Metformin abrogates pathological TNF-α-producing B cells through mTOR-dependent metabolic reprogramming in polycystic ovary syndrome
- National Engineering and Research Center of Human Stem Cells, China
- Central South University, China
- Hunan Normal University, China
- 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
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.
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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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
