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Risk of Iron Overload in Obesity and Implications in Metabolic Health.

ABSTRACT: Excessive adiposity is associated with several metabolic perturbations including disturbances in iron homeostasis. Increased systemic inflammation in obesity stimulates expression of the iron regulatory hormone hepcidin, which can result in a maldistribution of bodily iron, which may be implicated in metabolic dysfunction. This study aimed to investigate the effect of adiposity and any associated inflammation on iron homeostasis and the potential implications of dysregulated iron metabolism on metabolic health. Analyses are based on a subsample from the cross-sectional Irish National Adult Nutrition Survey (2008-2010) (n = 1120). Ferritin status and risk of iron overload were determined based on established WHO ferritin ranges. Participants were classed as having a healthy % body fat or as having overfat or obesity based on age- and gender-specific % body fat ranges as determined by bioelectrical impedance. Biomarkers of iron status were examined in association with measures of body composition, serum adipocytokines and markers of metabolic health. Excessive % body fat was significantly associated with increased serum hepcidin and ferritin and an increased prevalence of severe risk of iron overload amongst males independent of dietary iron intake. Elevated serum ferritin displayed significant positive associations with serum triglycerides and markers of glucose metabolism, with an increased but non-significant presentation of metabolic risk factors amongst participants with overfat and obesity at severe risk of iron overload. Increased adiposity is associated with dysregulations in iron homeostasis, presenting as increased serum hepcidin, elevated serum ferritin and an increased risk of iron overload, with potential implications in impairments in metabolic health.

SUBMITTER: Moore Heslin A

PROVIDER: S-EPMC8147503 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hereditary iron overload includes several disorders characterized by iron accumulation in tissues, organs, or even single cells or subcellular compartments. They are determined by mutations in genes directly involved in hepcidin regulation, cellular iron uptake, management and export, iron transport and storage. Systemic forms are characterized by increased serum ferritin with or without high transferrin saturation, and with or without functional iron deficient anemia. Hemochromatosis includes five different genetic forms all characterized by high transferrin saturation and serum ferritin, but with different penetrance and expression. Mutations in HFE, HFE2, HAMP and TFR2 lead to inadequate or severely reduced hepcidin synthesis that, in turn, induces increased intestinal iron absorption and macrophage iron release leading to tissue iron overload. The severity of hepcidin down-regulation defines the severity of iron overload and clinical complications. Hemochromatosis type 4 is caused by dominant gain-of-function mutations of ferroportin preventing hepcidin-ferroportin binding and leading to hepcidin resistance. Ferroportin disease is due to loss-of-function mutation of SLC40A1 that impairs the iron export efficiency of ferroportin, causes iron retention in reticuloendothelial cell and hyperferritinemia with normal transferrin saturation. Aceruloplasminemia is caused by defective iron release from storage and lead to mild microcytic anemia, low serum iron, and iron retention in several organs including the brain, causing severe neurological manifestations. Atransferrinemia and DMT1 deficiency are characterized by iron deficient erythropoiesis, severe microcytic anemia with high transferrin saturation and parenchymal iron overload due to secondary hepcidin suppression. Diagnosis of the different forms of hereditary iron overload disorders involves a sequential strategy that combines clinical, imaging, biochemical, and genetic data. Management of iron overload relies on two main therapies: blood removal and iron chelators. Specific therapeutic options are indicated in patients with atransferrinemia, DMT1 deficiency and aceruloplasminemia.

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Risk of Iron Overload in Obesity and Implications in Metabolic Health.

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