Systems genetics to identify neuronal genes for diet-induced obesity

项目摘要 肥胖是一种复杂的疾病，受遗传和环境的影响。目前超过三分之一的美国人 人口肥胖，儿童和青春期的肥胖率正在上升。饮食和生活方式是 环境因素是导致肥胖的主要因素。最近的研究表明，基因构成会影响我们 对饮食(例如，不是每个高脂肪饮食(HF)的人都会肥胖)和整个人类基因组做出反应 相关研究指出，大脑是影响肥胖的主要组织。毫不奇怪，大脑功能 也受饮食和遗传因素的影响。了解饮食和遗传学之间的相互作用， 包括它在影响大脑功能、肥胖症和新陈代谢健康方面的作用是理解 潜在的生理机制。这样的研究在人类群体中进行是具有挑战性的。这个 这项工作的中心前提是基因构成影响对肥胖环境的反应，例如 HF饮食，而大脑的调节功能在这种反应中起着主要作用。我们实验室使用了一种 异种系(HS)大鼠模型，用于肥胖性状的遗传作图。HS大鼠分别为 由8个近亲繁殖的创始人菌株组合而成，并以最大限度地减少近亲繁殖的方式保持它们。 我们已经证明肥胖症在HS中是可遗传的，并有精细的遗传基因座图，并确定了两者 导致肥胖的新的和已知的基因。与人类GWA相似，我们拥有的许多基因 在大脑中识别出改变肥胖症的行为。我们的初步数据表明，一些HS大鼠受到保护 反对HF饮食的负面后果，这可能是由基因驱动的。目前的提案 开始使用HS大鼠来了解基因组、饮食和大脑转录组之间的相互作用。整体而言 假设基因构成影响HS大鼠饮食诱导肥胖的易感性，这是， 这在一定程度上是通过改变大脑转录组来驱动的。在目标1中，我们将确定作为保护基础的遗传基因座 从(或易感性)饮食诱导的肥胖在HS大鼠。在目标2中，我们将确定大脑的变化 (特别是下丘脑和海马体)对HF饮食的反应以及对大脑转录组的映射 与饮食相互作用的变化，以推动HS大鼠的代谢结果。我们还将创建基因网络， 对饮食做出反应，影响肥胖。我们将使用各种统计和遗传技术，包括 与人类全基因组关联研究和DIETFITS试验的比较，以确定高优先级 然后将使用腺相关病毒过度表达或敲除来验证候选基因， 然后进行表型分析，以开始了解潜在的基因功能。我们预计这项工作将不会 只阐明了导致保护免受HF饮食负面后果的基因驱动因素，但将 还阐明了饮食、基因组和脑转录组之间在改变代谢健康方面的相互作用。 由于这项提议关注的是中枢神经系统，我们预计这些司机中的许多人将 作为新的治疗目标来影响人类行为，这是肥胖症流行的一个主要特征。

Project Summary Obesity is a complex disease, affected by genetics and the environment. Currently over one third of the US population is obese and obesity prevalence in childhood and adolescence is increasing. Diet and lifestyle are major environmental contributors to obesity. Recent work has shown that genetic make-up influences how we respond to diet (e.g., not everyone on a high fat diet (HF) becomes obese) and human genome-wide association studies point to the brain as the major tissue influencing obesity. Not surprisingly, brain function is also altered by diet and influenced by genetics. Understanding the interplay between diet and genetics, including its role in impacting brain function, adiposity, and metabolic health is essential for understanding underlying physiological mechanisms. Such studies are challenging to conduct in human populations. The central premise of this work is that genetic make-up influences response to obesogenic environments, such as a HF diet, and that regulatory brain function plays a major role in this response. Our laboratory uses an outbred rat model, heterogeneous stock (HS) rats, for genetic mapping of adiposity traits. HS rats were created by combining eight inbred founder strains and maintaining them in a way that minimizes inbreeding. We have shown that adiposity is heritable in the HS and have fine-mapped genetic loci and identified both novel and known genes that underlie adiposity. Similar to human GWAS, many of the genes we have identified act in the brain to alter adiposity. Our preliminary data indicates that some HS rats are protected against the negative consequences of a HF diet and that this is likely driven by genetics. The current proposal sets out to use HS rats to understand the interplay between genome, diet and brain transcriptome. The overall hypothesis is that genetic make-up influences susceptibility to diet-induced obesity in HS rats and that this is, in part, driven by altering the brain transcriptome. In Aim 1, we will identify genetic loci that underlie protection from (or susceptibility to) diet-induced obesity in HS rats. In Aim 2, we will identify changes in the brain (specifically hypothalamus and hippocampus) in response to a HF diet as well as map brain transcriptome changes that interact with diet to drive metabolic outcomes in HS rats. We will also create gene networks that respond to diet and influence adiposity. We will use a variety of statistical and genetic techniques, including comparison to human genome wide association studies and the DIETFITS trial, to identify high priority candidate genes which will then be verified using adeno-associated virus over-expression or knock-down, followed by phenotyping to begin to understand underlying gene function. We expect that this work will not only shed light on genetic drivers that lead to protection from the negative consequences of a HF diet, but will also elucidate interactions between diet, genome and brain transcriptome in altering metabolic health. Because this proposal is focused on the central nervous system, we expect that many of these drivers will serve as novel therapeutic targets to impact human behavior, a central feature in the obesity epidemic.