Metformin abrogates pathological TNF-α-producing B cells through mTOR-dependent metabolic reprogramming in polycystic ovary syndrome

  1. Na Xiao
  2. Jie Wang
  3. Ting Wang
  4. Xingliang Xiong
  5. Junyi Zhou
  6. Xian Su
  7. Jing Peng
  8. Chao Yang
  9. Xiaofeng Li
  10. Ge Lin
  11. Guangxiu Lu
  12. Fei Gong  Is a corresponding author
  13. Lamei Cheng  Is a corresponding author
  1. National Engineering and Research Center of Human Stem Cells, China
  2. Central South University, China
  3. Hunan Normal University, China
  4. Reproductive and Genetic Hospital of CITIC-Xiangya, China

Abstract

B cells contribute to the pathogenesis of polycystic ovary syndrome (PCOS). Clinically, metformin is used to treat PCOS, but it is unclear whether metformin exerts its therapeutic effect by regulating B cells. Here, we showed that the expression level of TNF-α in peripheral blood B cells from PCOS patient was increased. Metformin used in vitro and in vivo was able to reduce the production of TNF-α in B cells from PCOS patient. Administration of metformin improved mouse PCOS phenotypes induced by dehydroepiandrosterone (DHEA) and also inhibited TNF-α expression in splenic B cells. Further, metformin induced metabolic reprogramming of B cells in PCOS patients, including the alteration in mitochondrial morphology, the decrease in mitochondrial membrane potential, ROS production and glucose uptake. In DHEA-induced mouse PCOS model, metformin altered metabolic intermediates in splenic B cells. Moreover, the inhibition of TNF-α expression and metabolic reprogramming in B cells of PCOS patients and mouse model by metformin were associated with decreased mTOR phosphorylation. Together, TNF-α-producing B cells are involved in the pathogenesis of PCOS, and metformin inhibits mTOR phosphorylation and affects metabolic reprogramming, thereby inhibiting TNF-α expression in B cells, which may be a new mechanism of metformin in the treatment of PCOS.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1, 2, 3, 4, 5, 6, 7 and 8.Figure 1-source data 1, Figure 2-source data 1, Figure 3-source data 1, Figure 4-source data 1, Figure 5-source data 1, Figure 6-source data 1, Figure 7-source data 1, Figure 8-source data 1 contain the numerical data used to generate the figures.

Article and author information

Author details

  1. Na Xiao

    National Engineering and Research Center of Human Stem Cells, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2376-4073
  2. Jie Wang

    National Engineering and Research Center of Human Stem Cells, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Ting Wang

    Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Xingliang Xiong

    Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Junyi Zhou

    Hunan Normal University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Xian Su

    National Engineering and Research Center of Human Stem Cells, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Jing Peng

    National Engineering and Research Center of Human Stem Cells, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Chao Yang

    National Engineering and Research Center of Human Stem Cells, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Xiaofeng Li

    Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Ge Lin

    Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Guangxiu Lu

    National Engineering and Research Center of Human Stem Cells, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Fei Gong

    Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China
    For correspondence
    gongfei0218@hotmail.com
    Competing interests
    The authors declare that no competing interests exist.
  13. Lamei Cheng

    Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China
    For correspondence
    LameiCheng@csu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8685-3674

Funding

National Natural Science Foundation of China

  • Lamei Cheng

China Postdoctoral Science Foundation

  • Na Xiao

Hunan Provincial National Science Foundation of China

  • Na Xiao

L.C.designed the research studies; analyzed the data; revised the manuscript. N.X. designed and performed the experiments; collected, analyzed, and interpreted the data; performed statistical analysis;wrote the manuscript.

Ethics

Animal experimentation: All animal experiments were approved by the ethic review committee of Central South University(NO.2019-S111)

Human subjects: Patients and control subjects were recruited from the Reproductive & Genetic Hospital of CITIC-Xiangya. This study was approved by the ethic committee of the Reproductive & Genetic Hospital of CITIC-Xiangya(NO.LL-SC-2015-007), and all participants provided informed consent.

Reviewing Editor

  1. Ricardo Azziz, University at Albany, SUNY, United States

Publication history

  1. Received: October 14, 2021
  2. Accepted: June 24, 2022
  3. Accepted Manuscript published: June 24, 2022 (version 1)

Copyright

© 2022, Xiao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Na Xiao
  2. Jie Wang
  3. Ting Wang
  4. Xingliang Xiong
  5. Junyi Zhou
  6. Xian Su
  7. Jing Peng
  8. Chao Yang
  9. Xiaofeng Li
  10. Ge Lin
  11. Guangxiu Lu
  12. Fei Gong
  13. Lamei Cheng
(2022)
Metformin abrogates pathological TNF-α-producing B cells through mTOR-dependent metabolic reprogramming in polycystic ovary syndrome
eLife 11:e74713.
https://doi.org/10.7554/eLife.74713

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