Epidemiological studies of multiple cohorts suggest an increased risk for obesity, cardiovascular disease- related death and type 2 diabetes in low birth weight infants. However, the molecular mechanisms underlying developmental programming of childhood obesity remain poorly understood. Alterations in DNA methylation during fetal life have been proposed to be one of the mechanisms that regulate this phenotype. Although association studies, using surrogate cells from cord or peripheral blood, demonstrate a relationship between changes in DNA methylation of loci and infant/child growth parameters, major knowledge gaps exist. Here, we address major questions about early childhood obesity programming by studying purified subpopulations of CD3+ T-cells from intrauterine growth restricted (IUGR) newborns who have an increased risk for obesity and other metabolic disorders in adult life. We elected to study CD3+ T-cells because of their crucial role in the regulation of adipose tissue inflammation and insulin sensitivity, factors which underlie obesity pathogenesis. We hypothesize that the adverse developmental milieu associated with IUGR will be strongly correlated with (1) altered DNA methylation profiles, and (2) functional changes in CD3+ T-cell subpopulations (e.g., CD4+, CD8+, regulatory T-cells ( Tregs)) that persist in peripheral blood T-cells until at least 24-months of age. Furthermore, the enduring epigenetic dysregulation of CD3+ T-cells and their inflammatory signaling processes will be tightly associated with increased adiposity in childhood. We propose three specific aims to address our hypothesis.
In Aim 1, we will characterize the effect of IUGR on DNA methylation profiles in purified CD3+ T-cells obtained from cord blood in a prospective cohort of 300 healthy term infants at birth. The persistence of these changes in differentially methylated loci (DML) will be assessed in peripheral blood CD3+ T-cells at 24-months of age.
In Aim 2, we will characterize the effect of IUGR-associated DNA methylation on CD3+ T-cell function and gene expression using purified CD4+, CD8+, and Treg cells.
In Aim 3, we will determine whether DNA methylation and functional profiles of CD3+ T-cell subpopulations are associated with growth velocity and development of adiposity in the first 24-months of life. Our ultimate goal is to identify epigenetic mechanisms underlying IUGR-mediated childhood obesity in a prospectively enrolled, longitudinally followed cohort of healthy term IUGR infants compared to appropriate for gestational age (AGA) newborns. Furthermore, we will characterize functional changes associated with the newly discovered DML in CD3+ T-cells, a mechanistically relevant cell type in the pathogenesis of obesity.
Obesity is an epidemic in the US that has a devastating impact on health and mortality. More than one third of US children are overweight or obese. Intrauterine growth restricted infants are at high risk for the development of obesity and other metabolic diseases. The molecular mechanisms underlying developmental programming of childhood obesity are poorly understood; however, epigenomic alterations during fetal life have been proposed to be important regulators of the child's phenotype. Immune cells, including T-cells and monocytes, play a key role in obesity pathogenesis. By studying whether DNA methylation and functional profiles of CD3+ T-cells mediate the association of intrauterine growth restriction with the development of adiposity in the first 24-months of life, we will characterize `obesity risk' stratifying biomarkers of early childhood obesity. Identification of stable biomarkers of `obesity risk' early in life can be used both for prediction of later obesity and to monitor the effects of preventive therapies as well as interventions.
