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Redox Imbalance and Methylation Disturbances in Early Childhood Obesity.

ABSTRACT: Obesity is increasing worldwide in prepubertal children, reducing the age of onset of associated comorbidities, including type 2 diabetes. Sulfur-containing amino acids, methionine, cysteine, and their derivatives play important roles in the transmethylation and transsulfuration pathways. Dysregulation of these pathways leads to alterations in the cellular methylation patterns and an imbalanced redox state. Therefore, we tested the hypothesis that one-carbon metabolism is already dysregulated in prepubertal children with obesity. Peripheral blood was collected from 64 children, and the plasma metabolites from transmethylation and transsulfuration pathways were quantified by HPLC. The cohort was stratified by BMI z-scores and HOMA-IR indices into healthy lean (HL), healthy obese (HO), and unhealthy obese (UHO). Fasting insulin levels were higher in the HO group compared to the HL, while the UHO had the highest. All groups presented normal fasting glycemia. Furthermore, high-density lipoprotein (HDL) was lower while triglycerides and lactate levels were higher in the UHO compared to HO subjects. S-adenosylhomocysteine (SAH) and total homocysteine levels were increased in the HO group compared to HL. Additionally, glutathione metabolism was also altered. Free cystine and oxidized glutathione (GSSG) were increased in the HO as compared to HL subjects. Importantly, the adipocyte secretory function was already compromised at this young age. Elevated circulating leptin and decreased adiponectin levels were observed in the UHO as compared to the HO subjects. Some of these alterations were concomitant with alterations in the DNA methylation patterns in the obese group, independent of the impaired insulin levels. In conclusion, our study informs on novel and important metabolic alterations in the transmethylation and the transsulfuration pathways in the early stages of obesity. Moreover, the altered secretory function of the adipocyte very early in life may be relevant in identifying early metabolic markers of disease that may inform on the increased risk for specific future comorbidities in this population.

SUBMITTER: Barbosa P

PROVIDER: S-EPMC8387800 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe pathophysiologic significance of redox imbalance is unquestionable as numerous reports and topic reviews indicate alterations in redox parameters during corona virus disease 2019 (COVID-19). However, a more comprehensive understanding of redox-related parameters in the context of COVID-19-mediated inflammation and pathophysiology is required.MethodsCOVID-19 subjects (n = 64) and control subjects (n = 19) were enrolled, and blood was drawn within 72 h of diagnosis. Serum multiplex assays and peripheral blood mRNA sequencing was performed. Oxidant/free radical (electron paramagnetic resonance (EPR) spectroscopy, nitrite-nitrate assay) and antioxidant (ferrous reducing ability of serum assay and high-performance liquid chromatography) were performed. Multivariate analyses were performed to evaluate potential of indicated parameters to predict clinical outcome.ResultsSignificantly greater levels of multiple inflammatory and vascular markers were quantified in the subjects admitted to the ICU compared to non-ICU subjects. Gene set enrichment analyses indicated significant enhancement of oxidant related pathways and biochemical assays confirmed a significant increase in free radical production and uric acid reduction in COVID-19 subjects. Multivariate analyses confirmed a positive association between serum levels of VCAM-1, ICAM-1 and a negative association between the abundance of one electron oxidants (detected by ascorbate radical formation) and mortality in COVID subjects while IL-17c and TSLP levels predicted need for intensive care in COVID-19 subjects.ConclusionHerein we demonstrate a significant redox imbalance during COVID-19 infection affirming the potential for manipulation of oxidative stress pathways as a new therapeutic strategy COVID-19. However, further work is requisite for detailed identification of oxidants (O2•-, H2O2 and/or circulating transition metals such as Fe or Cu) contributing to this imbalance to avoid the repetition of failures using non-specific antioxidant supplementation.

Project description:ObjectivesThe prevalence of childhood obesity is significantly higher among racial and/or ethnic minority children in the United States. It is unclear to what extent well-established obesity risk factors in infancy and preschool explain these disparities. Our objective was to decompose racial and/or ethnic disparities in children's weight status according to contributing socioeconomic and behavioral risk factors.MethodsWe used nationally representative data from ∼10 700 children in the Early Childhood Longitudinal Study Birth Cohort who were followed from age 9 months through kindergarten entry. We assessed the contribution of socioeconomic factors and maternal, infancy, and early childhood obesity risk factors to racial and/or ethnic disparities in children's BMI z scores by using Blinder-Oaxaca decomposition analyses.ResultsThe prevalence of risk factors varied significantly by race and/or ethnicity. African American children had the highest prevalence of risk factors, whereas Asian children had the lowest prevalence. The major contributor to the BMI z score gap was the rate of infant weight gain during the first 9 months of life, which was a strong predictor of BMI z score at kindergarten entry. The rate of infant weight gain accounted for between 14.9% and 70.5% of explained disparities between white children and their racial and/or ethnic minority peers. Gaps in socioeconomic status were another important contributor that explained disparities, especially those between white and Hispanic children. Early childhood risk factors, such as fruit and vegetable consumption and television viewing, played less important roles in explaining racial and/or ethnic differences in children's BMI z scores.ConclusionsDifferences in rapid infant weight gain contribute substantially to racial and/or ethnic disparities in obesity during early childhood. Interventions implemented early in life to target this risk factor could help curb widening racial and/or ethnic disparities in early childhood obesity.

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Redox Imbalance and Methylation Disturbances in Early Childhood Obesity.

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