Prospective longitudinal study of competing mechanisms and modifiers for obesity trajectories and comorbid metabolic outcomes in normative and high-risk females

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Treating and preventing obesity and comorbid metabolic outcomes in females is critical to halting the obesity epidemic because these diseases disproportionately burden females and perpetuate obesity and numerous additional health problems in offspring.2 Definitive evidence for causal mechanisms and modifiers of obesity development in females is currently limited by the dearth of prospective longitudinal, multi-level studies that can examine potential factors at multiple levels of human functioning across the lifespan. In addition, little is known about the unique effects of Hypothalamic-Pituitary-Adrenal (HPA) axis dysregulation, an important pathophysiologic mechanism induced by early-life stress, on long-term obesity-related health outcomes. Knowledge is limited by unconfirmed retrospective assessments of early-life stress, inability to control for confounds, and lack of multi-level methods that test the effects of dysregulated HPA axis in company with competing, plausible mechanisms including depressive symptoms and disordered eating. The proposed study aims to understand the most potent mechanisms and modifiers affecting obesity trajectories and comorbid metabolic outcomes in normative “comparison” and high-risk “stress-exposed” females by applying a multiple levels of analysis framework using the Female Growth and Development Study (FGDS; PI: Noll). FGDS began in 1987 and prospectively followed a diverse female sample (N=173; 46% racial/ethnic minority; 49% stress- exposed subsample with substantiated childhood sexual abuse) across 7 timepoints (T1-7) spanning ages 6 to 40 with 96% retention rate. A comprehensive, multi-level bio-psycho-social assessment was conducted three times in childhood/early adolescence (mean ages 11, 12 & 13), twice in late adolescence (mean ages 18 & 19), and twice in early/mid adulthood (mean ages 24 & 33), employing state-of-the-art measurements of anthropometrics, metabolic biomarkers, and psychological and behavioral constructs across the lifespan. The proposed aims are to (1) investigate the most potent stress-induced pathophysiologic mechanisms (hypothalamic-pituitary-adrenal axis dysregulation, depressive symptoms, and disordered eating) and developmental timing (childhood adolescence, and adulthood) that explain females’ obesity trajectories across the lifespan and comorbid metabolic outcomes in adulthood, informing optimal target and timing for interventions, (2) examine modifiable behaviors (i.e. diet, physical activity, and sleep) in for their potential to mitigate the impact of early-life stress on the development of obesity and comorbid metabolic outcomes, informing potential avenues for intervention, and (3) investigate the degree to which these mechanisms and modifiers account for the elevated obesity and comorbid metabolic outcomes risks for high- risk, stress-exposed sexually abused female population so that interventions that target pathophysiologic mechanisms can help all females to prevent the development of obesity. Results will provide valuable knowledge about potent mechanisms and modifiers, optimal timing, and potential avenues for prevention, mitigation, and reversibility of obesity and associated health problems.