1. Academic Validation
  2. Metformin abrogates pathological TNF-α-producing B cells through mTOR-dependent metabolic reprogramming in polycystic ovary syndrome

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

  • Elife. 2022 Jun 24;11:e74713. doi: 10.7554/eLife.74713.
Na Xiao 1 2 3 Jie Wang 2 3 Ting Wang 1 Xingliang Xiong 1 Junyi Zhou 4 Xian Su 2 3 Jing Peng 2 3 Chao Yang 2 3 Xiaofeng Li 5 Ge Lin 1 2 3 5 6 Guangxiu Lu 1 2 3 5 6 Fei Gong 1 5 6 Lamei Cheng 1 2 3 4 6
Affiliations

Affiliations

  • 1 Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, China.
  • 2 National Engineering and Research Center of Human Stem Cells, Changsha, China.
  • 3 Hunan Guangxiu Hi-tech Life Technology Co. Ltd, Changsha, China.
  • 4 Guangxiu Hospital, Hunan Normal University, Changsha, China.
  • 5 Clinical Research Center for Reproduction and Genetics in Hunan Province, Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China.
  • 6 NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Central South University, Changsha, 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 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.

Keywords

B lymphocytes; immunology; inflammation; mechanistic target of rapamycin; metabolic reprogramming; metformin; mouse; polycystic ovary syndrome.

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