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

项目摘要 肥胖是代谢性疾病发生和进展的最强独立预测因子，例如 2糖尿病与心血管疾病。体重增加是由于通过以下方式向正能量平衡转变 增加食物/能量摄入和减少总能量消耗的某种组合。能量平衡 不是恒定的或一致的，因此长期的体重增加是作为一个众多的，小的积极的总和发生的。 从几天到几个季节的时间尺度上的波动。这些正能量平衡的急性发作 作为当前致胖环境和不适当的代谢调节的复杂相互作用而发生。 代谢调节的一种途径可以是通过肝/脑轴控制食物/能量摄入。主要 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 从博士后到完全独立的学术科学家这将通过培训来实现 申请人在各种代谢，神经生理学和分子技术，将用于 确定肝脏线粒体功能影响短期西方饮食的机制- 诱导体重增加。肝脏脂肪酸氧化减少和肝脏能量状态降低导致 食物摄入，这需要大脑和肝脏之间完整的迷走神经通信。另外我们 已经表明，食物/能量摄入增加、体重增加和肥胖与肝细胞减少有关。 在3天高脂饮食（HFD）期间的脂肪酸氧化和线粒体呼吸能力。中央 该建议的假设是，肝线粒体功能降低导致急性HFD诱导的肝细胞凋亡增加。 体重增加通过：1）增加HFD食物摄入，和2）减少脂肪的肝脏和全身利用。在这 我们将使用肝脏特异性的PGC-1α杂合（LPGC 1a +/-）小鼠模型来研究 降低HFD诱导的体重增加的肝线粒体呼吸功能。将使用肝迷走神经切断术 以测试LPGC 1a +/-和野生型小鼠中肝/脑传入信号的参与。其他工作将包括 研究肝线粒体功能在代谢紊乱发作和 全身底物利用和肝腺嘌呤核苷酸水平在肝传出神经起始中的作用 迷走神经信号

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.