Location: Arkansas Children's Nutrition CenterTitle: Redox imbalance and methylation disturbances in early childhood obesity
|BARBOSA, PEDRO - University Of Coimbra|
|MELNYK, STEPAN - Arkansas Children'S Nutrition Research Center (ACNC)|
|BENNURI, SIRISH - Arkansas Children'S Nutrition Research Center (ACNC)|
|DELHEY, LEANNA - Arkansas Children'S Nutrition Research Center (ACNC)|
|REIS, ANDREIA - University Of Aveiro (UA)|
|MOURA, GABRIELA - University Of Aveiro (UA)|
|BORSHEIM, ELISABET - Arkansas Children'S Nutrition Research Center (ACNC)|
|ROSE, SHANNON - Arkansas Children'S Nutrition Research Center (ACNC)|
|CARVALHO, EUGENIA - Arkansas Children'S Nutrition Research Center (ACNC)|
Submitted to: Oxidative Medicine and Cellular Longevity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/3/2022
Publication Date: 8/18/2021
Citation: Barbosa, P., Melnyk, S., Bennuri, S.C., Delhey, L., Reis, A., Moura, G.R., Borsheim, E., Rose, S., Carvalho, E. 2021. Redox imbalance and methylation disturbances in early childhood obesity. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2021/2207125.
Interpretive Summary: The childhood obesity epidemic is associated with development of many associated health problems, including type 2 diabetes which is now being observed at younger ages. Dysregulation of certain pathways (transmethylation and the transsulfuration pathways) in the body may lead to damaging alterations in the cells. Together with collaborators, investigators at Arkansas Children’s Nutrition Center tested whether these pathways are dysregulated in prepubertal children with obesity. The investigators studied blood samples from 64 pre-pubertal children, including breakdown products from these pathways. The children were stratified into groups of healthy lean (HL), healthy obese (HO), and unhealthy obese (UHO), based on their degree of resistance to insulin (a metabolic health indicator). Fasting insulin concentrations were higher in the HO group compared to the HL, while the UHO had the highest insulin levels. The investigators found that UHO also had less favorable lipid concentrations in their blood compared to HO. Alterations that indicate dysregulations of the transmethylation and the transsulfuration pathways were found in children with obesity and with insulin resistance. Blood concentrations of hormones secreted from fat cells also differed in children with obesity vs. normal weight. The investigators concluded that changes in these important pathways starts at early stages of obesity. Moreover, the changes in circulating hormones, indicating altered secretory function of fat cells, may be relevant early markers of increased risk for future health problems in this population.
Technical 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. Sadenosylhomocysteine (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.