Obesity Genes, Energy Regulation in Response to Weight-Loss Diets

肥胖基因、减肥饮食的能量调节

• 批准号: 8464087
• 负责人: Lu Qi
• 金额: $ 48.2万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464087
• 关键词: Accounting; Address; Adipose tissue; Affect; Automobile Driving; Basal metabolic rate; Biochemical Markers; Biological Markers; Biopsy; Blood; Body Composition; Body Weight Changes; Body Weight decreased; Brain; Carbohydrates; Clinical; Clinical Trials; Clinical effectiveness; Cohort Studies; Computer Simulation; DNA; Desire for food; Diet; Dietary Factors; Dietary Intervention; Eating Behavior; Energy Intake; Energy Metabolism; Environment; Epidemic; Fat-Restricted Diet; Fatty acid glycerol esters; Framingham Heart Study; Funding; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genome Scan; Glucose; Goals; Grant; Health Professional; Hepatic; Heritability; Human; Hunger; Individual; Insulin; Intervention; Intervention Studies; Intervention Trial; Label; Left; Leptin; Life Style; Link; Macronutrients Nutrition; Measures; Metabolic; Metabolic Diseases; Methods; Nurses' Health Study; Obesity; Participant; Pathway interactions; Patient Care; Pharmacologic Substance; Prevention; Public Health; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Regulation; Resistance; Resources; Sampling; Satiation; Skeletal Muscle; Solid; System; Time; United States; Validation; Variant; Visceral; Water; Weight; Woman; adiponectin; base; cohort; cost; cost effective; energy balance; experience; follow-up; food craving; genetic epidemiology; genetic variant; genome wide association study; ghrelin; glucagon-like peptide 1; high risk; improved; insight; lifestyle factors; men; novel; nutrition; obesity prevention; obesity treatment; response; statistics; woman health professional

DESCRIPTION (provided by applicant): Obesity has become an epidemic in the United States and worldwide. During the past few years, genome-wide association studies (GWAS) have identified ~50 loci for obesity. However, those loci only account for small proportion (<5%) of the heritability of obesity, and the current GWAS have given us little insight into how these genetic variants are linked with obesity, and how they may response to environment (diet and lifestyle) modulation. The goal of this study is to address these GWAS limitations to provide further insights into a system-based understanding of the genetics of obesity. We propose to apply newly-developed pathway-based analysis by combining functional pathways, genetics of gene expression (GGE) analysis, and genome scans to identify novel obesity loci beyond conventional GWAS, in 11,577 men and women from the Nurses' Health Study (NHS) and Health Professionals' Follow-up Study (HPFS) with genome scans. The in silico validation will be performed in Framingham Heart Study (N=9,171) and GIANT consortium (N=121,600). We will determine the newly-identified and the established obesity variants in 811 individuals from a 2-year randomized diet intervention study, the POUNDS LOST trial. We will examine genetic effects on the 2-year weight changes in response to weight-loss diets varying in macronutrient compositions. The validation will be conducted in a separately-funded 2-year weight-loss trial, the Dietary Intervention Randomized Controlled Trial (DIRECT, n=322). We will also assess the genetic effects on the markers regulating energy intake and energy expenditure, including: 1) psychiatric measures for food craving, fullness, and hunger; 2) energy expenditure (resting metabolic rate [RMR] and total energy expenditure [TEE]); 3) biochemical markers of brain-gut- adipose axis, including leptin, insulin, glucose, ghrelin, GLP-1, adiponectin and RBP4; and 4) adipose gene expression profile. Because the genome-wide scans, diet intervention, and measures of energy intakes and expenditure, adipose gene expression, as well as body composition are funded through other grants, the proposed project will be extremely cost-effective. We have assembled a solid group of experienced collaborators with expertise in genetic epidemiology, statistics, pathway GGE analyses, clinical trial, obesity and nutrition. We believe that the unprecedented resources available in this project will provide a unique opportunity to identify novel genetic factors for obesity, and to get insights into the mechanisms of genetic and dietary factors in controlling long-term weight change in humans.

描述（由申请人提供）：肥胖已成为美国和全球的流行病。在过去的几年中，全基因组关联研究（GWAS）已确定约50个基因座的肥胖基因座。但是，这些基因座仅占肥胖症的遗传力的小比例（<5％），而当前的GWAS对这些遗传变异如何与肥胖相关，以及它们如何应对环境（饮食和生活方式）调节。这项研究的目的是解决这些GWAS的限制，以进一步了解基于系统的肥胖遗传学的理解。我们建议通过将功能途径，基因表达（GGE）分析的遗传学（GGE）分析和基因组扫描相结合，以鉴定来自常规GWA的新型肥胖基因座，在常规GWAS之外进行新的肥胖基因座，在护士健康研究（NHS）的11,577名男性和女性中，以及卫生专业人员的随访研究（HPFS）与基因组的11,577名男性和女性，以识别新的肥胖基因座（HPFS）。在Framingham心脏研究（n = 9,171）和巨型联盟（n = 121,600）中，将进行计算机验证。我们将通过一项为期两年的随机饮食干预研究，损失试验，确定811名个人中的新鉴定和已建立的肥胖变体。我们将检查对大量营养素组合物变化的减肥饮食的2年体重变化的遗传作用。该验证将在单独资助的2年减肥试验中进行饮食干预随机对照试验（直接，n = 322）。我们还将评估对调节能量摄入和能量消耗的标志物的遗传作用，包括：1）食物渴望，丰满和饥饿的精神病学措施； 2）能量支出（静息代谢率[RMR]和总能量消耗[TEE]）； 3）脑粘脂蛋白轴的生化标志物，包括瘦素，胰岛素，葡萄糖，生长素蛋白，GLP-1，脂联素和RBP4； 4）脂肪基因表达谱。由于全基因组扫描，饮食干预以及能量摄入和支出的度量，脂肪基因表达以及身体成分是通过其他赠款资助的，因此拟议的项目将非常成本效益。我们组建了一组稳固的经验丰富的合作者，具有遗传流行病学，统计学，途径GGE分析，临床试验，肥胖和营养方面的专业知识。我们认为，该项目中可用的前所未有的资源将提供一个独特的机会，以识别肥胖症的新遗传因素，并了解控制人类长期体重变化的遗传和饮食因素的机制。