A Long-Term High-Fat Diet Changes Iron Distribution in the Body, Increasing Iron Accumulation Specifically in the Mouse Spleen

Abstract

Summary Although iron is an essential trace metal, its presence in excess causes oxidative stress in the human body. Recent studies have indicated that iron storage is a risk factor for type 2 diabetes mellitus. Dietary iron restriction or iron chelation ameliorates symptoms of type 2 diabetes in mouse models. However, whether iron content in the body changes with the development of diabetes is unknown. Here, we investigated the dynamics of iron accumulation and changes in iron absorption-related genes in mice that developed obesity and diabetes by consuming a high-fat diet (HFD-fed mice). HFD-fed mice (18-20 wk) were compared with control mice for hematologic features, serum ferritin levels, and iron contents in the gastrocnemius muscle, heart, epididymal fat, testis, liver, duodenum, and spleen. In addition, the spleen was examined histologically. Iron absorption-related gene expression in the liver and duodenum was also examined. Hemoglobin and serum ferritin levels were increased in HFD-fed mice. The HFD-fed mice showed iron accumulation in the spleen, but not in the heart or liver. Increased percentages of the splenic red pulp and macrophages were observed in HFD-fed mice and iron accumulation in the spleen was found mainly in the splenic red pulp. The HFD-fed mice also showed decreased iron content in the duodenum. The mRNA expression of divalent metal transporter-1 (DMT-1), an iron absorption-related gene, was elevated in the duodenum of HFD-fed mice. These results indicate that iron accumulation (specifi cally accumulation in the spleen) is enhanced by the development of type 2 diabetes induced by HFD. Key Words iron/spleen/diet, high fat/diabetes mellitus, type 2/DMT1 protein (iron transporter)

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ A significant relationship between HFD intake and splenic disorganization in mice has been documented 18 . Yamano et al 19 noted an increased percentage of splenic red pulp and macrophages in mice fed a HFD, and elemental iron was deposited mainly in red pulp. During splenomegaly, many immune cells are released to participate in immune defense when the host is infected 11,20 .…”

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Neuroprotective Effect of HIF Prolyl Hydroxylase Inhibition in an In Vitro Hypoxia Model

“…The following genes specific for HIF-1 have been selected: , phosphofructokinase (PFKFB3) [29,30], pyruvate kinase (PKM) [31,32], and Lon protease (LONP1) [33], the enzyme that catalyzes degradation of the subunit 4 of cytochrome c oxidase to adapt the latter activity to hypoxia. Genes specific for HIF-2 include erythropoietin (EPO) [34,35], cyclin D1 (CCND1) [36], matrix metalloproteinase 2 (MMP2) [32,37], and divalent metal transporter (DMT1) [38]. Common targets for both HIFs include vascular endothelial growth factor (VEGFA) and RGS4 gene coding for a protein regulating signaling activity of G-proteins, which enhanced expression is specific for hypoxic neuroblastoma cells [39].…”