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.

Targeted improvement of plant‐based protein: Genome‐wide association mapping of a lentil (Lens culinaris Medik.) diversity panel

“…The body can synthesize Cys from Met; consequently, they are combined for intake requirements. Cys is vital in protein folding because of its ability to form disulfide bonds; Met is significant for its role as the AA that begins translation as well for its derivatives, glutathione, and S‐adenosyl methionine (SAM), which are important in oxidative protection and DNA methylation, respectively, and have been examined in such diverse pathologies as obesity and Parkinson's disease (Barbosa et al, 2021; Jalgaonkar et al, 2022). In addition to AA composition, protein quality also depends on PDg, which determines how well the protein can be catabolized during digestion and utilized by the body.…”

The Role of Nutraceutical Containing Polyphenols in Diabetes Prevention

“…T2D is preceded by insulin resistance, one of the underlying causes of diabetes development [14][15][16][17][18]. Insulin resistance can begin years before symptoms are present, with high insulin levels even in the presence of normal glycemia, as demonstrated in pre-pubertal children with obesity [19]. Hypertension and heart disease are diagnosed at younger ages, as the age of T2D onset decreases [20,21].…”

“…This suggests that glycemic control per se is not sufficient to prevent vascular and metabolic complications from developing. One of the possible hypotheses is that chronic exposure to high insulin levels, observed in insulin resistant subjects, even in a setting of normal glycemia is a major cause of inflammation, immune and metabolic dysregulation, increasing oxidative stress and inflammation, potentiating diabetes, and vascular complications [19,28].…”

Regulatory T cells and bioenergetics of peripheral blood mononuclear cells linked to pediatric obesity

“…We previously reported evidence that T2D-driving inflammation is present very early, perhaps years before the onset of glucose intolerance. In a cohort of 5- to 9-year-old prepubertal children with overweight and obesity, we observed early insulin resistance driven by high insulin levels, as fasting glucose levels remained normal, and elevated markers of inflammation including CRP and the leptin/adiponectin ratio [6,17] . This is consistent with National Health and Nutrition Examination Survey (NHANES) data showing elevated CRP in very young overweight/obese children, as young as age 3 years [4] .…”