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

肥胖风险 CREBRF p.Arg457Gln 变异对萨摩亚人能量消耗、摄入和底物利用的影响

基本信息

批准号：
10089476
负责人：
James P DeLany
金额：
$ 74.88万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10089476
关键词：
Address Adherence Adipocytes Adult Affect African American Alleles American Samoa Basal metabolic rate Behavior Therapy Biological Body Composition Body Weight Body Weight decreased Body fat Body mass index CREB3 gene Caucasians Cell model Child Data Detection Dual-Energy X-Ray Absorptiometry Energy Intake Energy Metabolism Equilibrium Expenditure Fatty acid glycerol esters Food Gene Frequency Genes Goals Gold Health Heart Diseases High Prevalence Homeostasis Human Indirect Calorimetry Individual Intake Intervention Knowledge Lipids Longitudinal Studies Measures Metabolic Metabolism Methodology Methods Minor Mission Mitochondria Modeling Monitor Morbid Obesity Muscle Mitochondria Obesity Other Genetics Outcome Overweight Participant Pathogenesis Pathway interactions Pattern Phosphotransferases Physical activity Play Population Positioning Attribute Prevalence Prevention Prevention strategy Properdin Public Health Research Research Project Grants Respiration Risk Role Samoa Samoan Skeletal Muscle Techniques United States National Institutes of Health Variant Water consumption Weight Weight Gain Woman base doubly-labeled water energy balance excessive weight gain experience genetic variant genome wide association study high risk high risk population human subject improved insight novel obesity risk obesity treatment overexpression overweight adults oxidation risk variant total energy expenditure translational impact

项目摘要

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.

项目概要我们对肥胖高发背后的原因的理解存在根本差距萨摩亚是全球观测到的最高温度之一。超过 80% 的萨摩亚成年人超重或肥胖，美属萨摩亚女性的严重肥胖率高达 33%，令人震惊。在全基因组范围内关联研究中，我们最近发现了一种新的错义变异（p.Arg457Gln，次要等位基因频率 0.259） CREB3 调节因子 (CREBRF) 与 BMI 高度相关，其效应大小大于任何已知的常见 BMI 风险变异。该研究项目的总体目标是深入了解代谢差异导致与 CREBRF 变异相关的体重过度增加。基于我们的观察发现错义变体的过度表达促进脂质储存并减少能量底物脂肪细胞模型中的氧化（线粒体呼吸减少），我们的假设是，较低的静息状态涉及代谢率（RMR）。支持低线粒体呼吸和低线粒体呼吸之间的关系 RMR，我们最近观察到较低的骨骼肌线粒体呼吸与较低的 RMR 相关非洲裔美国女性 (AAW)。此外，我们最近证明了干预引起的体重降低与白人女性相比，由于 RMR 较低，AAW 有所下降，从而导致能量需求较低。基于这些观察结果，以及大多数已知导致人类肥胖的基因确实因此，我们建议主要通过影响能量摄入和/或支出的中央控制来确定能量消耗（EE）和能量摄入（EI）在萨摩亚人肥胖风险增加中所起的作用与 CREBRF 错义变异相关的人群。根据我们长期合作的经验萨摩亚人口的肥胖和健康风险，结合我们评估能量的丰富经验和底物代谢，我们的研究团队非常适合进行这些研究。我们提出了一项纵向研究来定义该变异对人类受试者能量平衡的影响零、一个或两个风险等位基因副本，以实现以下三个具体目标：1) 确定 EE 和底物代谢的组成部分 [RMR; TEF，食物的热效应；总能量效率； 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动监测； 2）使用金标准方法确定EI DLW摄入平衡技术； 3）确定能量代谢与体重之间的关系通过比较上述能量代谢参数和 24-36 个月内的体重增加来获得增益。在申请人认为拟议的研究将为代谢差异提供新颖且重要的见解导致 CREBRF 变异体体重过度增加的原因，这反过来又起着重要作用萨摩亚的肥胖症极其普遍。这项研究将促进人们的理解、预防和对这一高危人群的肥胖和心脏病进行适当的治疗。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human biology of the Pacific.

DOI：
10.1080/03014460.2018.1477483
发表时间：
2018-05
期刊：
Annals of human biology
影响因子：
1.7
作者：
Hawley NL;McGarvey ST
通讯作者：
McGarvey ST

Nonmydriatic fundus photography in a high-risk population of Samoans with diabetes: The Soifua Manuia eye screening program.

萨摩亚糖尿病高危人群的免散瞳眼底摄影：Soifua Manuia 眼部筛查计划。

DOI：
10.1111/ceo.13527
发表时间：
2019
期刊：
Clinical & experimental ophthalmology
影响因子：
4
作者：
LaMonica,LaurenC;Hawley,NicolaL;Bhardwaj,MaheshK;Naseri,Take;Reupena,MuagatutiaS;Ramsey,DavidJ
通讯作者：
Ramsey,DavidJ

Association between age at menarche and cardiometabolic risk among Samoan adults.

萨摩亚成年人初潮年龄与心脏代谢风险之间的关联。

DOI：
10.1002/ajhb.23982
发表时间：
2024
期刊：
American journal of human biology : the official journal of the Human Biology Council
影响因子：
0
作者：
Oyama,Sakurako;Duckham,RachelL;Pomer,Alysa;Rivara,AnnaC;Kershaw,ErinE;Wood,Ashlee;Fidow,UlaiT;Naseri,Take;Reupena,MuagututiaS;Viali,Satupaitea;McGarvey,StephenT;Hawley,NicolaL
通讯作者：
Hawley,NicolaL

Remote Screening for Optic Nerve Cupping Using Smartphone-based Nonmydriatic Fundus Photography.

DOI：
10.1097/ijg.0000000000001680
发表时间：
2021-01-01
期刊：
Journal of glaucoma
影响因子：
2
作者：
LaMonica LC;Bhardwaj MK;Hawley NL;Naseri T;Reupena MS;Cooper ML;Cotran PR;Roh S;Ramsey DJ
通讯作者：
Ramsey DJ

Assessing the impact of high blood pressure referrals on hypertension awareness and management, BMI, and blood pressure values in adult Samoans 2010-2019.