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风险因素。 在成年后。因此，迫切需要了解儿童肥胖的病因并找出机会 寻求尽可能早的干预措施，以促进一生的健康。为此，这一行动的目标是 建议使用代谢组学来更好地了解肥胖和身体变异的基础。 婴儿期和早期的营养成分(如脂肪质量、瘦质量、骨量、按年龄计算的体重)。长期的 该项目的培训目标是支持海因斯伯格博士成为一名有计划的独立调查员 致力于了解和预防肥胖以及改善孕产妇/儿童健康的研究。这个 导师K99将专注于来自萨摩亚国家的参与者，因为太平洋岛民患上 与肥胖相关的并发症是美国人口增长最快的国家之一，但 在健康研究中的代表性不足。在太平洋岛民成人中，CREB3的错义变异(Rs373863828) 调节因子(CREBRF)对体重指数的影响比任何其他常见变量都大。 矛盾的是，肥胖风险等位基因对糖尿病具有保护作用，这使得它的功能作用尚不清楚。 在考虑干预之前，有必要进行进一步的机械性研究。老年人肥胖表型的研究 变异体在出生时不存在，但在儿童以后的临床上存在。鉴于CREBRF临床前的结果 在婴儿模型和我们的初步工作中，我们假设该变体的生物学效应是 出现在生命的更早的时候。为了研究这一假设，K99将从Foafoaga o le Ola中抽出 (“生命的开始”)萨摩亚婴儿队列研究。现有资源包括婴儿CREBRF基因数据， 用双能X射线吸收法测量的生物样品和身体成分以及富含 母婴出生后1周、4个月和20个月的行为/环境数据。我们会 使用时间的、非靶向的代谢组学来增加我们对糖尿病的生化机制的理解 CREBRF变种，强调行为/环境(目标1)和身体组成的基础 在生命的头两年(目标2)。预计结果将提供可转化为 改善萨摩亚和美国太平洋岛民社区的儿童健康和健康公平 现有的生物标本和来自地理上与世隔绝的出生队列的丰富数据，无与伦比的指导， 和一流的资源，培训环境真的很出色。支持过渡的K99培训目标 独立性包括(1)代谢数据的收集/分析，(2)肥胖者的代谢数据解释 表型，(3)在代表性不足的群体中进行儿童肥胖症研究，以及(4)职业 发展。在R00中，K99方法将被应用于更多样化的样本中的早期肥胖研究 (目标3)。所获得的见解将为未来预防儿童肥胖的工作提供关键背景，促进 健康，优化精准医疗，促进公共健康。

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.