Altered Metal Homeostasis Associates with Inflammation, Oxidative Stress, Impaired Glucose Metabolism, and Dyslipidemia in the Crosstalk between Childhood Obesity and Insulin Resistance

Abstract

Metals are redox-active substances that participate in central biological processes and may be involved in a multitude of pathogenic events. However, considering the inconsistencies reported in the literature, further research is crucial to disentangle the role of metal homeostasis in childhood obesity and comorbidities using well-characterized cohorts and state-of-the-art analytical methods. To this end, we studied an observational population comprising children with obesity and insulin resistance, children with obesity without insulin resistance, and healthy control children. A multi-elemental approach based on the size-fractionation of metal species was applied to quantify the total content of various essential and toxic elements in plasma and erythrocyte samples, and to simultaneously investigate the metal fractions conforming the metalloproteome and the labile metal pool. The most important disturbances in childhood obesity were found to be related to elevated circulating copper levels, decreased content of plasmatic proteins containing chromium, cobalt, iron, manganese, molybdenum, selenium, and zinc, as well as the sequestration of copper, iron, and selenium within erythrocytes. Interestingly, these metal disturbances were normally exacerbated among children with concomitant insulin resistance, and in turn were associated to other characteristic pathogenic events, such as inflammation, oxidative stress, abnormal glucose metabolism, and dyslipidemia. Therefore, this study represents one-step further towards a better understanding of the involvement of metals in the crosstalk between childhood obesity and insulin resistance.

Keywords: childhood obesity; erythrocyte; inflammation; insulin resistance; metals; oxidative stress.

Figure 1

Network representations of Pearson’s correlations between anthropometric and biochemical variables, including parameters related to obesity, inflammation, oxidative stress, glucose and lipid metabolism, and total metal levels in plasma (A), HMM metal species in plasma (B), and LMM metal species in plasma (C). Positive and negative correlations are represented as red and blue lines, respectively (the thicker the line, the stronger the correlation). Abbreviations: AISI, aggregate index of systemic inflammation; AUCGlc, area under the curve for glucose; AUCIns, area under the curve for insulin; BMI, body mass index; CAT, catalase; Co, cobalt; Cr, chromium; CRI-I, Castelli risk index-I; CRP, C-reactive protein; Cu, copper; Fe, iron; Glc0, fasting plasma concentration of glucose; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; Ins0, fasting plasma concentration of insulin; LDL-C, low-density lipoprotein cholesterol; MeanGlc, mean glucose concentration along the oral glucose tolerance test; MeanIns, mean insulin concentration along the oral glucose tolerance test; Mn, manganese; Mo, molybdenum; NLR, neutrophil-to-lymphocyte ratio; PC, protein carbonyl; Se, selenium; SII, systemic immune inflammation index; SIRI, systemic inflammation response index; TBARS, thiobarbituric acid reactive substances; TC, total cholesterol; TG, triglycerides; WBISI, whole-body insulin sensitivity index; WC, waist circumference; Zn, zinc.

Figure 2

Network representations of Pearson’s correlations between anthropometric and biochemical variables, including parameters related to obesity, inflammation, oxidative stress, glucose and lipid metabolism, and total metal levels in erythrocytes (A) and HMM metal species in erythrocytes (B). Positive and negative correlations are represented as red and blue lines, respectively (the thicker the line, the stronger the correlation). Abbreviations: AISI, aggregate index of systemic inflammation; AUCIns, area under the curve for insulin; BMI, body mass index; CAT, catalase; Cu, copper; Fe, iron; HbA1c, glycated hemoglobin; HOMA-IR, homeostasis model assessment of insulin resistance; Ins0, fasting plasma concentration of insulin; LDL-C, low-density lipoprotein cholesterol; MeanGlc, mean glucose concentration along the oral glucose tolerance test; MeanIns, mean insulin concentration along the oral glucose tolerance test; Mn, manganese; Mo, molybdenum; NLR, neutrophil-to-lymphocyte ratio; PC, protein carbonyl; PLR, platelet-to-lymphocyte ratio; Se, selenium; SII, systemic immune inflammation index; SIRI, systemic inflammation response index; TBARS, thiobarbituric acid reactive substances; TG, triglycerides; WBISI, whole-body insulin sensitivity index; Zn, zinc.