Systems genetics to identify neuronal genes for diet-induced obesity

系统遗传学识别饮食引起的肥胖的神经元基因

基本信息

批准号：
10646341
负责人：
Leah Catherine Solberg Woods
金额：
$ 58.66万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646341
关键词：
Accounting Adolescence Adolescent obesity Affect Animal Model Behavior Body Composition Body Weight Brain Brain Mapping Brain region Candidate Disease Gene Central Nervous System Childhood Chromosome Mapping Complex Consumption Data Dependovirus Diet Disease Dissection Eating Energy Metabolism Environment Exposure to Fasting Fat-Restricted Diet Fatty acid glycerol esters Food Energy Future Gene Expression Genes Genetic Genetic Techniques Genome Genomic Segment Genomics Genotype Glucose Glucose Intolerance Health Heritability High Fat Diet Hippocampus Human Human Genome Hypothalamic structure Inbreeding Insulin Insulin Resistance Laboratories Life Style Maps Measures Mediation Metabolic Metabolic Diseases Metabolism Modeling Neurons Obesity Obesity Epidemic Outcome Overweight Pathway Analysis Pathway interactions Phenotype Physiological Play Population Predisposition Prevalence Quantitative Trait Loci Rattus Regulation Research Design Risk Factors Rodent Model Role Running System Testing Tissues Transcript Work brain tissue candidate identification diet-induced obesity dietary control family structure gene function gene network genetic makeup genome sequencing genome wide association study genomic locus glucose tolerance insulin sensitivity knock-down new therapeutic target novel obesity in children obesogenic overexpression response tool trait transcriptome transcriptome sequencing whole genome

项目摘要

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.

项目概要肥胖是一种复杂的疾病，受遗传和环境的影响。目前美国三分之一以上人口肥胖，并且儿童和青少年的肥胖患病率正在增加。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，基因构成影响我们如何对饮食的反应（例如，并非所有高脂肪饮食 (HF) 的人都会变得肥胖）和人类全基因组关联研究指出大脑是影响肥胖的主要组织。毫不奇怪，大脑功能也受饮食改变和遗传影响。了解饮食和遗传学之间的相互作用，包括其在影响大脑功能、肥胖和代谢健康方面的作用对于理解这一点至关重要潜在的生理机制。在人群中进行此类研究具有挑战性。这这项工作的中心前提是基因构成影响对肥胖环境的反应，例如高频饮食，大脑的调节功能在这种反应中起着重要作用。我们的实验室使用远交大鼠模型，异质种（HS）大鼠，用于肥胖性状的遗传图谱。 HS大鼠是通过组合八种近交创始人品系并以尽量减少近交的方式维持它们而创建。我们已经证明，肥胖在 HS 中是可遗传的，并且有精细的遗传位点图谱，并鉴定了两者导致肥胖的新的和已知的基因。与人类 GWAS 类似，我们拥有的许多基因确定了大脑中改变肥胖的行为。我们的初步数据表明一些 HS 大鼠受到保护对抗高频饮食的负面后果，这可能是由遗传驱动的。目前的提案着手利用 HS 大鼠来了解基因组、饮食和大脑转录组之间的相互作用。整体假设是基因组成影响 HS 大鼠对饮食引起的肥胖的易感性，这是，部分是由改变大脑转录组驱动的。在目标 1 中，我们将识别受保护的基因位点 HS 大鼠中饮食诱导的肥胖（或易感性）。在目标 2 中，我们将识别大脑的变化（特别是下丘脑和海马）对高频饮食的反应以及大脑转录组图谱与饮食相互作用的变化可驱动 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并影响肥胖。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 试验进行比较，以确定高优先级然后使用腺相关病毒过度表达或敲低来验证候选基因，然后进行表型分析以开始了解潜在的基因功能。我们预计这项工作不会仅揭示了导致保护免受心力衰竭饮食负面影响的遗传驱动因素，但会还阐明了饮食、基因组和大脑转录组之间的相互作用在改变代谢健康方面的作用。由于该提案的重点是中枢神经系统，因此我们预计其中许多驾驶员将作为影响人类行为的新治疗靶点，这是肥胖流行病的一个核心特征。