Rethinking Iron Regulation and Assessment in Iron Deficiency, Anemia of Chronic Disease, and Obesity: Introducing Hepcidin

Abstract

Adequate iron availability is essential to human development and overall health. Iron is a key component of oxygen-carrying proteins, has a pivotal role in cellular metabolism, and is essential to cell growth and differentiation. Inadequate dietary iron intake, chronic and acute inflammatory conditions, and obesity are each associated with alterations in iron homeostasis. Tight regulation of iron is necessary because iron is highly toxic and human beings can only excrete small amounts through sweat, skin and enterocyte sloughing, and fecal and menstrual blood loss. Hepcidin, a small peptide hormone produced mainly by the liver, acts as the key regulator of systemic iron homeostasis. Hepcidin controls movement of iron into plasma by regulating the activity of the sole known iron exporter ferroportin-1. Downregulation of the ferroportin-1 exporter results in sequestration of iron within intestinal enterocytes, hepatocytes, and iron-storing macrophages reducing iron bioavailability. Hepcidin expression is increased by higher body iron levels and inflammation and decreased by anemia and hypoxia. Importantly, existing data illustrate that hepcidin may play a significant role in the development of several iron-related disorders, including the anemia of chronic disease and the iron dysregulation observed in obesity. Therefore, the purpose of this article is to discuss iron regulation, with specific emphasis on systemic regulation by hepcidin, and examine the role of hepcidin within several disease states, including iron deficiency, anemia of chronic disease, and obesity. The relationship between obesity and iron depletion and the clinical assessment of iron status will also be reviewed.

Iron Biology, Immunology, Aging, and Obesity: Four Fields Connected by the Small Peptide Hormone Hepcidin

“…It has been suggested that no cross-talk occurs between the signals that regulate hepcidin (4,20). Iron status, inflammation, and erythropoiesis seem to influence hepcidin expression independently from each other, with the strongest signal outweighing the others and determining hepcidin FIGURE 1 Post-translational regulation of iron homeostasis.…”

“…When iron sequestration occurs in cells without real iron deficiency, as may be the case with obese individuals, sTfR levels are normal. Tussing-Humphreys et al (20) suggested that in obesity chronic inflammation leads to real iron deficiency as a result of long-term decreased iron absorption and unregulated iron loss. The qualifiers for iron deficiency in obese individuals may therefore be similar to those seen in anemia of chronic disease coexisting with real iron deficiency.…”

Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response

“…Their mechanism involves perturbation of iron metabolism causing erythroid iron restriction, but they also may directly inhibit erythropoiesis. The molecular basis for perturbed iron metabolism in ACDI consists of increased liver production of hepcidin, resulting in downregulation of the iron exporter ferroportin expressed on histiocytes that recycle iron from senescent red cells and on enterocytes that absorb dietary iron (8,9). The discovery of this pathway has provided a breakthrough, allowing development of new diagnostic and therapeutic approaches to ACDI (10).…”

Identifying Contextual and Emotional Factors to Explore Weight Disparities between Obese Black and White Women

“…6 Weight loss interventions built on a foundation of deliberate behavior change have generally achieved 50% less short-term (months) and long-term (years) weight loss in black women compared to non-Hispanic white women. [7][8][9][10] With evidence that every 2 lbs of weight loss is associated with a 10% reduction in the 3-year risk of hypertension 11 and a 16% reduction in the 3-year risk of type 2 diabetes, 12 50% less weight loss translates into substantial lost opportunity for reductions in obesity-related morbidity.…”