Adipocyte iron regulates adiponectin and insulin sensitivity
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
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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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 2

Serum adiponectin and adipocyte mRNA levels decrease with dietary iron overload and with iron treatment in 3T3-L1 cells.

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Serum adiponectin and adipocyte mRNA levels decrease with dietary iron o...
(A) Tfrc mRNA quantified by RT-PCR and normalized to cyclophilin in collagenased adipocytes from epididymal fat pads of mice fed normal chow (NC) or a high-iron diet (HI) for 8 weeks. *P < 0.05. (B) Serum adiponectin levels were measured in 7-month-old 129/SvEvTac background mice following 2 months of being fed low-iron (7 mg/kg carbonyl iron), normal chow (330 mg/kg), or high-iron (20 g/kg) diets. *P = 0.004, low iron vs. normal chow; ‡P = 0.0002, high iron vs. normal chow. (C) Adiponectin mRNA levels in isolated epididymal adipocytes from mice fed high-iron diet or normal chow. P = 0.07. (D) Body weights were determined in C57BL6/J mice after 8 weeks on normal chow or high-iron diets, and body composition was determined by magnetic resonance imaging (n = 6/group or 8/group, *P < 0.05, ‡P < 0.01). (E) Body weights were determined in mice with knockout of the adiponectin gene compared with those of controls after 8 weeks on normal chow or high-iron diets (n = 5–12/group, ‡P < 0.001). (F) Euglycemic hyperinsulinemic clamps were performed on WT mice on normal or high-iron diets. Glucose infusion rates (GIRs) trended lower when normalized to total body weight (P = 0.22) but differed significantly when normalized to lean body mass (‡P < 0.0005).