Diet Composition and Spontaneous Physical Activity in a Zebrafish Obesity Model

斑马鱼肥胖模型中的饮食组成和自发身体活动

• 批准号: 7258232
• 负责人: JAY Robert HOVE
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258232
• 关键词: Adult; Affect; Animal Model; Arts; Behavioral; Biological Models; Body Weight; Body fat; Brain; Candidate Disease Gene; Cause of Death; Collaborations; Consumption; Custom; Deposition; Development; Diet; Dietary Fats; Disease; Eating; Economics; Energy Intake; Energy Metabolism; Environment; Exercise; Expenditure; Exposure to; Failure; Fat-Restricted Diet; Fatty acid glycerol esters; Fertility; Fishes; Gene Expression Regulation; Generations; Genes; Genetic; Harvest; Healthcare Systems; Homologous Gene; Human; Indirect Calorimetry; Intake; Libraries; Life; Mammals; Measures; Metabolic; Metabolism; Metric; Microarray Analysis; Modeling; Monitor; Motion; Obesity; Obesity associated disease; Pathway interactions; Phenotype; Physical activity; Population; Prevalence; Principal Investigator; Rate; Regulation; Research; Research Design; Research Personnel; Resistance; Rest; Rodent; System; Technology; Testing; Therapeutic Intervention; Thermogenesis; Time; Tissue Extracts; Transcript; Treatment Protocols; United States; Weight Gain; Zebrafish; base; brain tissue; cDNA Library; cost; energy balance; fight against; increased appetite; pandemic disease; programs; response; social

DESCRIPTION (provided by applicant): Obesity is the leading cause of death in the United States affecting nearly one-third of our adult population and costing our healthcare system approximately $100 billion and yet the exact genetic and metabolic mechanisms of this pandemic disease remain unclear. To date, non-mammalian model systems have been largely ignored in this regard despite having short generation times, high fecundity and genetic tractability. We propose that the zebrafish is an optimal model system in which to identify the pathways regulating obesity-related phenotypes so that new targets for potentially life-saving treatments can be made available. We intend to use zebrafish to physiologically and genetically characterize the most important determinent of energy expenditure, spontaneous physical activity (SPA). We will take advantage of the absence of resting thermogenesis in the poikilothermic zebrafish to quantify their SPA (through videotracking analyses) and associated metabolic rates (via indirect calorimetry) and demonstrate their correlation with body fat levels. The propensity of fish possessing low levels of SPA to develop an obese phenotype will be demonstrated by exposing them, and their high SPA counterparts, to either high-fat, low-fat or control diets. As a result, diet-sensitive and diet-resistant fish, as well as those which change SPA in response to altered dietary fat intake, will be identified. Baseline and diet-induced changes in SPA will then be correlated with changes in routine metabolism and body fat mass. Finally, we will identify candidate genes that regulate SPA by creating a custom zebrafish brain cDNA library enriched in transcripts for our obesity-related phenotype by subtractive suppression hybridization. Brain tissue will be harvested from zebrafish with low or high SPA levels before and after exposure to the hypercaloric diet. Activity-based regulation of genes in the library will be confirmed by microarray analysis. In this way we will identify genes that are responsible for high or low baseline levels of SPA as well those genes controlling an appropriate increase in SPA as a result of exposure to a high dietary fat environment. Despite its wide-spread occurrence and tremendous cost to our national healthcare system, the precise genetic and metabolic causes of obesity remain undefined. We will take advantage of a suite of state-of-the-art technologies and a unique collaboration between key investigators at UC-GRI to make significant progress towards establishing zebrafish as a unique model organism for studying obesity and to use this system to expedite the search for homologues responsible for fat deposition in mammals, including humans.

描述（由申请人提供）：肥胖是美国影响我们成年人口的近三分之一的主要死因，使我们的医疗保健系统造成约1000亿美元，但这种流行病的确切遗传和代谢机制尚不清楚。迄今为止，尽管生成时间短，繁殖力和遗传性障碍，但在这方面，非哺乳动物模型系统在这方面已被忽略。我们建议斑马鱼是一种最佳模型系统，可以在其中识别调节与肥胖相关表型的途径，以便可以提供潜在的挽救生命治疗的新目标。我们打算在生理和遗传上使用斑马鱼来表征能量消耗，自发体育锻炼（SPA）的最重要的决定。我们将利用斑马斑马鱼中缺乏静息生热来量化其水疗中心（通过录像带分析）和相关的代谢率（通过间接量热法），并证明了它们与体内脂肪水平的相关性。通过将其暴露于高脂，低脂或对照饮食的高水疗中心，可以证明拥有低水平的水疗中心发展肥胖表型的鱼类的倾向。结果，将确定对饮食敏感和耐饮食敏感的鱼类，以及随着饮食脂肪摄入改变而改变水疗中心的鱼类。然后，基线和饮食引起的水疗中心变化将与常规代谢和体内脂肪量的变化相关。最后，我们将通过创建一个自定义的斑马鱼脑cDNA文库来鉴定调节水疗的候选基因，该脑cDNA文库通过减法抑制杂交富含转录本中的转录本。暴露于高平热饮食之前和之后，将从斑马鱼中收获脑组织。基于活性的基因在库中的调节将通过微阵列分析确认。通过这种方式，我们将确定负责高或低基线水疗水平的基因，以及那些由于暴露于高饮食脂肪环境而控制水疗中心的基因。尽管我们的国家医疗保健系统的发生量很大，而且巨大的成本，但肥胖的确切遗传和代谢原因仍然不确定。我们将利用一套最先进的技术和UC-GRI的主要研究人员之间的独特合作，以取得重大进展，以建立斑马鱼作为研究肥胖症的独特模型生物体，用于研究肥胖症，并使用该系统加快对包括人类在内的哺乳动物（包括人类）的脂肪沉积负责的同源物进行搜索。