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
  13. Lamei Cheng

  • Curated by eLife

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    Evaluation Summary:

    Overall this study confirms that TNF-α is increased in peripheral blood B cells from PCOS and metformin decreased production. The study demonstrates the potential mechanism for the increase in TNF-α and reduction due to metformin. This is demonstrated in humans as well as in a mouse model of PCOS. Overall this is a well designed study demonstrating the impact of Metformin on immune function in PCOS.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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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 tumor necrosis factor-alpha (TNF-α) in peripheral blood B cells from PCOS patients was increased. Metformin used in vitro and in vivo was able to reduce the production of TNF-α in B cells from PCOS patients. Administration of metformin improved mouse PCOS phenotypes induced by dehydroepiandrosterone (DHEA) and also inhibited TNF-α expression in splenic B cells. Furthermore, metformin induced metabolic reprogramming of B cells in PCOS patients, including the alteration in mitochondrial morphology, the decrease in mitochondrial membrane potential, Reactive Oxygen Species (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.

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  1. Version published to 10.7554/elife.74713 on eLife
  2. eLife

    Evaluation Summary:

    Overall this study confirms that TNF-α is increased in peripheral blood B cells from PCOS and metformin decreased production. The study demonstrates the potential mechanism for the increase in TNF-α and reduction due to metformin. This is demonstrated in humans as well as in a mouse model of PCOS. Overall this is a well designed study demonstrating the impact of Metformin on immune function in PCOS.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

  3. eLife

    Reviewer #2 (Public Review):

    The authors state the role of TNF-α in PCOS is mainly driven by mTOR pathway, validated that level of TNF-α is contributed mainly by Bcells. Authors further showed the molecular mechanism involved in Bcells when exposed to metformin drug. Overall, the study is well written, and the finding is important for a logical design of immunotherapeutic strategy for PCOS.

    The current study holds the key in better understanding the molecular mechanism induced in Bcells by metformin. The signaling molecule(s) from the current study may hold promising target for further validation at preclinical and clinical level.

    The current hypothesis is strongly supported and validated with strong experimental designs. The key question has been addressed with multiple experiments. Overall, the manuscript is well designed and concluded.

  4. eLife

    Reviewer #1 (Public Review):

    Strengths of the manuscript
    1. Comparative human and mouse studies
    3. Studies carried are methodical demonstrating-
    a) Increased production of TNF-α in B cells in women with PCOS.
    b) Inhibition of TNF-α by Metformin which is done through inhibition of phosphorylation of mTOR
    c) Metformin induces mitochondrial remodeling in pathological B cells
    d) Metformin reduces glucose uptake in pathological B cells
    e) Inhibition of mTOR resulting in the inhibitory effect on the expression of TNF-α in pathological B cells, decreased the MMP, ROS levels and glucose uptake in pathological B cells

    Weaknesses
    1. Better final culmination of data possible final diagram/schematic of pathway leading to TNF-α elevations in PCOS B cells, downstream effects and impact of Metformin.

  5. Version published to 10.1101/2021.12.03.471141v1 on bioRxiv