Iron metabolism in obesity: How interaction between homoeostatic mechanisms can interfere with their original purpose. Part I: Underlying homoeostatic mechanisms of energy storage and iron metabolisms and their interaction

doi:10.1016/j.jtemb.2014.10.011

Journal of Trace Elements in Medicine and Biology

Volume 30, April 2015, Pages 195-201

https://doi.org/10.1016/j.jtemb.2014.10.011 Get rights and content

Abstract

Adipose tissue plasticity mediated by inflammation is an important evolutionary achievement to survive seasonal climate changes. It permits to store excessive calories and to release them if required, using inflammatory cells to remove the debris. This process is regulated by a complex interaction of cytokines (TNF-α, IL-6), adipokines (adiponectin, apelin, liptin), adhesion molecules (ICAM-1, VCAM-1, E-selectin) and transcription factors (NF-κB, HIF-1α). Iron mediates electron transfer as an essential component of e.g. myeloperoxidase, hemoglobin, cytochrome C and ribonucleotide reductase. Conversely, unbound iron can catalyze oxidation of lipids, proteins, and DNA. To balance the essential with the potentially toxic function requires an efficient iron homoeostasis. This is mediated by hepcidin's interaction with the iron-exporter ferroportin, to adapt intestinal iron absorption and body iron-sequestration to changes in demand. In addition, the interaction of iron-responsive elements (IRE) and iron-responsive proteins (IRP), the IRE/IRP-mechanism, regulates cellular iron homoeostasis. Obesity-induced inflammation interacts with both these mechanisms and disturbs iron availability by impairing its absorption, and by sequestering it in the reticuloendothelial system. Both mechanisms lead to anemia and reduce physical fitness which, in a vicious cycle, can support the development of pathological obesity. Thus, interaction between these two sets of beneficial regulatory mechanisms can become detrimental in situations of ample calorie supply.

Section snippets

Obesity and inflammation

Worldwide prevalence of overweight and obesity, as defined e.g. by a Body-Mass-Index (BMI) in excess of 25 kg/m² and 30 kg/m², respectively, has gained pandemic dimensions. Literature suggests that the increase in prevalence relates to a sedentary life-style and improved food security in an increasing number of countries and for increasing fractions of the population. On the one hand, these changes reflect marvelous successes in the attempt to avoid undernutrition and famine. On the other hand,

Essential functions of iron

Iron has the rare ability to oscillate between the divalent and trivalent state. On the one hand, after integration in the prosthetic groups of enzymes and regulatory proteins, this feature permits iron to transfer electrons and makes iron essential for a considerable number of biological key-functions. Among these are oxygen transport by hemoglobin, cellular ATP-synthesis by cytochrome C and aconitase, and synthesis of DNA by ribonucleotide-reductase. Leukotriene synthesis is catalyzed by

Conflict of interest

The authors declare that they do not have any conflict of interest.

