Effects of iron supplementation in mice with hypoferremia induced by obesity

Abstract

Iron is an important micronutrient, but it can also act as a dangerous element by interfering with glucose homeostasis and inflammation, two features that are already disturbed in obese subjects. In this work, we study the effects of systemic iron supplementation on metabolic and inflammatory responses in mice with hypoferremia induced by obesity to better characterize whether iron worsens the parameters that are already altered after 24 weeks of a high-fat diet (HFD). Mice were maintained on a control diet or a HFD for 24 weeks and received iron-III polymaltose (50 mg/kg/every 2 days) during the last two weeks. Glucose homeostasis (basal glucose and insulin test tolerance) and systemic and visceral adipose tissue (VAT) inflammation were assessed. Iron levels were measured in serum. The Prussian blue reaction was used in isolated macrophages to detect iron deposition. Iron supplementation resulted in an increased number of VAT macrophages that were positive for Prussian blue staining as well as increased serum iron levels. Systemic hepcidin, leptin, resistin, and monocyte chemoattractant protein-1 (MCP-1) levels were not altered by iron supplementation. Local adipose tissue inflammation was also not made worse by iron supplementation because the levels of hepcidin, MCP-1, leptin, and interleukin (IL)-6 were not altered. In contrast, iron supplementation resulted in an increased production of IL-10 by adipose tissue and VAT macrophages. Leukocytosis and VAT plasminogen activator inhibitor-1 (PAI-1) level were reduced, but insulin resistance was not altered after iron supplementation. In conclusion, systemic iron supplementation in mice with hypoferremia induced by obesity did not worsen inflammatory marker or adipose tissue inflammation or the metabolic status established by obesity. Iron deposition was observed in adipose tissue, mainly in macrophages, suggesting that these cells have mechanisms that promote iron incorporation without increasing the production of inflammatory mediators.

Ferric Citrate Supplementation Reduces Red‐Blood‐Cell Aggregation and Improves CD163+ Macrophage‐Mediated Hemoglobin Metabolism in a Rat Model of High‐Fat‐Diet‐Induced Obesity

“…Surprisingly, a 12‐week pharmacological dose of ferric citrate supplementation did not alter the liver pathology despite the increased hepatic iron content in obese rats. The present finding is consistent with that of Gotardo et al, who reported that short‐term iron supplementation increased iron retention in tissues but did not reduce inflammatory biomarkers or deteriorate the metabolic status in animals with HFD‐induced obesity. It is reasonable to speculate that the iron‐mediated upregulation of Nrf‐2/HO‐1 expression may prevent liver inflammation.…”

“…Increased hepcidin reduces the iron absorption rate through the posttranslational downregulation of ferroportin, the only known cellular iron exporter . The effects of iron or obesity on RBC rheology or membrane structure have been examined in animal models usually by employing one of two broad approaches: the diet‐induced iron deficiency anemia (IDA) model in lean animals and the HFD‐induced obesity on RBC hemorheological properties or iron distribution . Overall, these data suggest that a low‐iron diet or an HFD cause RBC dysfunction by increasing RBC oxidative stress and decreasing RBC survival.…”

“…We hypothesize that obesity alters RBC–Hb degradation pathways and iron supplementation influences this relationship. The hypothesis was motivated by observations of the association of obesity with impaired RBC hemorheological properties, macrophages’ ability to handle iron, and membrane structure of erythrocyte being substantially ameliorated by iron supplementation . Although the spleen is the major organ where the degradation of senescent RBCs occurs, the liver is the major iron storage organ in the body.…”

Regulation of tissue iron homeostasis: the macrophage “ferrostat”

“…Flow cytometric analysis of F4/80 and CD11b confirmed that the vast majority of ferromagnetic-positive cells were indeed Mɸs (18). ATMɸs seemingly compensate for iron overload during a high-iron diet or intraperitoneal iron administration (17,127), increasing their iron content while adipocyte iron concentrations remain stable in the face of iron overload (17). Importantly, MFe hi ATMɸs accumulate excess iron in AT while maintaining an M2-like polarization that is disturbed with diet-induced obesity (17).…”

A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations

“…Nuclei were visualized using Haematoxilin. The Fe 3+ levels were detected using Prussian blue staining [31]. …”