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      Transferrin Receptor 1 Regulates Thermogenic Capacity and Cell Fate in Brown/Beige Adipocytes

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          Abstract

          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.

          Abstract

          A role of transferrin receptor 1 (Tfr1) in brown/beige adipocytes is reported. Ablation of Tfr1 in adipose tissue attenuates the thermogenic capacity and induces transdifferentiation of brown adipocytes via distinct mechanisms. The findings shed light on how Tfr1 and iron homeostasis affect thermogenesis, suggesting the Tfr1 and iron metabolic pathway as potential targets for preventing metabolic diseases.

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          Author and article information

          Contributors
          fwang@zju.edu.cn
          junxiamin@zju.edu.cn
          xielw@gdim.cn
          Journal
          Adv Sci (Weinh)
          Adv Sci (Weinh)
          10.1002/(ISSN)2198-3844
          ADVS
          Advanced Science
          John Wiley and Sons Inc. (Hoboken )
          2198-3844
          24 April 2020
          June 2020
          : 7
          : 12 ( doiID: 10.1002/advs.v7.12 )
          : 1903366
          Affiliations
          [ 1 ] The First Affiliated Hospital Institute of Translational Medicine School of Public Health Zhejiang University School of Medicine Hangzhou 310058 China
          [ 2 ] Beijing Advanced Innovation Center for Food Nutrition and Human Health China Agricultural University Beijing 100193 China
          [ 3 ] Department of Nutrition Precision Nutrition Innovation Center School of Public Health Zhengzhou University Zhengzhou 450001 China
          [ 4 ] State Key Laboratory of Applied Microbiology Southern China Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application Guangdong Open Laboratory of Applied Microbiology Guangdong Institute of Microbiology Guangdong Academy of Sciences Zhujiang Hospital Southern Medical University Guangzhou 510070 China
          [ 5 ] Nanfang Hospital Southern Medical University Guangzhou 510515 China
          [ 6 ] BGI Institute of Applied Agriculture BGI‐Shenzhen Shenzhen 518120 China
          Author notes
          Author information
          https://orcid.org/0000-0001-8730-0003
          Article
          ADVS1675
          10.1002/advs.201903366
          7312276
          32596110
          adf7a831-4011-4237-80a3-be52a61d56e5
          © 2020 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim

          This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

          History
          : 28 November 2019
          : 24 February 2020
          Page count
          Figures: 7, Tables: 0, Pages: 17, Words: 11898
          Funding
          Funded by: GDAS
          Award ID: 2018GDASCX‐0806
          Funded by: National Key Research and Development Program of China , open-funder-registry 10.13039/501100012166;
          Award ID: 2018YFA0507802
          Award ID: 2018YFA0507801
          Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
          Award ID: 81900797
          Award ID: 31530034
          Award ID: 31930057
          Award ID: 31570791
          Funded by: China Postdoctoral Science Foundation , open-funder-registry 10.13039/501100002858;
          Award ID: 2018M640565
          Categories
          Full Paper
          Full Papers
          Custom metadata
          2.0
          June 2020
          Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:24.06.2020

          beigeing,brown fat determination,hif1α,thermogenesis,transferrin receptor 1

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