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Iron Status and Associated Factors among Canadian Women: Results from the Canadian Health Measures Survey
2023, Journal of Nutrition
Iron deficiency and overload may negatively impact women’s health. There has been limited assessment of iron status and its associated factors among Canadian women.
This study investigated associations of various sociodemographic, lifestyle, medication, and dietary factors with body iron stores among pre- and postmenopausal women in Canada.
Analyses were conducted using cross-sectional, nationally representative survey and biomarker data from women aged 20–79 y (n = 6362) in the Canadian Health Measures Survey (2009–2017). Body iron stores were assessed by measuring serum concentrations of ferritin (SF). Information on potential correlates was collected during an in-home interview. Multivariable linear regression analyses were performed to evaluate associations with SF concentration, and logistic regression was used to estimate associations with iron deficiency (SF <15 μg/L) or elevated iron stores (SF >150 μg/L).
Geometric mean SF concentrations were significantly higher in postmenopausal than in premenopausal women (73.2 versus 33.8 μg/L; P < 0.001). The prevalence of iron deficiency among pre- and postmenopausal women was 16.0% and 4.0%, respectively, whereas that of elevated iron stores was 2.7% and 21.0%, respectively. After simultaneous adjustment for multiple factors, including high-sensitivity CRP (inflammation marker), we found that age, East/Southeast Asian (versus White) race/ethnicity, alcohol, and red meat consumption were positively associated with SF concentration among pre- and postmenopausal women. In addition, aspirin use and dairy consumption were inversely associated with SF concentration among postmenopausal women only. Similar patterns were observed for associations with elevated iron stores among postmenopausal women, whereas higher grain consumption was associated with an increased prevalence of iron deficiency among premenopausal women.
Sociodemographic, lifestyle, medication, and dietary factors are correlated with iron status determined by SF concentration among Canadian women. The findings may have implications for intervention strategies aimed at optimizing body iron stores in pre- and postmenopausal women.
Content of essential and toxic trace elements in organs of obese Wistar and Zucker lepr<sup>fa</sup> rats receiving quercetin
2021, Journal of Trace Elements in Medicine and Biology
Citation Excerpt :
The observed correlation dependences between the bioaccumulations of a large number of essential and toxic elements in rat organs during obesity are consistent with known data from the literature [11]. This indicates the complex nature of the processes that underlie the homeostasis of mineral substances, which occur at the level of competition of mineral ions for transport systems and binding sites, and apparently also at the level of gene expression [35–37]. The negative correlation of the liver accumulation of Fe, Se, V, and Mg with indicators that characterize the level of anabolic processes (lipids, plasma proteins) and positive correlation with an indicator of increased catabolism (De Ritis Ratio) are also notable.
The levels of a number of essential and toxic trace elements in organs and tissues are affected by the disruptions in body homeostasis caused by obesity. Some of these elements may also be influenced by the consumption of biologically active substances of polyphenolic origin, which possess potent abilities to complex with transition metal ions.
The aim of this study was to determine the content of essential and toxic trace elements in Wistar outbred and hereditary obese Zucker Lepr^fa (Z) rats consuming a standard balanced diet or hypercaloric diet with excess fat and fructose, supplemented with quercetin or not supplemented.
Male Wistar and Z rats were fed a control AIN-93M-based semi-synthetic diet or a high-fat-high-carbohydrate diet (HFCD, with 30% fat by weight and 20% fructose provided in the drinking water). A portion of the animals in each line and diet group was administered quercetin at 50 mg/kg body weight. Essential trace elements were included in the diets as a high-purity salt mixture. After the termination of feeding on day 63, the livers, kidneys, and brains of the rats were excised and the content of 16 elements (Fe, Mg, Cu, Mn, Co, Se, Zn, Cr, Ni, Al, Cd, As, Pb, V, Cs, and Ag) was measured by inductively coupled plasma mass spectrometry (ICP-MS).
In the livers of the Z rats, the contents of Co, Zn, Mg, Fe, Se, and V were reduced and the content of Cr was increased compared to that of the Wistar rats. Supplementation with quercetin significantly decreased liver Fe, V, and Se content, which was more noticeable in the Wistar rats than in the Z rats. In kidneys of Z rats consuming control diet, the contents of Co, Cu, and Cs were decreased whereas those of Ni, Al, and Se were increased compared with the contents in the Wistar rats. The same trend was observed with HFCD feeding except for Cs content. Quercetin reduced kidney V content in both rat lines fed both diets, whereas it reduced Se and Cs only in the Z rats fed control diet. In the brains of the Z rats, a large increase was observed in some trace elements including Pb, Cd, Al, Cr, Ni, Fe, and V compared with the levels in the Wistar rat brains. Supplementation of the control diet with quercetin decreased Al and Ni in the brains of the Z rats.
There were significant differences in the mineral content of organs between the Wistar and Z rats, with different propensities for obesity. Moreover some of these effects had no straightforward association with decreased feed consumption or hepatic fat accumulation. When introduced into the diets, quercetin affected the content of essential and toxic elements, but with ambiguous physiological significance. Thus, indicators of essential and toxic trace elements deserve to be used in the protocols of preclinical as well as clinical trials of biologically active substances and food supplements.
A mitophagic response to iron overload-induced oxidative damage associated with the PINK1/Parkin pathway in pancreatic beta cells
2020, Journal of Trace Elements in Medicine and Biology
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When overloaded, although it is essential, iron can also harm the body, since there is no adequate physiological mechanism in place to excrete excessive iron. Iron overload can increase the factors comprising the metabolic syndrome, including obesity, dyslipidemia, hypertension, fasting hyperglycemia and diabetes [1,2]. For example, thalassemia, a significant disease that succeeds iron overload, is associated with continuous hemolysis, requires frequent transfusion and increases the risk of diabetes.
Iron overload can result in a disorder in glucose metabolism. However, the underlining mechanism through which iron overload induces beta cell death remains unknown.
