Genetics of Macronutrient Selection and Energy Balance

描述（由申请人提供）：我们开发了一种独特的实验系统，以确定大量营养素选择和能量摄入的遗传决定因素，饮食行为对肥胖表型的发展至关重要。以前，我们确定了第一个遗传基因座在小鼠控制复杂性状（数量性状基因座或QTL）的脂肪，碳水化合物，总热量摄入量的映射人口C57 BL/6 J（B6）x CAST/Ei（CAST）小鼠近交系，选择他们的优先消费的脂肪或碳水化合物，分别。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，具有CAST供体片段的B6遗传背景上的同源菌株已确认了一个Chr 17 QTL，该QTL指定了两个原始的连锁性状：Mnic 1（大量营养素摄入量-碳水化合物）和Kcal 2（千卡摄入量）。具体而言，与同窝B6对照组相比，该同类品系每体重摄入的碳水化合物和总热量明显更多，但脂肪量相似。重要的是，这种同源间隔也赋予了增加体力活动的表型。我们假设17号染色体上的QTL由（a）决定食物摄入和自发体力活动的单个基因位点编码，或者由（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，行为性状的致病基因位于与转录调控基因共定位的Chr 17同源片段内的QTL（cis eQTL）中。因此，在本申请中，我们提出：1）通过在同源受体F2杂交中对营养摄入的已知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QTL内的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基因型与定制的低密度基因阵列相结合，以及3）通过确定基因候选物的序列、表达和功能，基于它们的位置和转录调控（eQTL）来表征从精细定位的QTL区域选择的基因候选物。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产热的分子机制。公共卫生相关性：该研究项目已经确定了基因与脂肪和碳水化合物的饮食偏好以及总卡路里摄入量的联系。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和控制食物摄入的遗传因素之间的关系。发现与这些特征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至关重要。

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.