title: High-fat diet causes iron deficiency via hepcidin-independent reduction of duodenal iron absorption.
abstract: Obesity is often associated with disorders of iron homeostasis; however, the underlying mechanisms are not fully understood. Hepcidin is a key regulator of iron metabolism and may be responsible for obesity-driven iron deficiency. Herein, we used an animal model of diet-induced obesity to study high-fat-diet-induced changes in iron homeostasis. C57BL/6 mice were fed a standard (SD) or high-fat diet (HFD) for 8 weeks, and in addition, half of the mice received high dietary iron (Fe+) for the last 2 weeks. Surprisingly, HFD led to systemic iron deficiency which was traced back to reduced duodenal iron absorption. The mRNA and protein expressions of the duodenal iron transporters Dmt1 and Tfr1 were significantly higher in HFD- than in SD-fed mice, indicating enterocyte iron deficiency, whereas the mRNA levels of the duodenal iron oxidoreductases Dcytb and hephaestin were lower in HFD-fed mice. Neither hepatic and adipose tissue nor serum hepcidin concentrations differed significantly between SD- and HFD-fed mice, whereas dietary iron supplementation resulted in increased hepatic hepcidin mRNA expression and serum hepcidin levels in SD as compared to HFD mice. Our study suggests that HFD results in iron deficiency which is neither due to intake of energy-dense nutrient poor food nor due to increased sequestration in the reticulo-endothelial system but is the consequence of diminished intestinal iron uptake. We found that impaired iron absorption is independent of hepcidin but rather results from reduced metal uptake into the mucosa and discordant oxidoreductases expressions despite enterocyte iron deficiency.
authors.affiliation: Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sonnweber
authors.forename: Claudia
authors.initials: C
authors.lastname: Ress
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.forename: Andrea
authors.initials: A
authors.lastname: Schroll
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Murphy
authors.forename: Victor
authors.initials: V
authors.lastname: Wroblewski
authors.forename: Derrick R
authors.initials: DR
authors.lastname: Witcher
authors.forename: Patrizia
authors.initials: P
authors.lastname: Moser
authors.forename: Christoph F
authors.initials: CF
authors.lastname: Ebenbichler
authors.forename: Susanne
authors.initials: S
authors.lastname: Kaser
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
mesh_terms: D054392:Adipokines / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000097:blood / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects*; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D064451:Hepcidins; D007408:Intestinal Absorption; D007501:Iron / Q000097:blood / Q000378:metabolism; D000090463:Iron Deficiencies; D019266:Iron, Dietary / Q000493:pharmacokinetics / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000235:genetics; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D054392:Adipokines; D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; D064451:Hepcidins; D007501:Iron; D019266:Iron, Dietary; D011990:Receptors, Transferrin; D000099236:Solute Carrier Family 11, Member 2; C579599:Hamp protein, mouse; C480029:Tfrc protein, mouse