According to the concentration of ferric ammonium citrate (FAC) and N-acetylcysteine, INS-1 cells were randomly divided into four groups: normal control (FAC 0 μM) group, FAC 80 μM group, FAC 160 μM group, FAC 160μM + NAC group. Cell proliferation was assessed by Cell Counting Kit-8. Reactive oxygen species (ROS) level was further evaluated using flow cytometer with a fluorescent probe. The mitochondrial membrane potential was detected by JC-1 kit, and transmission electron microscopy was used to observe the mitochondrial changes. The related protein expressions were detected by western bolt to evaluate mitophagy status.
It was shown that FAC treatment decreased INS-1 cell viability in vitro, resulted in a decline in mitochondrial membrane potential, increased oxidative stress level and suppressed mitophagy. Furthermore, these effects could be alleviated by the ROS scavenger.
We proved that increased iron overload primarily increased oxidative stress and further suppressed mitophagy via PTEN-induced putative kinase 1/Parkin pathway, resulting in cytotoxicity in INS-1 cells.
Iron status at opposite ends of the menstrual function spectrum
2019, Journal of Trace Elements in Medicine and Biology
Citation Excerpt :
Low energy availability, defined as energy intake minus exercise energy expenditure [69], triggers biological conservation of energy, such as reproductive suppression resulting in EAMD [32]. Low energy availability may also result in iron conservation, given that obesity (a state of high energy availability) affects iron metabolism [70,71]. Lastly, it should be determined if progesterone and estradiol exposure are associated with iron status indices, given that these hormones regulate hepcidin [72,73].
Although exercising women are at high risk of poor iron status, it is unknown how non-pathological, physiological menstrual function affects iron status. As such, this study investigates the association between menstrual function and iron status in exercising women with amenorrhea and exercising women with ovulatory, eumenorrheic menstrual cycles.
Cross-sectional analysis of iron depletion prevalence, iron status indices, exercise parameters, and diet composition.
Women aged 18–35 years performing at least 2 h per week of aerobic exercise were recruited. Women with amenorrhea (AMEN) were defined by the absence of menses for at least 90 days or less than 6 menses in the past 12 months (n = 82). Women with ovulatory, eumenorrheic menstrual cycles (OvEU) were defined by the presence of ovulatory cycles of 26-35 days in length for the past 6 months (n = 109). Group differences in serum ferritin (Ft), soluble transferrin receptor (sTfR), total body iron (TBI), hemoglobin (Hb), hematocrit (Hct), iron depletion prevalence (Ft <15 μg/L), peak oxygen consumption (VO_2peak), exercise minutes per week, and diet logs were assessed.
The prevalence of iron depletion was greater in OvEU when compared to AMEN (26% vs. 15%, p = 0.04). No significant differences were observed between AMEN and OvEU in Ft (30.2 ± 2.2 vs. 24.9 ± 2.6 μg/L; p = 0.62), sTfR (5.2 ± 1.4 vs. 4.9 ± 1.5 mg/L; p = 0.95), TBI (5.3 ± 2.7 vs. 4.8 ± 3.7 mg/kg; p = 0.42), Hb (13.2 ± 0.4 vs. 13.4 ± 0.6 g/dL; p = 0.80), Hct (39.5 ± 0.8% vs. 39.8 ± 4.1%; p = 0.93), or exercise parameters. AMEN consumed more vitamin C than OvEU (269 ± 180 vs. 129 ± 141 mg/day, p < 0.001), but all other dietary factors were similar between AMEN and OvEU.
Exercising women with ovulatory, eumenorrheic cycles are at a greater risk of iron depletion than exercising, amenorrheic women. Thus, menstrual function must be considered when screening for poor iron status in exercising women.
Benefits of selenium, magnesium, and zinc in obesity and metabolic syndrome
2018, Obesity: Oxidative Stress and Dietary Antioxidants
Selenium (Se) is an essential trace element, with biological functions of importance for human health. Se has four natural oxidation states: elemental selenium, selenide, selenite, and selenate. Many biological functions of Se are carried out by selenoproteins, and may play a significant role in cellular defense against reactive oxygen species. Low Se levels are associated with oxidative stress and a decrease protection the blood vessels against oxidative damage. An association between Se and type 2 diabetes mellitus is controversial.
Magnesium (Mg) is an essential mineral that functions as a cofactor for hundreds of enzymes. Low levels of Mg in blood are related to obesity and metabolic syndrome. Cross-sectional and longitudinal studies have found an inverse relationship between Mg intake and the prevalence or incidence of metabolic syndrome. The consumption of Mg through the diet is a protective factor, but not exclusive since the foods that contain it are also sources of other beneficial compounds, such as dietary fiber and antioxidant vitamins.
Zinc (Zn) is an essential trace element which plays a role the activity of all types of enzymes (as either a catalytic, a structural, or a regulatory element). One of the main activities of Zn is its participation in insulin synthesis and regulation, and it also has antioxidant and antiinflammatory effects.
Induction of copper and iron in acute cold-stimulated brown adipose tissues
2017, Biochemical and Biophysical Research Communications
Citation Excerpt :
All this evidence demonstrated the key role of Cu in lipid metabolism. Comparably, the interaction among iron metabolism, adipocyte inflammation and obesity has been well established [2,8,9], and cytosolic aconitase (ACO1) activity plays a critical role to link iron metabolism and adipogenesis [10]. As an endocrine organ, adipose tissue has been demonstrated to play central roles not only in energy balance and glucose homeostasis, but also in other important biological functions, such as reproduction, development, and metabolic diseases, including obesity and diabetes.
Copper (Cu) and iron (Fe), the enzymatic cofactors required for various biochemical processes, have been recently linked to lipid metabolism. Adipose tissues play central roles in energy balance and whether copper and iron homeostasis is involved in cold-stimulated energy metabolism remains unknown. In this study, the Cu and Fe contents in interscapular brown adipose tissue (BAT) and subcutaneous white adipose tissue (subWAT) from mice at different developmental stages were measured. Our results revealed the dynamic changes of Cu and Fe levels during development, suggesting their potential roles in energy homeostasis. Furthermore, the significantly increased Cu and Fe contents and the markedly up-regulated CTR1 and ATP7A expression in acute cold-stimulated BAT indicates the involvement of both Cu and Fe in the BAT-mediated thermogenesis. Comparably, no change in the Cu and Fe levels in cold-stimulated subWAT was observed at the indicated time points, suggesting that both metals are not involved in the cellular process of cold-induced WAT browning. Taken together, these data demonstrate the induction of Cu and Fe in acute cold-stimulated BAT activation, thus providing the direct evidences of the involvement of copper and iron homeostasis in BAT-mediated non-shivering energy metabolism.

