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
  • 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: [email protected].
  • 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: [email protected].
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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