Hepatic mitochondrial function control of high-fat diet-induced weight gain

肝线粒体功能控制高脂饮食引起的体重增加

基本信息

批准号：
9751299
负责人：
E Matthew Morris
金额：
$ 15.82万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-08 至 2022-09-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751299
关键词：
5&apos -AMP-activated protein kinase 6-Phosphofructo-2-kinase Ablation Acute Adenine Nucleotides Adipose tissue American Brain Capsaicin Carbohydrates Cardiovascular Diseases Carnitine Palmitoyltransferase I Chemicals Chronic Communication Complex Data Development Plans Diet Eating Energy Intake Environment Fatty acid glycerol esters Feeding behaviors Food Energy Functional disorder Glucose Goals Hepatic Hepatitis B Virus Hepatocyte High Fat Diet Holidays Human Impairment Indirect Calorimetry Individual Liver Liver Mitochondria Macronutrients Nutrition Mediating Metabolic Metabolic Diseases Metabolism Mitochondria Molecular Mus Nerve Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Overweight Population Postdoctoral Fellow Rattus Regulation Research Respiratory physiology Role Route Scientist Seasons Signal Transduction Societies Sum System Techniques Testing Time Training Vagotomy Weight Weight Gain Wild Type Mouse Work career development energy balance experimental study fatty acid oxidation flexibility gain of function liver function liver metabolism mouse model neurophysiology obesogenic overexpression oxidation prevent respiratory stable isotope therapeutic target total energy expenditure western diet

项目摘要

PROJECT SUMMARY Obesity is the strongest independent predictor for the onset and progression of metabolic diseases, such as type 2 diabetes and cardiovascular disease. Weight gain occurs due to a shift to a positive energy balance through some combination of increased food/energy intake and decreased total energy expenditure. Energy balance is not constant or consistent, and therefore long-term weight gain occurs as a sum of numerous, small positive fluctuations over time scales ranging from days to seasons. These acute episodes of positive energy balance occur as a complex interaction of the current obesogenic environment and inappropriate metabolic regulation. One route of metabolic regulation may be the control of food/energy intake through a liver/brain axis. The main goal of the proposed 5-year research career development plan is to facilitate the applicant's transition from postdoctoral fellow to a fully independent academic scientist. This will be accomplished by training the applicant in a variety of metabolic, neurophysiology, and molecular techniques that will be used to identify mechanisms by which the hepatic mitochondrial function impacts short-term, western diet- induced weight gain. Reduced liver fatty acid oxidation and lower hepatic energy status results in increased food intake, which requires intact vagal nerve communication between the brain and the liver. Additionally, we have shown that increased food/energy intake, weight gain, and adiposity are associated with decreased hepatic fatty acid oxidation and mitochondrial respiratory capacity during a 3-day high fat diet (HFD). The central hypothesis of this proposal is that reduced hepatic mitochondrial function results in increased acute HFD-induced weight gain via: 1) increased HFD food intake, and 2) decreased hepatic and systemic utilization of fat. In this proposal, we will use a liver-specific, PGC-1α heterozygous (LPGC1a+/-) mouse model to study the role of reduced hepatic mitochondrial respiratory function on HFD-induced weight gain. Hepatic vagotomy will be used to test the involvement of liver/brain afferent signals in LPGC1a+/- and wildtype mice. Additional work will include experiments to study the role of hepatic mitochondrial function in onset of metabolic inflexibility and control of systemic substrate utilization, and the role of liver adenine nucleotide levels in the initiation of hepatic efferent vagal signal.

项目概要肥胖是代谢疾病（例如类型）发生和进展的最强独立预测因素 2 糖尿病和心血管疾病是由于向正能量平衡的转变而发生的。增加食物/能量摄入和减少总能量消耗的某种组合是能量平衡。不是恒定的或一致的，因此长期的体重增加是由许多小的正值的总和产生的随时间尺度的波动，从几天到季节不等，这些正能量平衡的急性发作。当前肥胖环境和不适当的代谢调节之间复杂的相互作用而发生。代谢调节的一种途径可能是通过肝脏/大脑轴控制食物/能量摄入。拟议的五年研究职业发展计划的目标是促进申请人的过渡从博士后研究员到完全独立的学术科学家，这将通过培训来完成。申请人掌握各种代谢、神经生理学和分子技术，这些技术将用于确定肝线粒体功能影响短期西方饮食的机制肝脏脂肪酸氧化减少和肝脏能量状态降低导致肝脏脂肪酸氧化增加食物摄入，这需要大脑和肝脏之间完整的迷走神经通讯。研究表明，食物/能量摄入增加、体重增加和肥胖与肝功能下降有关三天高脂肪饮食 (HFD) 期间的脂肪酸氧化和线粒体呼吸能力。该提议的假设是，肝线粒体功能降低导致急性 HFD 诱发的体重增加的途径是：1) 增加 HFD 食物摄入量，2) 减少肝脏和全身对脂肪的利用。根据建议，我们将使用肝脏特异性 PGC-1α 杂合子 (LPGC1a+/-) 小鼠模型来研究肝脏迷走神经切断术会降低肝脏线粒体呼吸功能，导致 HFD 引起的体重增加。测试 LPGC1a+/- 和野生型小鼠中肝脏/大脑传入信号的参与情况。研究肝线粒体功能在代谢不灵活的发生和控制中的作用的实验全身底物利用以及肝脏腺嘌呤核苷酸水平在肝传出信号启动中的作用迷走神经信号。