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ReviewIron metabolism in obesity: How interaction between homoeostatic mechanisms can interfere with their original purpose. Part I: Underlying homoeostatic mechanisms of energy storage and iron metabolisms and their interaction

Abstract

Section snippets

Obesity and inflammation

Essential functions of iron

Conflict of interest

J Lipid Res

Biochem Biophys Res Commun

Cell

Cell Metab

Cell Metab

Cell Metab

Cell Metabol

Gastroenterology

Lancet

Am J Clin Nutr

J Am Diet Assoc

J Nutr

Gastroenterology

J Nutr

Blood Rev

Blood

Homo

On the origin of species by means of natural selection

Childhood obesity in America

Curr Opin Endocrinol Diabetes Obes

Angiogenesis inhibitor, TNP-470, prevents diet-induced and genetic obesity in mice

Circ Res

Relationship of childhood obesity to coronary heart disease risk factors in adulthood: the Bogalusa Heart Study

Pediatrics

Relationship between adipocyte size and adipokine expression and secretion

J Clin Endocrinol Metab

Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the comorbidities of obesity

J Clin Endocrinol Metab

Macrophage heterogeneity and tissue lipids

J Clin Investig

Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss

Diabetes

Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects

Arterioscler Thromb Vasc Biol

The role of endothelial cells in inflamed adipose tissue

J Intern Med

From monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes

Diabetes

In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue

J Clin Investig

Early upregulation of endothelial adhesion molecules in obese hypertensive men

Hypertension

Dynamics off at cell turnover in humans

Nature

Review
Iron metabolism in obesity: How interaction between homoeostatic mechanisms can interfere with their original purpose. Part I: Underlying homoeostatic mechanisms of energy storage and iron metabolisms and their interaction