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The objective of the current study was to determine whether and how adipose tissue macrophages (ATMs) regulate adipocyte iron concentrations and whether this is impacted by obesity. Using bone marrow-derived macrophages (BMDMs) polarized to M0, M1, M2, or metabolically activated (MMe) phenotypes, we showed that MMe BMDMs and ATMs from obese mice have reduced expression of several iron-related proteins. Furthermore, the bioenergetic response to iron in obese ATMs was hampered. ATMs from iron-injected lean mice increased their glycolytic and respiratory capacities, thus maintaining metabolic flexibility, while ATMs from obese mice did not. Using an isotope-based system, we found that iron exchange between BMDMs and adipocytes was regulated by macrophage phenotype. At the end of the co-culture, MMe macrophages transferred and received more iron from adipocytes than M0, M1, and M2 macrophages. This culminated in a decrease in total iron in MMe macrophages and an increase in total iron in adipocytes compared with M2 macrophages. Taken together, in the MMe condition, the redistribution of iron is biased toward macrophage iron deficiency and simultaneous adipocyte iron overload. These data suggest that obesity changes the communication of iron between adipocytes and macrophages and that rectifying this iron communication channel may be a novel therapeutic target to alleviate insulin resistance.<\/jats:p>","DOI":"10.3390\/ijms23137417","type":"journal-article","created":{"date-parts":[[2022,7,3]],"date-time":"2022-07-03T22:50:46Z","timestamp":1656888646000},"page":"7417","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["An Iron Refractory Phenotype in Obese Adipose Tissue Macrophages Leads to Adipocyte Iron Overload"],"prefix":"10.3390","volume":"23","author":[{"given":"Magdalene K.","family":"Ameka","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN 37212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William N.","family":"Beavers","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciara M.","family":"Shaver","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9429-4702","authenticated-orcid":false,"given":"Lorraine B.","family":"Ware","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA"},{"name":"Department of Pathology, Microbiology, and Immunology, School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0342-1965","authenticated-orcid":false,"given":"Vern Eric","family":"Kerchberger","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA"},{"name":"Department of Pathology, Microbiology, and Immunology, School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly Q.","family":"Schoenfelt","sequence":"additional","affiliation":[{"name":"Department of Cancer Research, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8908-9165","authenticated-orcid":false,"given":"Tatsuki","family":"Koyama","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric P.","family":"Skaar","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology, and Immunology, School of Medicine, Vanderbilt University Medical Center, Nashville, TN 37212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lev","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Cancer Research, University of Chicago, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7302-8045","authenticated-orcid":false,"given":"Alyssa H.","family":"Hasty","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, TN 37212, USA"},{"name":"VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1111\/eci.12032","article-title":"Iron homeostasis in the metabolic syndrome","volume":"43","author":"Datz","year":"2013","journal-title":"Eur. 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