title: Dietary iron overload induces visceral adipose tissue insulin resistance.
abstract: Increased iron stores associated with elevated levels of the iron hormone hepcidin are a frequent feature of the metabolic syndrome. The aim of this study was to assess the effect of dietary iron supplementation on insulin resistance and the role of hepcidin in C57Bl/6 male mice fed a standard or iron-enriched diet for 16 weeks. Iron supplementation increased hepatic iron and serum hepcidin fivefold and led to a 40% increase in fasting glucose due to insulin resistance, as confirmed by the insulin tolerance test, and to threefold higher levels of triglycerides. Iron supplemented mice had lower visceral adipose tissue mass estimated by epididymal fat pad, associated with iron accumulation in adipocytes. Decreased insulin signaling, evaluated by the phospho-Akt/Akt ratio, was detected in the visceral adipose tissue of iron overloaded mice, and gene expression analysis of visceral adipose tissue showed that an iron-enriched diet up-regulated iron-responsive genes and adipokines, favoring insulin resistance, whereas lipoprotein lipase was down-regulated. This resulted in hyperresistinemia and increased visceral adipose tissue expression of suppressor of cytokine signaling-3 (Socs3), a target of resistin and hepcidin implicated in insulin resistance. Acute hepcidin administration down-regulated lipoprotein lipase and up-regulated Socs3 in visceral adipose tissue. In conclusion, we characterized a model of dysmetabolic iron overload syndrome in which an iron-enriched diet induces insulin resistance and hypertriglyceridemia and affects visceral adipose tissue metabolism by a mechanism involving hepcidin up-regulation.
authors.affiliation: Department of Pathophysiology and Transplantation, Centro Malattie Metaboliche del Fegato, Università degli Studi di Milano, and Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Ruscica
authors.forename: Raffaela
authors.initials: R
authors.lastname: Rametta
authors.forename: Stefania
authors.initials: S
authors.lastname: Recalcati
authors.forename: Liliana
authors.initials: L
authors.lastname: Steffani
authors.forename: Stefano
authors.initials: S
authors.lastname: Gatti
authors.forename: Domenico
authors.initials: D
authors.lastname: Girelli
authors.forename: Gaetano
authors.initials: G
authors.lastname: Cairo
authors.forename: Paolo
authors.initials: P
authors.lastname: Magni
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D064451:Hepcidins; D015228:Hypertriglyceridemia / Q000139:chemically induced; D007333:Insulin Resistance / Q000502:physiology*; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007501:Iron / Q000378:metabolism; D019190:Iron Overload / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D019266:Iron, Dietary / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D023181:Antimicrobial Cationic Peptides; D001786:Blood Glucose; C579599:Hamp protein, mouse; D064451:Hepcidins; D019266:Iron, Dietary; D012333:RNA, Messenger; D007501:Iron