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

项目总结 肥胖是代谢性疾病发生和发展的最强独立预测因子，如 2糖尿病和心血管疾病。体重增加是由于通过以下方式转变为积极的能量平衡 食物/能量摄入量增加和总能量消耗减少的某种组合。能量平衡是 不恒定的或不一致的，因此长期的体重增加是无数个小的正数的总和 在从几天到四季的时间尺度上波动。这些正能量平衡的急性期 发生是当前肥胖环境和不适当的代谢调节的复杂相互作用。 代谢调节的一条途径可能是通过肝脏/脑轴控制食物/能量摄入。主 拟议的5年研究职业发展计划的目标是促进申请者的过渡 从博士后到完全独立的学术科学家。这将通过培训来实现 应聘者将学习各种代谢、神经生理学和分子技术 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。减少肝脏脂肪酸氧化和降低肝脏能量状态会导致 食物摄入，这需要大脑和肝脏之间完整的迷走神经联系。此外，我们 研究表明，食物/能量摄入增加、体重增加和肥胖与肝脏功能下降有关。 高脂饮食(HFD)3天期间的脂肪酸氧化和线粒体呼吸能力。中环 这一建议的假设是，肝脏线粒体功能降低会导致急性HFD诱导的增加 体重增加通过：1)增加HFD食物摄入量，以及2)降低肝脏和全身对脂肪的利用。在这 建议，我们将使用肝脏特异的PGC-1α杂合子(LPGC1a+/-)小鼠模型来研究其作用 高脂饲料诱导的体重增加使肝脏线粒体呼吸功能降低。将使用肝迷走神经切断术 检测LPGC1a+/-和野生型小鼠肝/脑传入信号的参与情况。其他工作将包括 肝线粒体功能在代谢不灵活发生和控制中作用的实验研究 全身性底物利用和肝腺嘌呤核苷酸水平在启动肝传出中的作用 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.