiao
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; Research Units of Comprehensive Diagnosis and Treatment of Oocyte Maturation Arrest, Chinese Academy of Medical Sciences, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinery Studies Peking University, Beijing 100871, China; Corresponding author. Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, No. 49 North HuaYuan Road, HaiDian District, Beijing, 100191, China.
Summary: Background: 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. Methods: 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 Mg2+/Mn2+-dependent 1K (PPM1K) was further explored by using Ppm1k-deficient mouse model and PPM1K down-regulated human ovarian granulosa cells. Findings: 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. Interpretation: 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. Funding: 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).
