Metal Homeostasis and Exposure in Distinct Phenotypic Subtypes of Insulin Resistance among Children with Obesity

Background: Trace elements and heavy metals have proven pivotal roles in childhood obesity and insulin resistance. However, growing evidence suggests that insulin resistance could encompass distinct phenotypic subtypes. Methods: Herein, we performed a comprehensive metallomics characterization of plasma samples from children and adolescents with obesity and concomitant insulin resistance, who were stratified as early (N = 17, 11.4 ± 2.4 years), middle (N = 16, 11.8 ± 1.9 years), and late (N = 33, 11.7 ± 2.0 years) responders according to the insulin secretion profile in response to an oral glucose tolerance test. To this end, we employed a high-throughput method aimed at determining the biodistribution of various essential and toxic elements by analyzing total metal contents, metal-containing proteins, and labile metal species. Results: Compared with the early responders, participants with delayed glucose-induced hyperinsulinemia showed a worsened insulin resistance (HOMA-IR, 4.5 vs. 3.8) and lipid profile (total cholesterol, 160 vs. 144 mg/dL; LDL-cholesterol, 99 vs. 82 mg/dL), which in turn was accompanied by sharpened disturbances in the levels of plasmatic proteins containing chromium (4.8 vs. 5.1 µg/L), cobalt (0.79 vs. 1.2 µg/L), lead (0.021 vs. 0.025 µg/L), and arsenic (0.077 vs. 0.17 µg/L). A correlation analysis demonstrated a close inter-relationship among these multielemental perturbations and the characteristic metabolic complications occurring in childhood obesity, namely impaired insulin-mediated metabolism of carbohydrates and lipids. Conclusions: These findings highlight the crucial involvement that altered metal homeostasis and exposure may have in regulating insulin signaling, glucose metabolism, and dyslipidemia in childhood obesity.This research was funded by the Spanish Government through Instituto de Salud Carlos III (PI22/01899). AGD is supported by an intramural grant from the Biomedical Research and Innovation Institute of Cádiz (LII19/16IN-CO24), and RGD is a recipient of a “Miguel Servet” fellowship (CP21/00120) funded by Instituto de Salud Carlos III

Sexually dimorphic metal alterations in childhood obesity are modulated by a complex interplay between inflammation, insulin, and sex hormones

Although growing evidence points to a pivotal role of perturbed metal homeostasis in childhood obesity, sexual dimorphisms in this association have rarely been investigated. In this study, we applied multi-elemental analysis to plasma and erythrocyte samples from an observational cohort comprising children with obesity, with and without insulin resistance, and healthy control children. Furthermore, a wide number of variables related to carbohydrate and lipid metabolism, inflammation, and sex hormones were also determined. Children with obesity, regardless of sex and insulin resistance status, showed increased plasma copper-to-zinc ratios. More interestingly, obesity-related erythroid alterations were found to be sex-dependent, with increased contents of iron, zinc, and copper being exclusively detected among female subjects. Our findings suggest that a sexually dimorphic hormonal dysregulation in response to a pathological cascade involving inflammatory processes and hyperinsulinemia could be the main trigger of this female-specific intracellular sequestration of trace elements. Therefore, the present study highlights the relevance of genotypic sex as a susceptibility factor influencing the pathogenic events behind childhood obesity, thereby opening the door to develop sex-personalized approaches in the context of precision medicine.INiBICA, Grant/Award Number: LII19/16IN-CO24; Instituto de Salud Carlos III, Grant/Award Numbers: CP21/00120, PI22/0189

Exploring the association between circulating trace elements, metabolic risk factors, and the adherence to a Mediterranean diet among children and adolescents with obesity

