Effect of excess weight and insulin resistance on DNA methylation in prepubertal children

Authors: BARBOSA, PEDRO - University Of Coimbra; LANDES, REID - University Arkansas For Medical Sciences (UAMS); GRAW, STEFAN - Everest Clinical Research Corporation; BYRUM, STEFANIE - University Arkansas For Medical Sciences (UAMS); BENNURI, SIRISH - University Arkansas For Medical Sciences (UAMS); DELHEY, LEANNA - University Arkansas For Medical Sciences (UAMS); RANDOLPH, CHRIS - University Arkansas For Medical Sciences (UAMS); MACLEOD, STEWART - University Arkansas For Medical Sciences (UAMS); REIS, ANDREIA - University Of Aveiro (UA); BORSHEIM, ELISABET - University Arkansas For Medical Sciences (UAMS); ROSE, SHANNON - University Arkansas For Medical Sciences (UAMS); CARVALHO, EUGENIA - University Of Coimbra

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/3/2022
Publication Date: 5/19/2022
Citation: Barbosa, P., Landes, R.D., Graw, S., Byrum, S.D., Bennuri, S., Delhey, L., Randolph, C., Macleod, S., Reis, A., Borsheim, E., Rose, S., Carvalho, E. 2022. Effect of excess weight and insulin resistance on DNA methylation in prepubertal children. Scientific Reports. https://doi.org/10.1038/s41598-022-12325-y.
DOI: https://doi.org/10.1038/s41598-022-12325-y

Interpretive Summary: Pediatric overweight and obesity are a major public health concern. Being overweight or obese early in life increases the odds of additional health problems at a younger age, such as cardiovascular disease and type 2 diabetes. One important link between chronic disease development and overweight/obesity is resistance towards the insulin hormone. Interestingly, not everyone with obesity develops insulin resistance as some people appear to be protected and remain metabolically healthy. The causes for this are not fully known. Various lifestyle factors may affect the expression of genes (epigenetics) which may be of importance for regulation of these processes. In the current study, the researchers attempted to identify associations between obesity levels and insulin resistance and various metabolic outcomes, and also epigenetic modifications in circulating cells that may occur at an early stage in children. Thus, the aim of this study was to evaluate how overweight/obesity and insulin resistance, either alone or in combination, associated with metabolic outcomes and with expression of genes in circulating cells in pre-pubertal children. A total of 41 children ages 5-9 years were studied. Children with more resistance towards insulin had higher blood pressure and plasma lactate concentrations, while children with higher degree of obesity had higher lipid levels in their blood compared to those with normal weight. It was also found that obesity may affect expression of a specific gene involved in inflammatory responses. In summary, the results suggested that obesity and insulin resistance independently may impact metabolic health in pre-pubertal children.

Technical Abstract: Epigenetic mechanisms, such as DNA methylation, regulate gene expression and play a role in the development of insulin resistance. This study evaluates how the BMI z-score (BMIz) and the homeostatic model assessment of insulin resistance (HOMA-IR), alone or in combination, relate to clinical outcomes and DNA methylation patterns in prepubertal children. DNA methylation in peripheral blood mononuclear cells (PBMCs) and clinical outcomes were measured in a cohort of 41 prepubertal children. Children with higher HOMA-IR had higher blood pressure and plasma lactate levels while children with higher BMIz had higher triglycerides levels. Moreover, the DNA methylation analysis demonstrated that a 1 unit increase in the BMIz was associated with a 0.41 (95% CI: 0.29,0.53) increase in methylation of a CpG near the PPP6R2 gene. This gene is important in the regulation of NF-kB expression. However, there was no strong evidence that the BMIz and the HOMA-IR were synergistically related to any clinical or DNA methylation outcomes. In summary, the results suggest that obesity and insulin resistance may impact metabolic health both independently in prepubertal children. In addition, obesity also has an impact on the DNA methylation of the PPP6R2 gene. This may be a novel underlying starting point for the systemic inflammation associated with obesity and insulin resistance, in this population.