title: Adipocyte hypoxia increases hepatocyte hepcidin expression.
abstract: Hepcidin plays a key role in regulating iron metabolism by blocking iron efflux from macrophages and enterocytes. Hepcidin is synthesized primarily in the liver, and its expression is increased by iron overload and inflammation. Obesity is associated with chronic inflammation as well as poor iron status. Central obesity causes adipocyte hypoxia resulting in chronic inflammation. Therefore, the objective of the present study was to determine if adipocyte hypoxia and associated inflammation signal hepatocyte hepcidin expression. The effect of adipocyte hypoxia on hepcidin expression was modeled using a 3T3-L1 adipocyte/Huh7 hepatocyte co-culture model. Adipocytes were cultured at either standard conditions (19% O2) or hypoxic conditions (1% O2). Compared to standard conditions, hypoxic 3T3-L1 cells had significantly higher IL-6 and leptin expression. Treatment of Huh7 cells with media from hypoxic or LPS-treated 3T3-L1 adipocytes significantly increased hepcidin promoter activity and mRNA compared to cells treated with normoxic 3T3-L1 media or control media. When the hepcidin STAT3 binding site was mutated, promoter activation by hypoxic media was abrogated. These data suggest that adipocyte hypoxia (a feature of central obesity) may increase hepcidin expression and plays a role in the association between obesity and poor iron status.
authors.affiliation: Department of Nutrition, Dietetics, & Food Sciences, Utah State University, 8700 Old Main Hill, 750 North 1200 East, Logan, UT 89322-8700, USA. korry.hintze@usu.edu
authors.forename: Korry Joseph
authors.initials: KJ
authors.lastname: Hintze
authors.forename: Dallin
authors.initials: D
authors.lastname: Snow
authors.forename: Darren
authors.initials: D
authors.lastname: Nabor
authors.forename: Hunter
authors.initials: H
authors.lastname: Timbimboo
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D064451:Hepcidins; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D023181:Antimicrobial Cationic Peptides; D017077:Culture Media, Conditioned; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D008070:Lipopolysaccharides