Biobehavioral and Environmental Contributions to Metabolomic Profiles and Early Life Body Composition

摘要：儿童肥胖是一个重要的公共卫生问题，也是慢性疾病的关键危险因素 在成年期。因此，迫切需要了解儿童肥胖的病因，并确定机会 尽可能早地进行干预，以促进整个生命周期的健康。为此，本报告的目的是 一项建议是利用代谢组学来更好地了解肥胖和身体变化的基础， 组合物（例如，脂肪量、瘦体重、骨量、年龄别体重）。长期 该项目的培训目标是支持Heinsberg博士成为一名独立的研究者， 致力于了解和预防肥胖和改善孕产妇/儿童健康的研究。的 辅导K99将侧重于来自萨摩亚国家的参与者，因为太平洋岛民的风险最高， 肥胖相关的并发症，是美国增长最快的人口之一，但 在健康研究中的代表性不足。在太平洋岛民成年人中，CREB 3基因的错义变体（rs373863828） 调节因子（CREBRF）对体重指数的影响大于任何其他常见变异。 奇怪的是，肥胖风险等位基因对糖尿病具有保护作用，使其功能作用不清楚， 在考虑干预之前需要进一步的机制研究。肥胖症的表型 变异在出生时不存在，但在儿童后期临床上存在。鉴于CREBRF临床前的结果 模型和我们在婴儿中的初步工作，我们假设变异的生物学效应是 在生命的早期就出现了。为了研究这一假设，K99将借鉴Foafoaga o le奥拉 （“生命的开始”）萨摩亚婴儿队列研究。现有资源包括婴儿CREBRF基因型数据， 生物标本，和身体成分测量使用双能X射线吸收法以及丰富的 出生后1周、4个月和20个月时母婴成对体的行为/环境数据。我们将 使用时间，非靶向代谢组学，以增加我们的理解的生化机制， CREBRF变体强调行为/环境（目标1）和身体组成的基础 在生命的前两年（目标2）。预计结果将提供可转化为 改善美国萨摩亚和太平洋岛民社区的儿童健康和健康公平性 现有的生物标本和丰富的数据，从一个地理上孤立的出生队列，无与伦比的指导， 和一流的资源，训练环境确实是一流的。K99培训目标，以支持过渡 包括（1）代谢组学数据收集/分析，（2）肥胖患者代谢组学数据解释 表型，（3）在代表性不足的群体中进行儿童肥胖研究，以及（4）职业 发展在R 00中，K99方法将用于研究更多样化样本中的早期肥胖 (Aim 3）。所获得的见解将为今后预防儿童肥胖、促进 健康，并优化精准医疗以促进公共卫生。

ABSTRACT: Childhood obesity is a significant public health problem and key risk factor for chronic conditions in adulthood. As such, there is critical need to understand childhood obesity etiology and identify opportunities for the earliest possible interventions to promote wellness across the lifespan. To that end, the objective of this proposal is to use metabolomics to better understand the foundations of variation in adiposity and body composition (e.g., fat mass, lean mass, bone mass, weight-for-age) in infancy and early life. The long-term training goal of this project is to support Dr. Heinsberg in becoming an independent investigator with a program of research dedicated to understanding and preventing obesity and improving maternal/child health. The mentored K99 will focus on participants from the nation of Samoa, as Pacific Islanders have the highest risk of obesity-related complications in the world, are one of the fastest-growing U.S. populations, but are underrepresented in health research. In Pacific Islander adults, a missense variant (rs373863828) in CREB3 Regulatory Factor (CREBRF) has an effect on body mass index larger than any other common variant. Paradoxically, the obesity-risk allele is protective against diabetes, making its functional role unclear and necessitating further mechanistic study before intervention can be considered. The obesity phenotypes of the variant are not present at birth but present clinically later in childhood. Given the results of CREBRF pre-clinical modeling and our preliminary work in infants, we hypothesize that the biological effects of the variant are present much earlier in life. To investigate this hypothesis, the K99 will draw from the Foafoaga o le Ola (“Beginning of Life”) Samoan infant cohort study. Existing resources include infant CREBRF genotype data, biospecimens, and body composition measured using dual-energy X-ray absorptiometry as well as rich behavioral/environmental data for mother-infant dyads at 1 week, 4 months, and 20 months post-birth. We will use temporal, untargeted metabolomics to increase our understanding of the biochemical mechanisms of the CREBRF variant with an emphasis on behavior/environment (Aim 1) and the foundations of body composition over the first two years of life (Aim 2). The results are expected to provide knowledge that can be translated to improved child wellness and health equity in Samoa and Pacific Islander communities in the U.S. With access to existing biospecimens and rich data from a geographically isolated birth cohort, unparalleled mentorship, and superb resources, the training environment is truly outstanding. K99 training goals to support the transition to independence include (1) metabolomic data collection/analysis, (2) metabolomic data interpretation in obese phenotypes, (3) conduct of childhood obesity research in underrepresented groups, and (4) career development. In the R00, the K99 methods will be applied to study early life adiposity in a more diverse sample (Aim 3). The insights gained will provide critical context for future work to prevent childhood obesity, promote wellness, and optimize precision medicine for public health.