Iron Deficiency Anemia (IDA) Promotes Visceral Obesity Due to Defective Adipose Tissue Browning (OR09-07-19)

Abstract Objectives Iron deficiency anemia (IDA) is a common disease related to malnutrition. Epidemiological studies revealed a positive correlation between IDA and obesity, but the underlying mechanism is uncertain. Emerging evidence suggests that adipose browning significantly contributes to weight loss by dissipating extra energy into heat. Adipose tissue browning is concurrent with mitochondrial biogenesis, an iron-demanding process. We aimed to investigate whether iron deficiency downregulat adipose tissue browning. Methods To simulate the IDA, C57BL/6 mice were fed a high-fat diet in an iron-deficient (3 ppm) setting for 14 weeks compared with an isocaloric iron-sufficient (50 ppm) diet. Iron status was evaluated by measuring serum levels of ferritin, hemoglobin (Hb) and hematocrit (HCt). Iron content of tissue levels was measured by ICP-Mass spectrometer. For assessment of capability to keep the temperature homeostasis, core body temperature and heat release by the infrared camera were determined upon acute cold exposure (4°C). Adipose browning was induced by administrating β3-adrenoceptor agonist, CL316243 (CL) for 5 days. The significance of iron on adipocyte browning was validated in vitro by silencing of the transferrin receptor (TfR), or by iron chelator (DFO, deferoxamine) treatment during beige adipogenesis. Results The chronic iron-deficiency significantly reduced serum ferritin concentration (P < 0.01) with marginal impact on Hb or HCt. Despite no apparent difference in body weight, fat mass was higher in IDA mice (P < 0.001). Consistently, total iron content in the inguinal fat, where adipose browning occurs, was markedly lower in IDA mice. IDA mice were more susceptible to cold treatment, maintaining the body temperature lower than control and defective in heat release. Upon CL stimulation, IDA mice showed reduced expression of uncoupling protein 1 (UCP1) and Cytc, and beige-like morphology in the inguinal fat. Supporting these in vivo results, inhibition of iron import by depleting TfR or reducing liable iron dampened the beige adipogenesis by attenuating brown-specific markers and mitochondrial biogenesis. Conclusions IDA is an independent risk factor for visceral obesity by decreasing thermogenic energy expenditure. Funding Sources National Institutes of Health Grant 1R21HD094273.

Download Full-text

Diet-Induced Non-anemic Iron Deficiency Attenuates Adaptive Thermogenesis via Defective Iron Metabolism of Adipose Tissue in C57BL/6 Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzab059_031 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 1330-1330

Author(s):

Jin-Seon Yook ◽

Shalom Sara Thomas ◽

Soonkyu Chung

Keyword(s):

Adipose Tissue ◽

Iron Deficiency ◽

Heat Release ◽

Serum Ferritin ◽

Iron Metabolism ◽

Iron Content ◽

Critical Role ◽

Dietary Iron ◽

Adaptive Thermogenesis ◽

Tissue Browning

Abstract Objectives Iron deficiency is one of the most common nutrient deficiencies worldwide. Adaptive thermogenesis plays a critical role for maintaining energy homeostasis. Currently, the role of dietary iron deficiency on adaptive thermogenesis is unknown. We hypothesized that dietary iron deficiency attenuates adaptive thermogenesis via dysfunctional iron metabolism in adipose tissue. Methods C57BL/6 male mice were fed a diet containing either adequate-iron (Cont: 35ppm) or deficient-iron (ID: 3ppm) throughout for 14 weeks and the last 10 weeks were fed a high-fat diet to induce obesity. Systemic iron status was evaluated by measuring serum ferritin, hemoglobin (Hb), and hematocrit (HCt). The iron content of adipose tissue was determined by ICP-MS spectrometer. The protein and gene expressions related to iron-handling and thermogenesis were measured in adipose tissue by Western blot analysis and qPCR. To assess adaptive thermogenic function, mice were exposed to cold temperature acutely (3 hour) or administrated with β3-adrenoceptor agonist (CL) for 5 days. The core body temperature and thermogenesis were determined by a rectal thermometer and infrared camera, respectively. Results The ID mice displayed a non-anemic iron deficiency with reduced serum ferritin (p < 0.01), increased weight gain (p < 0.05) and decreased insulin sensitivity (p < 0.05) compared to Cont. The iron content was significantly reduced in the inguinal (iWAT, p < 0.05) of the ID mice, which was linked with reduced thermogenic heat release upon acute cold treatment. In addition, ID mice markedly reduced the adipose tissue browning and thermogenic heat release upon CL stimulation compared with Cont. In terms of iron metabolism, CL-induced coordinated iron uptake for mitochondrial biogenesis in the iWAT was impaired in the ID mice, which was comparable to inflammation-mediated defective adipose tissue browning and thermogenesis. Conclusions Iron deficiency induced visceral obesity and compromised thermogenic function due to defective iron metabolism in C57BL6 mice. Funding Sources National Institutes of Health Grant 1R21HD094273.

