Iron Metabolism in Obesity and Metabolic Syndrome

Abstract

Obesity is an excessive adipose tissue accumulation that may have detrimental effects on health. Particularly, childhood obesity has become one of the main public health problems in the 21st century, since its prevalence has widely increased in recent years. Childhood obesity is intimately related to the development of several comorbidities such as nonalcoholic fatty liver disease, dyslipidemia, type 2 diabetes mellitus, non-congenital cardiovascular disease, chronic inflammation and anemia, among others. Within this tangled interplay between these comorbidities and associated pathological conditions, obesity has been closely linked to important perturbations in iron metabolism. Iron is the second most abundant metal on Earth, but its bioavailability is hampered by its ability to form highly insoluble oxides, with iron deficiency being the most common nutritional disorder. Although every living organism requires iron, it may also cause toxic oxygen damage by generating oxygen free radicals through the Fenton reaction. Thus, iron homeostasis and metabolism must be tightly regulated in humans at every level (i.e., absorption, storage, transport, recycling). Dysregulation of any step involved in iron metabolism may lead to iron deficiencies and, eventually, to the anemic state related to obesity. In this review article, we summarize the existent evidence on the role of the most recently described components of iron metabolism and their alterations in obesity.

Keywords: anemia; childhood obesity; iron; metabolic syndrome; metabolism; obesity.

Figure 1

Volumetric dispersion of erythrocytes in pubescent controls versus obese children. ** p < 0.01.

Figure 2

Physiology of Iron Metabolism. Iron ingested from the diet (A), is reduced from Fe³⁺ to Fe²⁺ in the stomach (B). In the duodenum, enterocytes transport Fe²⁺, heme groups and ferritin across the microvillus membrane (C). Fe²⁺ is transported by ferroportin across the basolateral membrane into the portal system and must be oxidized to Fe³⁺ for binding to transferrin and other molecules with high affinity for Fe³⁺ to be transported to the liver. Transferrin-bound iron is necessary for cells expressing transferrin receptors for uptake of iron, mainly for production of heme proteins (D). Transferrin-bound iron is taken up by myocytes, where Fe³⁺ is oxidized again to Fe²⁺ in order to be incorporated into myoglobin (E), hepatocytes being the main ferritin store (F), and by proerythroblasts for synthesis of hemoglobin (G). When mature erythrocytes die, macrophages liberate Fe²⁺ from hemoglobin, which is oxidized again to recirculate bound to transferrin (H). Finally, 1–2 mg iron is lost per day from the organism by desquamation, bleeding and other mechanisms (I). Vit. C: vitamin C; DMT1: divalent metal transporter 1; ZIP 14/8: Zrt–Irt-like protein 14 and 8; DcytB: duodenal cytochrome B; STEAP 2: six-transmembrane epithelial antigen of the prostate 2; HCP1: heme carrier protein 1; AP2: adaptor-related 2 protein; PCBP: poly (rC) binding protein; LIP: labile iron pool; HO1: heme oxygenase 1; FPN1: ferroportin 1; HEPH: hephaestin; CP: ceruloplasmin; FLVCR: feline leukemia virus subgroup C; BCRP: breast cancer-resistant protein; Tf: transferrin; TfR: transferrin receptor; CAT: catalase; Scara 5: scavenger receptor class A, member 5; TIM2: T-cell immunoglobulin and mucin domain-containing protein 2; STEAP 3: six-transmembrane epithelial antigen of the prostate 3; NCOA4: nuclear receptor coactivator 4; BFU-e: burst forming unit-erythroid; CFU-e: colony forming unit-erythroid; EPO: erythropoietin; Hb: hemoglobin; Hp: haptoglobin; CD163: cluster of differentiation 163; CD91/LRP: cluster of differentiation/ low-density lipoprotein receptor related protein; HRG: heme responsive gene.

Figure 3

Iron metabolism dysregulation in obesity. Obesity influences iron metabolism at many steps of the cycle. No alterations have been proven in iron ingested from the diet (A), nor in its reduction from Fe³⁺ to Fe²⁺ in the stomach (B). In the duodenum enterocytes in obese patients, DMT1 density increases at the apical membrane, whereas ZIP14 and 8 co transporters decrease. HO1 levels increase intracellularly and at the basal membrane CP and FLVCR increase, whereas FPN1, BCRP and HEPH decrease (C). Ferritin circulating levels increase (D). Myocyte and hepatocyte transferrin receptor density increases, together with an increase in DMT1 and a decrease in ZIP14 (E,F). Additionally, in hepatocytes, NCOA4 decreases, preventing ferritin degradation, and HEPH and FPN1 decrease, reducing the Fe²⁺ sent to circulation (F). Decreased levels of transferrin receptors are found in proerythroblasts (G). Changes in macrophages recycling Fe²⁺ from hemoglobin include an increase in hemopexin, Hp and CD163, indicating an increase in the capacity to uptake heme groups and hemoglobin, and an increase in CP with a decrease in FPN1, suggesting a decrease in the Fe²⁺ liberated to circulation, but an increased oxidizing capacity to Fe³⁺ (H). Finally, no changes in daily iron loss has been described (I). Vit. C: vitamin C; DMT1: divalent metal transporter 1; ZIP 14/8: Zrt–Irt-like protein 14 and 8; DcytB: duodenal cytochrome B; STEAP 2: six-transmembrane epithelial antigen of the prostate 2; HCP1: heme carrier protein 1; AP2: adaptor-related 2 protein; PCBP: poly (rC) binding protein; LIP: labile iron pool; HO1: heme oxygenase 1; FPN1: ferroportin 1; HEPH: hephaestin; CP: ceruloplasmin; FLVCR: feline leukemia virus subgroup C; BCRP: breast cancer-resistant protein; Tf: transferrin; TfR: transferrin receptor; CAT: catalase; Scara 5: scavenger receptor class A, member 5; TIM2: T-cell immunoglobulin and mucin domain-containing protein 2; STEAP 3: six-transmembrane epithelial antigen of the prostate 3; NCOA4: nuclear receptor coactivator 4; BFU-e: burst forming unit-erythroid; CFU-e: colony forming unit-erythroid; EPO: erythropoietin; Hb: hemoglobin; Hp: haptoglobin; CD163: cluster of differentiation 163; CD91/LRP: cluster of differentiation/ low-density lipoprotein receptor related protein; HRG: heme responsive gene. Upregulated transporters and enzymes are shown with a green arrow pointing upwards, whereas downregulated transporters and enzymes are shown with a red arrow pointing down.