Diet is one of the most important modifiable lifestyle factors for preventing and treating obesity. In this respect, the Mediterranean diet (MD) has proven to be a rich source of a myriad of micronutrients with positive repercussions on human health. Herein, we studied an observational cohort of children and adolescents with obesity (N = 26) to explore the association between circulating blood trace elements and the degree of MD adherence, as assessed through the KIDMED questionnaire. Participants with higher MD adherence showed better glycemic/insulinemic control and a healthier lipid profile, as well as raised plasma levels of selenium, zinc, cobalt, molybdenum, and arsenic, and increased erythroid content of selenium. Interestingly, we found that these MD-related mineral alterations were closely correlated with the characteristic metabolic complications behind childhood obesity, namely hyperglycemia, hyperinsulinemia, and dyslipidemia (p 0.35). These findings highlight the pivotal role that dietary trace elements may play in the pathogenesis of obesity and related disorders.This research was partially funded by the Spanish Government through Instituto de Salud Carlos III- (PI22/01899). ÁG-D was supported by an intramural grant from the Biomedical Research and Innovation Institute of Cádiz (LII19/16INCO24), and RG-D was recipient of a “Miguel Servet” fellowship (CP21/00120) funded by Instituto de Salud Carlos III

Mechanistic Insights into Alzheimer’s Disease Unveiled through the Investigation of Disturbances in Central Metabolites and Metabolic Pathways

Hydrophilic metabolites are closely involved in multiple primary metabolic pathways and, consequently, play an essential role in the onset and progression of multifactorial human disorders, such as Alzheimer's disease. This review article provides a comprehensive revision of the literature published on the use of mass spectrometry-based metabolomics platforms for approaching the central metabolome in Alzheimer's disease research, including direct mass spectrometry, gas chromatography-mass spectrometry, hydrophilic interaction liquid chromatography-mass spectrometry, and capillary electrophoresis-mass spectrometry. Overall, mounting evidence points to profound disturbances that affect a multitude of central metabolic pathways, such as the energy-related metabolism, the urea cycle, the homeostasis of amino acids, fatty acids and nucleotides, neurotransmission, and others

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

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 childrenwith 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.This research was partially funded by the Spanish Government through Instituto de Salud Carlos III (CP21/00120, PI18/01316). Á.G.-D. is supported by an intramural grant from the Biomedical Research and Innovation Institute of Cádiz (LII19/16IN-CO24), and R.G.-D. is recipient of a “Miguel Servet” fellowship (CP21/00120) funded by Instituto de Salud Carlos III

Trace elements as potential modulators of puberty-induced amelioration of oxidative stress and inflammation in childhood obesity

Although puberty is known to influence obesity progression, the molecular mechanisms underlying the role of sexual maturation in obesity-related complications remains largely unexplored. Here, we delve into the impact of puberty on the most relevant pathogenic hallmarks of obesity, namely oxidative stress and inflammation, and their association with trace element blood status. To this end, we studied a well-characterized observational cohort comprising prepubertal (N = 46) and pubertal (N = 48) children with obesity. From all participants, plasma and erythrocyte samples were collected and subjected to metallomics analysis and determination of classical biomarkers of oxidative stress and inflammation. Besides the expected raise of sexual hormones, pubertal children displayed better inflammatory and oxidative control, as reflected by lower levels of C-reactive protein and oxidative damage markers, as well as improved antioxidant defense. This was in turn accompanied by a healthier multielemental profile, with increased levels of essential elements involved in the antioxidant system and metabolic control (metalloproteins containing zinc, molybdenum, selenium, and manganese) and decreased content of potentially deleterious species (total copper, labile free iron). Therefore, our findings suggest that children with obesity have an exacerbated inflammatory and oxidative damage at early ages, which could be ameliorated during pubertal development by the action of trace element-mediated buffering mechanisms.This research was funded by the Spanish Government through Instituto de Salud Carlos III (PI22/01899, PI18/01316). Állvaro González-Domínguez is supported by an intramural grant from the Biomedical Research and Innovation Institute of Cádiz (LII19/16IN-CO24), and Raúl González-Domínguez is recipient of a “Miguel Servet” fellowship funded by Instituto de Salud Carlos III (CP21/00120)

Iron Metabolism in Obesity and Metabolic Syndrome

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

Mechanistic Insights into Alzheimer’s Disease Unveiled through the Investigation of Disturbances in Central Metabolites and Metabolic Pathways

Hydrophilic metabolites are closely involved in multiple primary metabolic pathways and, consequently, play an essential role in the onset and progression of multifactorial human disorders, such as Alzheimer’s disease. This review article provides a comprehensive revision of the literature published on the use of mass spectrometry-based metabolomics platforms for approaching the central metabolome in Alzheimer’s disease research, including direct mass spectrometry, gas chromatography-mass spectrometry, hydrophilic interaction liquid chromatography-mass spectrometry, and capillary electrophoresis-mass spectrometry. Overall, mounting evidence points to profound disturbances that affect a multitude of central metabolic pathways, such as the energy-related metabolism, the urea cycle, the homeostasis of amino acids, fatty acids and nucleotides, neurotransmission, and others

Analysis of Sport Supplement Consumption and Body Composition in Spanish Elite Rowers.

