Investigating Multiple Biological Mechanisms of Obesity in a High-Risk Pediatric Cohort with Confirmed Maltreatment

PROJECT SUMMARY Childhood obesity, conceptualized as a “ticking time bomb”, is a prevalent condition with major adverse health consequences. A potent risk factor for childhood obesity is early-life adversity, such as child maltreatment (e.g. physical/sexual abuse and neglect). Our preliminary data from a cohort of high-risk children with confirmed maltreatment replicates prior studies that have linked early-life adversity with accelerated accumulation of body mass and a dysregulated metabolic profile. Extant research, however, has yet to characterize mechanistic multi-omic pathways of obesity in vulnerable pediatric populations. Prior research in adult populations has shown that when considered separately, child maltreatment and obesity are associated with dysregulated immune and metabolic pathways, and accelerated biological aging, suggesting plausible mechanistic pathways to target for obesity prevention and intervention. The proposed project aims to elucidate biological mechanisms of obesity in a vulnerable population with confirmed child maltreatment using multiple levels of analysis. We will leverage the Child Health Study (P50 HD089922), a prospective longitudinal cohort of 700 maltreated and comparison children aged 8–13 (50% females, 29.5% minority). The study includes a baseline assessment and two follow-up assessments with multiple system-biology and phenotypic measures, including BMI, biological aging measured via telomere length and epigenetic clocks, as well as genomics information. We propose secondary data analysis and collection of new data. Specifically, an important next step is to expand upon the current knowledge by evaluating the impact of maltreatment on obesity through transcriptomics (the comprehensive profiling of gene expression), and metabolomics (the comprehensive profiling of metabolites). We will further seek to replicate findings in independent cohorts. Aim 1 will examine cross-sectional and longitudinal associations between BMI and biological aging (telomere length and epigenetic clocks) at baseline (T1), 2-year post (T2), and 4-year post (T3) baseline, and will evaluate the potential moderation of child maltreatment (including type, onset, severity) and sex. Aim 2 will examine cross-sectional and longitudinal associations between BMI and transcriptomic pathways at T1, T2 and T3, and will evaluate the potential moderation of child maltreatment and sex. Aim 3 will examine cross-sectional and longitudinal associations between BMI and metabolomic enrichment in immune and metabolic pathways at T1, T2 and T3, and will evaluate the potential moderation of child maltreatment and sex. The novel insights gained from this proposal will facilitate future hypothesis generation and downstream mechanistic research by narrowing the focus onto pathways driving holistic dysregulation in maltreated children of biological aging, metabolic and immune systems activity associated with obesity risk and resilience. The effectiveness of future obesity intervention and clinical treatments hinges on developing this mechanistic understanding of how potent childhood stressors akin to child maltreatment ‘stick’ with an individual as they age to increase obesity-associated diseases.