Surplus fatty acid synthesis increases oxidative stress in adipocytes and induces lipodystrophy

Li Weng, Wen-Shuai Tang, Xu Wang, Yingyun Gong, Changqin Liu, Ni-Na Hong, Ying Tao, Kuang-Zheng Li, Shu-Ning Liu, Wanzi Jiang, Ying Li, Ke Yao, Li Chen, He Huang, Yu-Zheng Zhao, Ze-Ping Hu, Youli Lu, Haobin Ye, Xingrong Du, Hongwen Zhou (), Peng Li () and Tong-Jin Zhao ()
Additional contact information
Li Weng: Fudan University
Wen-Shuai Tang: Fudan University
Xu Wang: School of Life Science, Anhui Medical University, Research Center for Translational Medicine, the Second Affiliated Hospital of Anhui Medical University
Yingyun Gong: the First Affiliated Hospital of Nanjing Medical University
Changqin Liu: the First Affiliated Hospital, Xiamen University, Xiamen
Ni-Na Hong: Xiamen University
Ying Tao: Fudan University
Kuang-Zheng Li: Fudan University
Shu-Ning Liu: Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology
Wanzi Jiang: the First Affiliated Hospital of Nanjing Medical University
Ying Li: Northern Jiangsu People’s Hospital
Ke Yao: Tsinghua University
Li Chen: Fudan University
He Huang: Fudan University
Yu-Zheng Zhao: Optogenetics & Synthetic Biology Interdisciplinary Research Center, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology
Ze-Ping Hu: Tsinghua University
Youli Lu: Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Institute of Clinical Mass Spectrometry, Shanghai Academy of Experimental Medicine
Haobin Ye: Fudan University
Xingrong Du: Fudan University
Hongwen Zhou: the First Affiliated Hospital of Nanjing Medical University
Peng Li: Fudan University
Tong-Jin Zhao: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Adipocytes are the primary sites for fatty acid storage, but the synthesis rate of fatty acids is very low. The physiological significance of this phenomenon remains unclear. Here, we show that surplus fatty acid synthesis in adipocytes induces necroptosis and lipodystrophy. Transcriptional activation of FASN elevates fatty acid synthesis, but decreases NADPH level and increases ROS production, which ultimately leads to adipocyte necroptosis. We identify MED20, a subunit of the Mediator complex, as a negative regulator of FASN transcription. Adipocyte-specific male Med20 knockout mice progressively develop lipodystrophy, which is reversed by scavenging ROS. Further, in a murine model of HIV-associated lipodystrophy and a human patient with acquired lipodystrophy, ROS neutralization significantly improves metabolic disorders, indicating a causal role of ROS in disease onset. Our study well explains the low fatty acid synthesis rate in adipocytes, and sheds light on the management of acquired lipodystrophy.

Date: 2024
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DOI: 10.1038/s41467-023-44393-7

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