Download Full-text

Fighting Iron-Deficiency Anemia: Innovations in Food Fortificants and Biofortification Strategies

Foods ◽

10.3390/foods9121871 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1871

Author(s):

Ângela Liberal ◽

José Pinela ◽

Ana Maria Vívar-Quintana ◽

Isabel C. F. R. Ferreira ◽

Lillian Barros

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Iron Content ◽

Public Health Problem ◽

Food Product ◽

Deficiency Anemia ◽

Special Focus ◽

Food Fortification ◽

Iron Form ◽

Scientific Challenge

Iron deficiency remains one of the main nutritional disorders worldwide and low iron intake and/or bioavailability are currently the major causes of anemia. To fight this public health problem, the scientific challenge is to find an iron form with sufficient bioavailability to increase its levels in humans through food fortification. In turn, biofortification appears as a comparatively advantageous and bearable strategy for the delivery of vitamins and other micronutrients for people without access to a healthy and diverse diet. This approach relies on plant breeding, transgenic techniques, or agronomic practices to obtain a final food product with a higher iron content. It is also known that certain food constituents are able to favor or inhibit iron absorption. The management of these compounds can thus successfully improve the absorption of dietary iron and, ultimately, contribute to fight this disorder present all over the world. This review describes the main causes/manifestations of iron-deficiency anemia, forms of disease prevention and treatment, and the importance of a balanced and preventive diet. A special focus was given to innovative food fortification and biofortification procedures used to improve the iron content in staple food crops.

Download Full-text

An Experimental Model for Iron Deficiency Anemia in Sows and Offspring Induced by Blood Removal during Gestation

Animals ◽

10.3390/ani11102848 ◽

2021 ◽

Vol 11 (10) ◽

pp. 2848

Author(s):

Martin Peter Rydal ◽

Sheeva Bhattarai ◽

Jens Peter Nielsen

Keyword(s):

Iron Deficiency ◽

Experimental Model ◽

Iron Deficiency Anemia ◽

Iron Content ◽

Deficiency Anemia ◽

Control Group ◽

Liver Iron ◽

Liver Iron Content ◽

Tissue Iron ◽

Removal Group

Anemia is a common condition in sow herds. We aimed to study the effects of severe iron deficiency during gestation on sow and piglet health outcomes with an experimental model for blood-removal-induced iron deficiency anemia. In total, 18 multiparous sows (8 in trial I and 10 in trial II) were allocated to either a blood removal group or a control group. Hematologic parameters were monitored at regular intervals and the tissue iron concentrations were measured for the sows and newborn piglets after farrowing. In trial I, the mean liver iron content was reduced to 46.7 µg/g in the blood removal sows compared to 252.6 µg/g in the controls (p < 0.001). In trial II, sows in the blood removal group had lower iron content in the liver (147.8 µg/g), kidney (46.3 µg/g) and spleen (326.5 µg/g) compared to the control sows (323.2 µg/g, 81.3 µg/g and 728.9 µg/g, respectively; p = 0.009, 0.016, 0.01, respectively). In trial I, piglets from sows in the blood removal group had significantly decreased hematocrit (Hct), red blood cells (RBC) and a tendency for reduced hemoglobin (Hb) compared to the control piglets. We established a blood removal model that resulted in mild- to severe degrees of sow anemia and reduced tissue iron stores at farrowing.

