Iron homeostasis is essential for maintaining cellular function in a wide range of cell types. However, whether iron affects the thermogenic properties of adipocytes is currently unknown. Using integrative analyses of multi‐omics data, transferrin receptor 1 (Tfr1) is identified as a candidate for regulating thermogenesis in beige adipocytes. Furthermore, it is shown that mice lacking Tfr1 specifically in adipocytes have impaired thermogenesis, increased insulin resistance, and low‐grade inflammation accompanied by iron deficiency and mitochondrial dysfunction. Mechanistically, the cold treatment in beige adipocytes selectively stabilizes hypoxia‐inducible factor 1‐alpha (HIF1α), upregulating the Tfr1 gene, and thermogenic adipocyte‐specific Hif1α deletion reduces thermogenic gene expression in beige fat without altering core body temperature. Notably, Tfr1 deficiency in interscapular brown adipose tissue (iBAT) leads to the transdifferentiation of brown preadipocytes into white adipocytes and muscle cells; in contrast, long‐term exposure to a low‐iron diet fails to phenocopy the transdifferentiation effect found in Tfr1 ‐deficient mice. Moreover, mice lacking transmembrane serine protease 6 (Tmprss6) develop iron deficiency in both inguinal white adipose tissue (iWAT) and iBAT, and have impaired cold‐induced beige adipocyte formation and brown fat thermogenesis. Taken together, these findings indicate that Tfr1 plays an essential role in thermogenic adipocytes via both iron‐dependent and iron‐independent mechanisms.

中文翻译：

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转铁蛋白受体 1 调节棕色/米色脂肪细胞的产热能力和细胞命运。

铁稳态对于维持多种细胞类型的细胞功能至关重要。然而，铁是否影响脂肪细胞的产热特性目前尚不清楚。通过对多组学数据的综合分析，转铁蛋白受体 1 (Tfr1) 被确定为调节米色脂肪细胞生热作用的候选者。此外，研究表明，脂肪细胞中特异性缺乏Tfr1 的小鼠生热作用受损、胰岛素抵抗增加，以及伴有铁缺乏和线粒体功能障碍的低度炎症。从机制上讲，米色脂肪细胞中的冷处理选择性地稳定缺氧诱导因子 1-α (HIF1α)，上调Tfr1基因，而生热脂肪细胞特异性Hif1α缺失则减少米色脂肪中生热基因的表达，而不会改变核心体温。值得注意的是，肩胛间棕色脂肪组织（iBAT）中Tfr1缺乏导致棕色前脂肪细胞转分化为白色脂肪细胞和肌肉细胞；相比之下，长期暴露于低铁饮食无法复制Tfr1缺陷小鼠中发现的转分化效应。此外，缺乏跨膜丝氨酸蛋白酶6（Tmprss6）的小鼠腹股沟白色脂肪组织（iWAT）和iBAT均出现铁缺乏，并且寒冷诱导的米色脂肪细胞形成和棕色脂肪产热作用受损。综上所述，这些发现表明 Tfr1 通过铁依赖性和铁非依赖性机制在产热脂肪细胞中发挥重要作用。