浙江大学王福俤等研究人员合作发现，脂肪细胞来源的铁死亡信号减轻肥胖。2024年12月26日，《细胞—代谢》杂志在线发表了这项成果。

研究人员发现肥胖个体和小鼠的脂肪组织中铁死亡标志物较低。进一步研究发现，非致死剂量的铁死亡激动剂通过激活铁死亡信号，显著减少了原代脂肪细胞和高脂饮食（HFD）喂养小鼠的脂质积累。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），或删除铁蛋白重链（Fth）可以通过激活铁死亡信号，保护小鼠免受HFD诱导的脂肪扩展和代谢紊乱。

机制上，研究人员发现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）的降解，从而解除由c-Myc-过氧化物酶体增殖因子激活受体γ辅激活因子-1β（Pgc1β）通路调控的产热程序的抑制。这些研究结果表明，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性疾病。

据介绍，铁死亡是一种依赖铁且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的作用仍不明确。

附：英文原文

Title: Adipocyte-derived ferroptotic signaling mitigates obesity

Author: Xue Wang, Qian Wu, Meijuan Zhong, Ying Chen, Yudi Wang, Xin Li, Wenxi Zhao, Chaodong Ge, Xinhui Wang, Yingying Yu, Sisi Yang, Tianyi Wang, Enjun Xie, Wanting Shi, Junxia Min, Fudi Wang

Issue&Volume: 2024-12-26

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.

DOI: 10.1016/j.cmet.2024.11.010

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00456-X