Download Full-text

SUBCUTANEOUS ADIPOSE TISSUE IN FEMALE PATIENTS WITH IRON DEFICIENCY ANEMIA AND OBESE WOMEN DOES NOT DIFFER IN THE EXPRESSION OF IKBΑ*

The Medical and Ecological Problems ◽

10.31718/mep.2018.22.3-4.04 ◽

2018 ◽

Vol 22 (3-4) ◽

pp. 14-17

Author(s):

V.M. Nedoborenko ◽

O.А. Shlykova ◽

O.V. Izmailova ◽

K.E. Ishcheikin ◽

I.P. Kaidashev

Keyword(s):

Adipose Tissue ◽

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Subcutaneous Adipose Tissue ◽

Deficiency Anemia ◽

Control Group ◽

Obese Women ◽

Female Patients ◽

Significant Difference ◽

Subcutaneous Adipose

Prerequisites and objective: Abdominal obesity is a common metabolic disease characterized by excessive accumulation of white adipose tissue, with excessive production of inflammatory mediators that activate transcriptional nuclear factors, in particular the nuclear factor kB. Hepcidin is the main hormone in the systemic regulation of iron. Its expression increases with elevated level of pro-inflammatory cytokines, as a result of which the concentration of iron in the blood plasma decreases, which reliably results in the activation of NF-kB. Therefore, the aim of the research was to determine the level of expression of ІКβα in subcutaneous adipose tissue in iron deficiency anemia concurrent with obesity. Methods: The study included 40 female women. Hemogram parameters, parameters of iron metabolism (serum iron, ferritin, hepcidin, total iron binding ability of serum, saturation of transferrin by iron) in serum and level of expression of the IkBα gene in subcutaneous adipose tissue were evaluated. Research results. The examined women had an average age of 40.3 ± 7.59 years. In the distribution of patients due to the cause and degree of severity of IDA, there was no reliable difference between the groups. The control group consisted of 10 obese women without IDA. Expression of IkBα by subcutaneous adipose tissue in female patients with IDA with and without obesity compared with the control group did not display a significant difference between the groups (p <0.05). In the course of correlation analysis, the expression of IkBα by subcutaneous adipose tissue to BMI, iron and hemogram rates did not have a correlated significance. Conclusion. Subcutaneous adipose tissue in women with iron deficiency anemia with and without obesity compared with obese women has no difference in expression of IkBα.

Download Full-text

Low Iron Promotes Megakaryocytic Commitment of Megakaryocytic-Erythroid Progenitors in Human and Mice

Blood ◽

10.1182/blood-2018-99-115124 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2-2 ◽

Cited By ~ 1

Author(s):

Juliana Xavier-Ferrucio ◽

Xiuqi Li ◽

Vanessa Scanlon ◽

Ping-Xia Zhang ◽

Nadia Ayala-Lopez ◽

...

Keyword(s):

