2. Academic Validation
  3. Adipocyte-derived ferroptotic signaling mitigates obesity

Adipocyte-derived ferroptotic signaling mitigates obesity

  • Cell Metab. 2024 Dec 21:S1550-4131(24)00456-X. doi: 10.1016/j.cmet.2024.11.010.
Xue Wang 1,  Qian Wu 2,  Meijuan Zhong 3,  Ying Chen 4,  Yudi Wang 5,  Xin Li 3,  Wenxi Zhao 6,  Chaodong Ge 5,  Xinhui Wang 6,  Yingying Yu 5,  Sisi Yang 6,  Tianyi Wang 3,  Enjun Xie 6,  Wanting Shi 6,  Junxia Min 7,  Fudi Wang 8
Affiliations

Affiliations

  • 1 The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China; The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; School of Public Health, Basic Medical Sciences, School of Pharmacology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China; School of Public Health, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China.
  • 2 International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China.
  • 3 School of Public Health, Basic Medical Sciences, School of Pharmacology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China.
  • 4 Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 5 The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 6 The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 7 The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: junxiamin@zju.edu.cn.
  • 8 The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China; School of Public Health, Basic Medical Sciences, School of Pharmacology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China; School of Public Health, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, China. Electronic address: fwang@zju.edu.cn.
PMID: 39729998 DOI: 10.1016/j.cmet.2024.11.010
Abstract

Ferroptosis is characterized as an iron-dependent and lipophilic form of cell death. However, it remains unclear what role Ferroptosis has in adipose tissue function and activity. Here, we find a lower ferroptotic signature in the adipose tissue of individuals and mice with obesity. We further find that activation of ferroptotic signaling by a non-lethal dose of Ferroptosis agonists significantly reduces lipid accumulation in primary adipocytes and high-fat diet (HFD)-fed mice. Notably, adipocyte-specific overexpression of acyl-coenzyme A synthetase long-chain family member 4 (Acsl4) or deletion of ferritin heavy chain (Fth) protects mice from HFD-induced adipose expansion and metabolic disorders via activation of ferroptotic signaling. Mechanistically, we find that 5,15-dihydroxyeicosatetraenoic acid (5,15-DiHETE) activates ferroptotic signaling, resulting in the degradation of hypoxia-inducible factor-1α (HIF1α), thereby derepressing a thermogenic program regulated by the c-Myc-peroxisome proliferator-activated receptor gamma coactivator-1 beta (Pgc1β) pathway. Our findings suggest that activating Ferroptosis signaling in adipose tissues might help to prevent and treat obesity and its related metabolic disorders.

Keywords

5,15-DiHETE; 5,15-dihydroxyeicosatetraenoic acid; ACSL4; HIF1α; acyl-coenzyme A synthetase long-chain family member 4; adipose tissue; ferritin; ferrology; ferroptosis; ferroptotic signaling; hypoxia-inducible factor-1α; iron metabolism; obesity.

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