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

• 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
• 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

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.

项目摘要 我们对肥胖症高流行的原因的理解存在根本的差距 萨摩亚（Samoa），这是全球观察到的最高的之一。超过80％的萨摩亚成年人超重或 肥胖，在美国萨摩亚的女性中，严重的肥胖症达到33％。在全基因组中 协会研究我们最近确定了一种新型的错义变体（P.Arg457GLN，次要等位基因频率0.259） 在与BMI高度相关的CREB3调节因子（CREBRF）中，效果大小大于任何 已知的普通BMI风险变体。该研究项目的总体目标是深入了解代谢 导致与Crebrf变体相关的过量体重增加的差异。基于我们 观察到过表达错义变体可促进脂质存储并减少能量底物 在脂肪细胞模型中氧化（线粒体呼吸减少），我们的假设是较低的静止 涉及代谢率（RMR）。支持低线粒体呼吸与低点之间的关系 RMR，我们最近观察到较低的骨骼肌线粒体呼吸与较低的RMR有关 在非洲裔美国妇女（AAW）中。此外，我们最近证明了较低的干预诱导体重 与较低的RMR相比，AAW的损失与高加索妇女相比，导致能源需求较低。 基于这些观察结果，以及大多数已知有助于人类肥胖的基因的事实 因此，主要是通过影响能量摄入和/或支出的中心控制的，我们建议确定 能源消耗（EE）和能量摄入量（EI）在萨摩亚人肥胖风险增加的作用 与Crebrf错义变体相关的人群。根据我们与之合作的长期经验 萨摩亚人口中的肥胖和健康风险，加上我们评估能源的丰富经验 和底物代谢，我们的研究团队在进行这些研究方面有好处。 我们提出了一项纵向研究，以定义变体对人类受试者能量平衡的影响 零，一两份风险等位基因的副本，以解决以下三个特定目的：1）确定 EE和底物代谢的成分[RMR; tef，食物的热效应；总EE； RQ，基板 利用；和PA，体育活动]使用包括双标记水（DLW）的黄金标准方法， 间接量热法和客观活动监测； 2）使用黄金标准方法确定EI DLW进气平衡技术； 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并在24-36个月内比较体重增加来获得。在 申请人的意见拟议的研究将为新陈代谢差异提供新颖和重大的见解 负责Crebrf变体的人的体重增加，这反过来起着重要作用 在萨摩亚肥胖的极端流行中。这项研究将提高理解，预防和 在这种高风险人群中，适当治疗肥胖和心脏病。

项目成果

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

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
• 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

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

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

Cascades of diabetes and hypertension care in Samoa: Identifying gaps in the diagnosis, treatment, and control continuum - a cross-sectional study.

• DOI: 10.1016/j.lanwpc.2021.100313
• 发表时间: 2022-01
• 期刊: The Lancet regional health. Western Pacific
• 作者: LaMonica LC;McGarvey ST;Rivara AC;Sweetman CA;Naseri T;Reupena MS;Kadiamada H;Kocher E;Rojas-Carroll A;DeLany JP;Hawley NL
• 通讯作者: Hawley NL