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Transferrin Receptor ◽

Iron Content ◽

Differentially Expressed ◽

Lineage Commitment ◽

Deficiency Anemia ◽

Erythroid Progenitors ◽

Iron Deficient ◽

Cell Commitment

Abstract The mechanism underlying thrombocythemia in patients with iron deficiency anemia remains unknown. Iron metabolism is highly conserved in humans and mice. We used Tmprss6-/- knockout (KO) mice as a genetic model of chronic iron deficiency anemia to study the effects of iron deficiency on lineage commitment. Tmprss6 is expressed in the liver, but not in hematopoietic cells, and is required for iron uptake from the diet. We observed that Tmprss6-/- mice have elevated platelet counts compared to littermate controls (average x1000/uL ± SD in wild type (WT): 477.9 ± 53.68, Tmprss6-/-: 915.9 ± 57; p<0.001; males and females 6-10 weeks old). Based on immunophenotype, the percentage of hematopoietic stem cells (HSC), megakaryocytic (Mk)-biased HSC (CD41+), megakaryocytic-erythroid progenitor (MEP), (Mk)- or erythroid (E)-committed progenitors in bone marrow (BM) is comparable between the two genotypes. To address whether thrombocythemia in iron deficiency anemia is related to altered commitment of MEP, we assayed the effects of low iron conditions on the function, transcriptome and signaling in MEP. CFU assays of single MEPs showed a striking increase in CFU-Mk (unilineage committed Mk progenitors) within the MEP gate in Tmprss6-/- at the expense of the bipotent CFU-Mk/E compared to WT (p<0.001). Thus, MEP in KO mice are significantly biased toward the Mk lineage, suggesting that low iron content may reprogram cell commitment. Consistent with this reprogramming effect, MEPs from KO mice have a 50% decrease in the labile iron pool (p=0.03, measured by Calcein-AM), and a 30% decrease (p=0.04) in proliferation relative to WT as measured by CFSE. To test the effect of altered iron content in vivo, we transplanted WT or KO BM into sublethally irradiated WT or Tmprss6-/- recipients. Tmprss6-/- recipients (of WT or KO BM) exhibited microcytic anemia and hypoferremia when compared to WT recipients (of WT and KO BM). Interestingly, the Mk-bias observed in non-transplanted Tmprss6-/- MEPs was recapitulated in Tmprss6-/-recipients (regardless of transplanted BM genotype) 6 months post-transplant (p < 0.009, n= 3 per group). We show using index single cell sorting followed by CFU assays that in WT mice, surface expression of transferrin receptor 1 (CD71) is a predictor of cell fate; cells from the MEP gate that grow as BFU-E have a higher CD71 mean fluorescence intensity (MFI) (179.9 ± 38.9) than cells that grow bipotent CFU-Mk/E colonies (65.9 ± 13.9) or Mk-only (CFU-Mk) colonies (24.9 ± 7.06; p<0.006). However, this correlation is lost in KO recipients, where the CD71 expression is elevated in all cells compared to WT (MFI: 279.9 ± 49.81, p<0.0001). RNAseq of WT and KO MEPs showed that 137 genes are differentially expressed (fold change: 1.5; p<0.05) between the two genotypes; of these, 84 are up regulated (e.g. Tfrc and Mybl2) and 53 are downregulated in the KO compared to WT. Surprisingly, mRNA encoding transcription factors that are known to regulate E vs. Mk maturation such as Myb, Tal, Fli1, and Eklf were unchanged. Pathway analysis of the differentially expressed genes highlighted metabolic pathways (asparagine and cholesterol biosynthesis and b-alanine degradation, p<0.008). We then asked if the iron regulation of the MEP commitment observed in iron deficient mice was also true for human MEP. In order to disrupt the iron sensing pathways in primary human MEP, we performed shRNA-based knockdown of Transferrin Receptor 2 (TFR2) using two different sequence targets and found a similar decrease in proliferation (p=0.03) and skewing toward Mk commitment (p<0.04) as was observed in Tmprss6-/- MEPs. Signal transduction analyses revealed that both human and murine MEPs in iron deficient conditions have lower levels of phospho-ERK (Thr202/Tyr204) compared to WT or scrambled controls. Regulation of erythroid differentiation by iron is thought to prevent inappropriate iron utilization when body stores are limited. To function in a protective manner, this checkpoint must act at stages prior to erythropoietin-mediated expansion of erythroid progenitors. Here we propose a model where iron acts on the bipotent progenitor, one possible source of Mk and E cells, to bias lineage commitment. These data support that low iron in the environment affects MEP metabolism, leading to lower ERK phosphorylation, slower proliferation and increased Mk commitment. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Effect of cooking food in iron pot and with iron ingot on increase in hemoglobin level and iron content of the food

Nepal Journal of Epidemiology ◽

10.3126/nje.v11i2.36682 ◽

2021 ◽

Vol 11 (2) ◽

pp. 994-1005

Author(s):

Shally Sharma ◽

Ritika Khandelwal ◽

Kapil Yadav ◽

Gomathi Ramaswamy ◽

Kashish Vohra

Keyword(s):

Systematic Review ◽

Iron Deficiency ◽

Iron Deficiency Anemia ◽

Iron Content ◽

Hemoglobin Level ◽

Iron Bioavailability ◽

World Health ◽

Deficiency Anemia ◽

Cochrane Library ◽

Blood Hemoglobin

In developing countries there is a need for simple and cost-effective strategies to reduce the prevalence of iron deficiency anemia. The objective of the current systematic review is to summarize how cooking food in iron pots or iron ingots can increase the blood hemoglobin level and iron content of the food. Literature search was conducted using databases namely PubMed, Google Scholar, Medline-Ovid, IndMed, Cochrane library, World Health Organization bulletin and by cross-referencing articles. Thirteen researches were found to be suitable for inclusion in this systematic review. Four studies reported significant increase in blood hemoglobin levels while others reported only a minor increase. Significant improvement in amount of iron in food and iron bioavailability was also observed when food was cooked using iron pot or ingots. This can be used as a strategy for reduction of iron deficiency anemia. However, more research is required to understand the efficacy of this approach.

Download Full-text