The aim of this study was to analyze the anthropometric characteristics and sport supplement (SS) consumption patterns of heavyweight and lightweight international rowers. Methods: The 13 heavyweights (11 males) and seven lightweights (five males) of the Spanish National Rowing Team were recruited for the study. Body composition was measured by bio-impedance analysis, and the questionnaire used in this investigation was previously validated to assess SS consumption. According to anthropometrics parameters, it was reported that male heavyweight rowers were heavier (p < 0.001) and taller (p < 0.001), but no statistical di erences were reported for % body fat (p = 0.104) or % lean body mass (p = 0.161). All rowers reported consumption of at least one SS. Based on the Australian Institute of Sport’s classification, higher medical supplement consumption was observed when comparing heavyweight rowers to lightweight rowers (2.5 1.1 vs. 1.7 0.5, p = 0.040). There were no di erences in the totals of group A (strong scientific evidence for sports scenarios, p = 0.069), group B (emerging scientific support, deserving of further research, p = 0.776), or group C (scientific evidence not supportive of benefit and/or security amongst athletes, p = 0.484). The six most consumed SSs were iron (85%), ca eine (85%), -alanine (85%), energy bars (85%), vitamin supplements (80%), and isotonic drinks (80%), with no statistical di erences between heavyweight and lightweight rowers (p > 0.05). These results suggest that the absence of di erences in body composition (expressed as a percentage) do not represent anthropometric disadvantages for heavyweight rowers. In addition, SS consumption was similar between rowers, reporting only higher medical supplement consumption in heavyweight rowers.post-print931 K

Placental Adaptive Changes to Protect Function and Decrease Oxidative Damage in Metabolically Healthy Maternal Obesity

Pregnancy-related disorders, including preeclampsia and gestational diabetes, are characterized by the presence of an adverse intrauterine milieu that may ultimately result in oxidative and nitrosative stress. This scenario may trigger uncontrolled production of reactive oxygen species (ROS) such as superoxide anion (OBLACK CIRCLE-) and reactive nitrogen species (RNS) such as nitric oxide (NO), along with an inactivation of antioxidant systems, which are associated with the occurrence of relevant changes in placental function through recognized redox post-translational modifications in key proteins. The general objective of this study was to assess the impact of a maternal obesogenic enviroment on the regulation of the placental nitroso-redox balance at the end of pregnancy. We measured oxidative damage markers-thiobarbituric acid-reacting substances (TBARS) and carbonyl groups (C=O) levels; nitrosative stress markers-inducible nitric oxide synthase, nitrosothiol groups, and nitrotyrosine residues levels; and the antioxidant biomarkers-catalase and superoxide dismutase (SOD) activity and expression, and total antioxidant capacity (TAC), in full-term placental villous from both pre-pregnancy normal weight and obese women, and with absence of metabolic complications throughout gestation. The results showed a decrease in C=O and TBARS levels in obese pregnancies. Although total SOD and catalase concentrations were shown to be increased, both activities were significantly downregulated in obese pregnancies, along with total antioxidant capacity. Inducible nitric oxide sintase levels were increased in the obese group compared to the lean group, accompanied by an increase in nitrotyrosine residues levels and lower levels of nitrosothiol groups in proteins such as ERK1/2. These findings reveal a reduction in oxidative damage, accompanied by a decline in antioxidant response, and an increase via NO-mediated nitrative stress in placental tissue from metabolically healthy pregnancies with obesity. All this plausibly points to a placental adaptation of the affected antioxidant response towards a NO-induced alternative pathway, through changes in the ROS/RNS balance, in order to reduce oxidative damage and preserve placental function in pregnancy