Adipocyte iron regulates adiponectin and insulin sensitivity
J. Scott Gabrielsen, … , William T. Cefalu, Donald A. McClain
J. Scott Gabrielsen, … , William T. Cefalu, Donald A. McClain
Published September 10, 2012
Citation Information: J Clin Invest. 2012;122(10):3529-3540. https://doi.org/10.1172/JCI44421.
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Research Article Metabolism

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

J. Scott Gabrielsen, Yan Gao, Judith A. Simcox, Jingyu Huang, David Thorup, Deborah Jones, Robert C. Cooksey, David Gabrielsen, Ted D. Adams, Steven C. Hunt, Paul N. Hopkins, William T. Cefalu, Donald A. McClain

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Figure 4

Functional expression of ferroportin in adipocytes.

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Functional expression of ferroportin in adipocytes. (A) Fpn1 mRNA levels...
(A) Fpn1 mRNA levels quantified by RT-PCR in 3T3-L1 adipocytes exposed to different concentrations of iron (FeSO4) in the culture medium. *P < 0.05 compared with 0.1 mM, ‡P < 0.01, P < 0.0001 for overall trend. (B) FPN1 protein levels in 3T3-L1 adipocytes, as detected by immunoblotting in adipocytes treated with no iron, 100 μM FeSO4, or 1 μg/ml hepcidin for 8 hours. (C) Fpn1 mRNA in adipose tissue and spleen from WT (Fpn1fl/fl) and Fpn1–/– (AP2 Cre ferroportin knockout) mice. ‡P < 0.001. (D) Tfrc mRNA quantified by RT-PCR and normalized to cyclophilin in collagenased adipocytes from epididymal fat pads of WT and Fpn1–/– mice (n = 10–14/group, ‡P < 0.001). (E) Adiponectin mRNA in the adipocytes used in E. ‡P < 0.01. (F) Serum adiponectin in WT and Fpn1–/– mice (n = 9–12/group, *P < 0.01). (G) High molecular weight (HMW) adiponectin determined as a percentage of total in the same group depicted in F. (H) Glucose tolerance testing of WT and Fpn1–/– mice (n = 5–6/group, *P < 0.05 for individual glucose values). (I) Body composition by magnetic resonance imaging in WT and Fpn1–/– mice on normal chow or high-iron diets (n = 11–20/group, *P < 0.05).