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Genetics of Macronutrient Selection and Energy Balance

大量营养素选择和能量平衡的遗传学

基本信息

批准号：
8327462
负责人：
BRENDA K SMITH RICHARDS
金额：
$ 3.2万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-08-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8327462
关键词：
Affect Animal Model Award Behavioral Biological Body Weight CAST/Ei Mouse Calories Candidate Disease Gene Carbohydrates Chromosome Mapping Chromosomes, Human, Pair 17 Complex Congenic Mice Congenic Strain Consumption Control Locus Custom Development Diet Eating Eating Behavior Energy Intake Energy Metabolism Exhibits Fatty acid glycerol esters Food Intake Regulation Funding Genes Genetic Genetic Determinism Genotype Goals Grant Inbred Strain Intake Lactoylglutathione Lyase Lead Link Location Macronutrients Nutrition Maps Molecular Mus Nutrient Obesity Oxidants Pathway interactions Pattern Phenotype Physical activity Population Quantitative Trait Loci Research Project Grants Rest Specific qualifier value Structure System Thermogenesis Tissues Transcriptional Regulation base carbohydrate metabolism congenic density energy balance gene discovery gene function gene interaction lipid metabolism preference public health relevance tool trait

项目摘要

DESCRIPTION (provided by applicant): We have developed a unique experimental system to identify the genetic determinants of macronutrient selection and energy intake, eating behaviors fundamental to the development of obesity phenotypes. Previously we identified the first genetic loci in mouse controlling complex traits (quantitative trait loci or QTL) for fat, carbohydrate, and total calorie intake in mapping population C57BL/6J (B6) x CAST/Ei (CAST) mouse inbred strains, selected for their preferential consumption of fat or carbohydrate, respectively. Next we developed congenic strains to obtain independent evidence for linkage, to determine the locus more precisely, and to aid in identification of the underlying gene(s). Subsequently, a congenic strain possessing a CAST donor segment on the B6 genetic background has confirmed a Chr 17 QTL that specified two of the original, linked traits: Mnic1 (macronutrient intake-carbohydrate) and Kcal2 (kilocalorie intake). Specifically, this congenic strain eats significantly more carbohydrate and total calories per body weight, yet a similar amount of fat, compared with littermate B6 controls. Importantly, this congenic interval also confers a phenotype of increased physical activity. We hypothesize that the QTL on Chromosome 17 is either encoded by (a) a single gene locus that determines both food intake and spontaneous physical activity, or by (b) two or more genes, each determining a sub-phenotype of energy balance. A further hypothesis is that the causal gene(s) for the behavioral traits is located in a QTL within the Chr 17 congenic segment that co-localizes with transcriptionally regulated genes (cis eQTLs). Therefore in the current application, we propose: 1) To resolve the genetic regions responsible for nutrient intake and physical activity phenotypes in the Chr 17 QTL, through fine structure genetic mapping of known QTLs for nutrient intake in a congenic by recipient F2 cross, 2) To determine which genes within the fine mapped QTL exhibit expression patterns that segregate with the behavioral phenotype(s) (i.e., eQTL), by combining the congenic F2 genotypes with custom low density gene arrays, and 3) To characterize gene candidates selected from the fine mapped QTL region(s) based on their location and transcriptional regulation (eQTLs) by determining their sequence, expression and function. The long-term goal of the proposed studies is to identify the molecular mechanisms regulating food intake and activity-induced thermogenesis in the control of energy balance. Public Health Relevance: This research project has identified genetic links to dietary preferences for fat and carbohydrate, and to total calorie intake. We have developed a new animal model to study the relationship between the genetic factors responsible for physical activity and those controlling food intake. Discovering genes that are involved in these traits is of major importance toward understanding the mechanisms underlying eating behaviors that lead to obesity, and the control of energy balance.

描述（由申请人提供）：我们开发了一个独特的实验系统，以确定大量营养素选择和能量摄入的遗传决定因素，以及对肥胖表型发展至关重要的饮食行为。此前，我们在绘制群体 C57BL/6J (B6) x CAST/Ei (CAST) 小鼠近交系中确定了控制脂肪、碳水化合物和总热量摄入的复杂性状（数量性状位点或 QTL）的小鼠中的第一个遗传位点，分别选择其优先消耗脂肪或碳水化合物。接下来，我们开发了同源菌株以获得连锁的独立证据，更精确地确定基因座，并帮助识别潜在的基因。随后，在 B6 遗传背景上拥有 CAST 供体片段的同源菌株证实了 Chr 17 QTL，该 QTL 指定了两个原始的连锁性状：Mnic1（大量营养素摄入量-碳水化合物）和 Kcal2（千卡摄入量）。具体来说，与同窝 B6 对照组相比，这种同类品系每体重摄入的碳水化合物和总热量明显更多，但脂肪含量相似。重要的是，这种同类间隔还赋予体力活动增加的表型。我们假设 17 号染色体上的 QTL 要么由 (a) 决定食物摄入和自发体力活动的单个基因位点编码，要么由 (b) 两个或多个基因编码，每个基因决定能量平衡的亚表型。进一步的假设是，行为特征的因果基因位于 Chr 17 同源片段内的 QTL 中，该 QTL 与转录调节基因 (cis eQTL) 共定位。因此，在当前的申请中，我们建议：1）通过对受者F2同源杂交中已知的营养摄入QTL进行精细结构遗传作图，解析Chr 17 QTL中负责营养摄入和身体活动表型的遗传区域，2）确定精细作图的QTL中哪些基因表现出与行为表型分离的表达模式（即， eQTL)，通过将同源 F2 基因型与定制低密度基因阵列相结合，以及 3) 通过确定其序列、表达和功能，根据其位置和转录调控 (eQTL) 来表征从精细作图的 QTL 区域中选择的基因候选物。拟议研究的长期目标是确定在控制能量平衡中调节食物摄入和活动诱导生热的分子机制。公共健康相关性：该研究项目已确定与脂肪和碳水化合物饮食偏好以及总热量摄入之间的遗传联系。我们开发了一种新的动物模型来研究负责身体活动的遗传因素与控制食物摄入的遗传因素之间的关系。发现与这些性状相关的基因对于理解导致肥胖的饮食行为的机制以及能量平衡的控制非常重要。