Adipocyte-derived ferroptotic signaling mitigates obesity
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.
Authors
- Y. Wang (ORCID: https://orcid.org/0000-0003-0327-2717)
- Qian Wu (ORCID: https://orcid.org/0000-0003-3934-0128)
- Junxia Min (ORCID: https://orcid.org/0000-0001-8099-6327)
- Chaodong Ge (ORCID: https://orcid.org/0000-0003-4455-8877)
- Sisi Yang (ORCID: https://orcid.org/0009-0008-2696-9107)
- Xin Li (ORCID: https://orcid.org/0000-0002-3699-8912)
- Xinhui Wang (ORCID: https://orcid.org/0000-0001-7713-6262)
- Ying Chen (ORCID: https://orcid.org/0000-0001-6303-5858)
- Tianyi Wang (ORCID: https://orcid.org/0009-0009-9452-3956)
- Xue Chao Wang (ORCID: https://orcid.org/0000-0002-2381-9145)
- Fudi Wang (ORCID: https://orcid.org/0000-0001-8730-0003)
- Wenxi Zhao
- Yingying Yu (ORCID: https://orcid.org/0000-0002-9857-2407)
- Enjun Xie (ORCID: https://orcid.org/0000-0002-5739-0404)
- Wanting Shi (ORCID: https://orcid.org/0000-0002-0209-0930)
Institutions
- Sun Yat-sen University (CN)
- Fudan University (CN)
- Zhongshan Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- First Affiliated Hospital of University of South China (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
- University of South China (CN)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2024-12-26
- DOI
- https://doi.org/10.1016/j.cmet.2024.11.010
- Citations
- 48
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 20.11
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Postdoctoral Research Foundation of China