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.
Highlights
Obesity is a rapidly growing epidemic that is contributing to the significant increase in metabolic diseases worldwide
Obesity is normally characterized by dyslipidemia, this was not observed in the healthy obese (HO) group, as their lipid profile was similar to that of healthy lean (HL)
Our results show that obesity has already caused profound changes in several aspects of metabolism in a cohort of prepubertal children, in the one-carbon metabolism, of particular importance in the folate, transmethylation, and transsulfuration pathways
Summary
Obesity is a rapidly growing epidemic that is contributing to the significant increase in metabolic diseases worldwide. It is characterized by excess adipose tissue expansion and is associated with low-grade inflammation and metabolic dysfunction [1]. Due to the drastic increase in early childhood obesity, the journey to T2D development is starting earlier in life. This in turn increases the risk for other severe health complications over the lifespan, such as hypertension, cardiovascular diseases (CVD), retinopathy, and neuropathy, that appear to increase as the age of T2D onset decreases [4,5,6]. There are several important differences in the pathophysiology of obesity-associated comorbidities in adults compared to children, including early β-cell decline and time to T2D treatment failure, as well as the lack of appropriate pharmacological medications approved for earlier ages, and longer duration of the disease [7,8,9,10]
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