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.

项目摘要肥胖是一种复杂的疾病，受遗传学和环境的影响。目前超过三分之一的美国人口肥胖，儿童时期的肥胖症患病率正在增加。饮食和生活方式是肥胖的主要贡献者。最近的工作表明，遗传化妆会影响我们的方式对饮食的反应（例如，并非每个人都在高脂饮食（HF）中肥胖）和人类基因组关联研究将大脑视为影响肥胖症的主要组织。毫不奇怪，大脑功能是也因饮食而改变，受遗传学的影响。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至关重要潜在的生理机制。这样的研究在人群中的进行具有挑战性。这这项工作的主要前提是，遗传构成影响对肥胖环境的反应，例如 HF饮食，调节大脑功能在这一反应中起着重要作用。我们的实验室使用大鼠模型，异质种群（HS）大鼠，用于肥胖性状的遗传图。 HS大鼠是通过结合八个近交易所菌株并以最小化近交的方式维护它们而创建。我们已经表明，肥胖是在HS中遗传的，并且具有精细映射的遗传基因座，并确定了两者肥胖基础的新颖和已知基因。与人类GWA相似，我们拥有的许多基因确定在大脑中的作用以改变肥胖。我们的初步数据表明某些HS大鼠受到保护反对HF饮食的负面后果，这可能是由遗传学驱动的。当前的建议着手使用HS大鼠了解基因组，饮食和脑转录组之间的相互作用。总体假设是，遗传构成影响了HS大鼠饮食诱导的肥胖症的敏感性，这就是在某种程度上，由改变大脑转录组的驱动。在AIM 1中，我们将确定遗传基因座的保护基因座从（或易感性）到饮食引起的HS大鼠肥胖。在AIM 2中，我们将确定大脑的变化（特别是下丘脑和海马）响应HF饮食以及MAP脑转录组与饮食相互作用以驱动HS大鼠代谢结果的变化。我们还将创建基因网络应对饮食并影响肥胖。我们将使用各种统计和遗传技术，包括与人类基因组广泛关联研究和DietFits试验进行比较，以确定高优先级候选基因然后将使用腺相关病毒过表达或敲门验证，该基因将得到验证其次是表型开始理解潜在的基因功能。我们希望这项工作不会仅阐明遗传驱动因素，从而防止HF饮食的负面后果，但会还阐明了饮食，基因组和大脑转录组之间的相互作用，以改变代谢健康。因为该提议的重点是中枢神经系统，所以我们希望许多驱动程序将作为影响人类行为的新型治疗靶标，这是肥胖流行中的主要特征。