title: Adipocyte iron regulates adiponectin and insulin sensitivity.
abstract: Iron overload is associated with increased diabetes risk. We therefore investigated the effect of iron on adiponectin, an insulin-sensitizing adipokine that is decreased in diabetic patients. In humans, normal-range serum ferritin levels were inversely associated with adiponectin, independent of inflammation. Ferritin was increased and adiponectin was decreased in type 2 diabetic and in obese diabetic subjects compared with those in equally obese individuals without metabolic syndrome. Mice fed a high-iron diet and cultured adipocytes treated with iron exhibited decreased adiponectin mRNA and protein. We found that iron negatively regulated adiponectin transcription via FOXO1-mediated repression. Further, loss of the adipocyte iron export channel, ferroportin, in mice resulted in adipocyte iron loading, decreased adiponectin, and insulin resistance. Conversely, organismal iron overload and increased adipocyte ferroportin expression because of hemochromatosis are associated with decreased adipocyte iron, increased adiponectin, improved glucose tolerance, and increased insulin sensitivity. Phlebotomy of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role for adipocytes in modulating metabolism through adiponectin in response to iron stores.
authors.affiliation: Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Gabrielsen
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.forename: Judith A
authors.initials: JA
authors.lastname: Simcox
authors.forename: Jingyu
authors.initials: J
authors.lastname: Huang
authors.forename: David
authors.initials: D
authors.lastname: Thorup
authors.forename: Deborah
authors.initials: D
authors.lastname: Jones
authors.forename: Robert C
authors.initials: RC
authors.lastname: Cooksey
authors.forename: David
authors.initials: D
authors.lastname: Gabrielsen
authors.forename: Ted D
authors.initials: TD
authors.lastname: Adams
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.forename: Paul N
authors.initials: PN
authors.lastname: Hopkins
authors.forename: William T
authors.initials: WT
authors.lastname: Cefalu
authors.forename: Donald A
authors.initials: DA
authors.lastname: McClain
mesh_terms: D041721:3T3-L1 Cells / Q000187:drug effects / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D052242:Adiponectin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000328:Adult; D000818:Animals; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications; D005260:Female; D005293:Ferritins / Q000097:blood; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D007501:Iron / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D019190:Iron Overload / Q000150:complications / Q000378:metabolism* / Q000628:therapy; D019266:Iron, Dietary / Q000633:toxicity; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D024821:Metabolic Syndrome / Q000150:complications / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000150:complications; D018962:Phlebotomy; D012333:RNA, Messenger / Q000096:biosynthesis; D000098742:Ferroportin
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; C499919:Adipoq protein, mouse; D027682:Cation Transport Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D019266:Iron, Dietary; D008565:Membrane Proteins; D012333:RNA, Messenger; D000098742:Ferroportin; D005293:Ferritins; D007501:Iron