Genetics of Macronutrient Selection and Energy Balance

描述（由申请人提供）：我们已经开发了一个独特的实验系统，以确定对肥胖表型发展至关重要的宏量营养素选择和能量摄入的遗传决定因素。在此之前，我们在定位群体C57BL/6J (B6) x CAST/Ei （CAST）小鼠自交系中发现了第一个控制脂肪、碳水化合物和总热量摄入的复杂性状（数量性状位点或QTL）的基因座，这些小鼠分别因偏好脂肪或碳水化合物而被选择。接下来，我们开发同源菌株以获得连锁的独立证据，更精确地确定位点，并帮助鉴定潜在基因。随后，一个具有B6遗传背景的CAST供体片段的同源菌株证实了一个Chr 17 QTL，该QTL指定了两个原始的相关性状：Mnic1（常量营养素摄入量-碳水化合物）和Kcal2（千卡摄入量）。具体来说，与B6对照组相比，这一基因菌株摄入的碳水化合物和每体重总热量明显更多，但脂肪含量相似。重要的是，这个基因间隔也赋予了身体活动增加的表型。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身体活动的单个基因位点编码，要么由(b)两个或更多基因编码，每个基因决定能量平衡的一个亚表型。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（顺式eqtl）共定位的Chr 17同源片段内的QTL中。因此在目前的申请中，我们提出：1)通过受体F2杂交对已知营养摄入QTL进行精细结构遗传定位，确定Chr 17 QTL中负责营养摄入和身体活动表型的遗传区域。2)通过将同源F2基因型与定制的低密度基因阵列相结合，确定精细定位的QTL中哪些基因表现出与行为表型（即eQTL）分离的表达模式。3)根据定位和转录调控（eqtl），从精细定位的QTL区域中选择候选基因，通过确定候选基因的序列、表达和功能，对候选基因进行鉴定。本研究的长期目标是确定在能量平衡控制中调节食物摄入和活动诱导产热的分子机制。公共健康相关性：该研究项目已经确定了与脂肪和碳水化合物的饮食偏好以及总卡路里摄入量的遗传联系。我们已经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。发现与这些特征有关的基因对于理解导致肥胖的饮食行为的潜在机制以及能量平衡的控制具有重要意义。

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.