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

治疗和预防女性肥胖症和共病代谢结果对于阻止肥胖症流行至关重要，因为这些疾病不成比例地加重了女性的负担，并使肥胖症和后代的许多其他健康问题永久化。多层次研究，可以在整个生命周期中检查人类功能的多个层次的潜在因素。此外，下丘脑-垂体-肾上腺（HPA）轴失调的独特影响，一个重要的病理生理机制诱导的早期生活压力，对长期肥胖相关的健康结果知之甚少。 知识是有限的，未经证实的回顾性评估的早期生活压力，无法控制混淆，以及缺乏多层次的方法来测试的影响失调HPA轴与竞争，合理的机制，包括抑郁症状和饮食失调。拟议的研究旨在了解最有效的机制和修饰剂影响肥胖轨迹和共病代谢结果在规范的“比较”和高风险的“压力暴露”的女性，通过应用多层次的分析框架，使用女性生长和发育研究（FGDS; PI：Noll）。FGDS始于1987年，前瞻性随访了年龄6至40岁的7个时间点（T1-7）的多样化女性样本（N=173; 46%为少数种族/族裔; 49%为压力暴露的子样本，证实了儿童期性虐待），保留率为96%留存率。在儿童期/青春期早期（平均年龄11、12和13岁）进行了三次全面的多水平生物-心理-社会评估，在青春期晚期（平均年龄18和19岁）进行了两次，在成年早期/中期（平均年龄24和33岁）进行了两次，采用了最先进的人体测量学、代谢生物标志物以及整个生命周期的心理和行为结构测量。本研究的主要目的是：（1）研究应激诱导的最有效的病理生理机制（下丘脑-垂体-肾上腺轴失调、抑郁症状和饮食失调）和发育时机（童年、青春期和成年期），解释了女性在整个生命周期中的肥胖轨迹和成年期的共病代谢结果，为干预的最佳目标和时机提供了信息，（2）检查可改变的行为（即饮食、体力活动和睡眠），以减轻早期生活压力对肥胖发展的影响。 和共病代谢结果，告知潜在的干预途径，和（3）调查这些机制和修饰剂在多大程度上解释了高风险、压力暴露的性虐待女性人群的肥胖和共病代谢结果风险的升高，以便针对病理生理机制的干预可以帮助所有女性预防肥胖的发展。研究结果将提供有关有效机制和修饰剂，最佳时机，以及预防，缓解和可逆性肥胖和相关健康问题的潜在途径的宝贵知识。

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.