Impact of the obesity-risk CREBRF p.Arg457Gln variant on energy expenditure, intake, and substrate utilization in Samoans

项目总结 我们对肥胖率高的背后原因的理解存在着根本的差距。 萨摩亚是全球观测值最高的国家之一。超过80%的萨摩亚成年人超重或 肥胖，美属萨摩亚女性严重肥胖的比例高达33%，令人担忧。在全基因组中 关联研究我们最近发现了一个新的错义变异(p.Arg457Gln，次要等位基因频率0.259) 在CREB3调节因子(CREBRF)中，与BMI高度相关，其影响大小大于任何 已知的常见BMI风险变量。这项研究项目的总体目标是深入了解新陈代谢 与CREBRF变种相关的超重增加的差异。基于我们的 观察到错义变异体的过度表达促进了脂肪的储存并减少了能量底物 氧化(线粒体呼吸减少)在脂肪细胞模型中，我们的假设是较低的休息时间 包括代谢率(RMR)。支持低线粒体呼吸和低线粒体呼吸之间的关系 RMR，我们最近观察到骨骼肌线粒体呼吸减少与RMR减少有关 非裔美国妇女(AAW)。此外，我们最近还展示了较低的干预诱导体重。 与高加索女性相比，AAW的损失是由于RMR较低，导致能量需求较低。 基于这些观察，以及已知的导致人类肥胖的大多数基因确实 因此，主要通过影响能量摄入和/或支出的中央控制，我们建议确定 能量消耗(EE)和能量摄入(EI)在萨摩亚肥胖风险增加中的作用 与CREBRF错义变体相关的群体。根据我们长期的工作经验 萨摩亚人口中的肥胖和健康风险，结合我们评估能源的丰富经验 在与底物代谢相关的研究方面，我们的研究团队处于进行这些研究的理想位置。 我们建议进行一项纵向研究，以确定该变异对受试者能量平衡的影响 风险等位基因的零个、一个或两个副本，以解决以下三个特定目标：1)确定 能量和底物代谢的成分[RMR；TEF，食物的热效应；总能量；RQ，底物 利用；和PA，体力活动]使用黄金标准方法，包括双标记水(DLW)， 间接量热法和客观活度监测；2)用金标法测定Ei DLW摄入量平衡技术；3)测定能量代谢与体重的关系 通过比较上述能量代谢参数和24-36个月的体重增加。在 申请者认为，拟议的研究将为新陈代谢差异提供新的和重要的见解 对携带CREBRF变异体的人的超重负责，这反过来又起着重要作用 在萨摩亚肥胖症的极端流行。这项研究将促进对艾滋病的认识、预防和 在这一高危人群中适当治疗肥胖症和心脏病。

PROJECT SUMMARY There is a fundamental gap in our understanding of the reasons behind the high prevalence of obesity in Samoa, which is among the highest observed across the globe. Over 80% of Samoan adults are overweight or obese, with severe obesity reaching an alarming 33% in women in American Samoa. In a genome-wide association study we recently identified a novel missense variant (p.Arg457Gln, minor allele frequency 0.259) in CREB3 Regulatory Factor (CREBRF) that is highly associated with BMI, with an effect size greater than any known common BMI risk variant. The overall goal of this research project is to gain insight into the metabolic differences responsible for the excess weight gain associated with the CREBRF variant. Based on our observations that overexpression of the missense variant promotes lipid storage and reduces energy substrate oxidation (decreased mitochondrial respiration) in an adipocyte model, our hypothesis is that a lower resting metabolic rate (RMR) is involved. Supporting a relationship between low mitochondrial respiration and low RMR, we recently observed that lower skeletal muscle mitochondrial respiration is associated with lower RMR in African American women (AAW). In addition, we recently demonstrated lower intervention induced weight loss in AAW compared to Caucasian women due to a lower RMR, leading to lower energy requirements. Based on these observations, and the fact that the majority of genes known to contribute to human obesity do so primarily by influencing the central control of energy intake and/or expenditure, we propose to determine the role that energy expenditure (EE) and energy intake (EI) play in the increased obesity risk in the Samoan population associated with the CREBRF missense variant. Based on our long-term experience working with obesity and health risks in the Samoan population, combined with our extensive experience assessing energy and substrate metabolism, our research team is ideally positioned to conduct these studies. We propose a longitudinal study to define the impact of the variant on energy balance in human subjects with zero, one, or two copies of the risk allele to address the following three specific aims: 1) to determine the components of EE and substrate metabolism [RMR; TEF, thermic effect of food; total EE; RQ, substrate utilization; and PA, physical activity] using gold standard methods that include doubly-labeled water (DLW), indirect calorimetry, and objective activity monitoring; 2) to determine EI using the gold standard method of DLW intake balance technique; and 3) to determine the relationship between energy metabolism and weight gain by comparing the above energy metabolism parameters and weight gain over 24-36 months. In the applicants opinion the proposed studies will provide novel, and significant insight into the metabolic differences responsible for the excess weight gain in those with the CREBRF variant, which in turn plays a significant role in the extreme prevalence of obesity in Samoa. This research will advance the understanding, prevention, and appropriate treatment of obesity and heart diseases in this high risk population.