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

• 批准号: 10450906
• 负责人: E Matthew Morris
• 金额: $ 7.91万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2023-03-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450906
• 关键词: 5' -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; 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; dietary; energy balance; experimental study; fatty acid oxidation; flexibility; gain of function; liver function; liver metabolism; mouse model; neurophysiology; obese person; obesogenic; overexpression; oxidation; prevent; respiratory; stable isotope; therapeutic target; total energy expenditure; western diet

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.

项目摘要 肥胖是代谢性疾病的发作和进展的强有力的独立预测因子，例如类型 2种糖尿病和心血管疾病。体重增加是由于转移到正能量平衡的原因 食物/能量摄入量增加和总能量消耗增加的结合。能量平衡是 不恒定或一致，因此长期体重增加是作为众多，小正的总和。 随着时间的流逝，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 作为当前肥胖环境和不适当的代谢调节的复杂相互作用。 代谢调节的一种途径可能是通过肝脏/脑轴控制食物/能量的摄入量。主 拟议的5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 该应用在多种代谢，神经生理学和分子技术中的应用 确定肝脏线粒体功能会影响短期，西方饮食的机制 诱导体重增加。肝脏脂肪酸氧化和较低的肝能量状态降低导致增加 食物摄入需要完整的大脑和肝脏之间的迷走神经交流。另外，我们 已经表明，增加的食物/能量摄入量，体重增加和肥胖与肝脏降低有关 3天高脂肪饮食（HFD）期间的脂肪酸氧化和线粒体呼吸能力。中央 该提议的假设是肝脏线粒体功能的降低导致急性HFD诱导的增加 体重增加通过：1）HFD食物摄入量增加，以及2）肝脏的肝脏和全身利用降低。在这个 提案，我们将使用肝特异性PGC-1α杂合（LPGC1A +/-）小鼠模型来研究 在HFD诱导的体重增加方面，肝线粒体呼吸功能降低。将使用肝迷失术 测试肝脏/脑传入信号在LPGC1A +/-和WildType小鼠中的参与。其他工作将包括 研究肝线粒体功能在代谢僵硬性和控制中的作用的实验 系统性底物利用以及肝腺嘌呤核苷酸水平在肝效率启动中的作用 迷走神经信号。