Wang Xue, Wu Qian, Zhong Meijuan, Chen Ying, Wang Yudi, Li Xin, Zhao Wenxi, Ge Chaodong, Wang Xinhui, Yu Yingying, Yang Sisi, Wang Tianyi, Xie Enjun, Shi Wanting, Min Junxia, Wang Fudi
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.
International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China.
Cell Metab. 2025 Mar 4;37(3):673-691.e7. doi: 10.1016/j.cmet.2024.11.010. Epub 2024 Dec 26.
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.
铁死亡被表征为一种铁依赖性和亲脂性的细胞死亡形式。然而，铁死亡在脂肪组织功能和活性中发挥何种作用仍不清楚。在此，我们发现在肥胖个体和小鼠的脂肪组织中，铁死亡特征较低。我们进一步发现，用非致死剂量的铁死亡激动剂激活铁死亡信号，可显著减少原代脂肪细胞和高脂饮食（HFD）喂养小鼠中的脂质积累。值得注意的是，脂肪细胞特异性过表达酰基辅酶A合成酶长链家族成员4（Acsl4）或缺失铁蛋白重链（Fth），可通过激活铁死亡信号保护小鼠免受HFD诱导的脂肪扩张和代谢紊乱。从机制上讲，我们发现5,15-二羟基二十碳四烯酸（5,15-DiHETE）激活铁死亡信号，导致缺氧诱导因子-1α（HIF1α）降解，从而解除由c-Myc-过氧化物酶体增殖物激活受体γ共激活因子-1β（Pgc1β）途径调节的产热程序的抑制。我们的研究结果表明，激活脂肪组织中的铁死亡信号可能有助于预防和治疗肥胖及其相关的代谢紊乱。
