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率背后的原因的理解存在根本性的差距， 萨摩亚是地球仪观测到的最高的国家之一。超过80%的萨摩亚成年人超重或 在美属萨摩亚，严重肥胖的妇女比例达到惊人的33%。在一个全基因组的 关联研究我们最近发现了一个新的错义变体（p.Arg457Gln，次要等位基因频率0.259） CREB 3调节因子（CREBRF）与BMI高度相关，其效应量大于任何 已知的常见BMI风险变量。本研究项目的总体目标是深入了解代谢 与CREBRF变体相关的过度体重增加的差异。基于我们 观察到错义变体的过表达促进脂质储存并减少能量底物， 在脂肪细胞模型中，我们的假设是，较低的静息氧化（线粒体呼吸减少） 代谢率（RMR）。支持低线粒体呼吸和低 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 非裔美国人（AAW）此外，我们最近证明了较低的干预诱导体重 与白人女性相比，由于RMR较低，AAW损失，导致能量需求较低。 基于这些观察，以及大多数已知导致人类肥胖的基因确实 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）在萨摩亚人肥胖风险增加中的作用 与CREBRF错义变体相关的人群。基于我们长期与 萨摩亚人口的肥胖和健康风险，结合我们评估能源的丰富经验， 和底物代谢，我们的研究团队是进行这些研究的理想选择。 我们提出了一项纵向研究，以确定变异对人类受试者能量平衡的影响， 零、一或两个拷贝的风险等位基因，以解决以下三个具体目标：1）确定 EE组分和底物代谢[RMR; TEF，食物热效应;总EE; RQ，底物 利用率;和PA，体力活动]使用金标准方法，包括双标记水（DLW）， 间接量热法和客观活性监测; 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的关系 通过比较24-36个月以上的上述能量代谢参数和体重增加来确定体重增加。在 申请人认为，所提出的研究将提供对代谢差异的新颖且重要的见解， 导致CREBRF变异的人体重增加过多，而CREBRF变异又在 萨摩亚肥胖症的极端流行。这项研究将促进对疾病的理解、预防和 在这一高风险人群中进行适当的肥胖和心脏病治疗。

项目成果

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
• 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

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

评估高血压转介对成人萨摩亚人2010- 2019年的高血压意识和管理，BMI和血压值的影响。

• DOI: 10.1080/03014460.2020.1822914
• 发表时间: 2020-12
• 期刊: Annals of human biology
• 影响因子: 1.7
• 作者: Rivara AC;Pomer A;Naseri T;Reupena MS;Viali S;Choy CC;McGarvey ST;Hawley NL
• 通讯作者: Hawley NL

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