Lipid metabolism in obesity, weight loss, and exercise

描述(由申请人提供)：严重肥胖症(BMI和GT；40公斤/平方米)的发生率正在不成比例地增加，并与医疗保健费用的上升有关。我们已经报道，严重肥胖患者骨骼肌中的脂肪酸氧化(FAO)受到抑制，这可能使这些人容易发生异位脂肪堆积。我们的初步发现表明，粮农组织的这种减少是由于线粒体含量的减少，这与无法适当地诱导线粒体生物合成(代谢缺乏灵活性)有关。总而言之，这些数据表明，严重肥胖患者的“代谢计划”有利于脂肪沉积；相比之下，运动训练增加了粮农组织，挽救了严重肥胖症患者的代谢灵活性。这些发现导致了我们的中心假设，即严重肥胖者骨骼肌中明显的粮农组织抑制和代谢缺乏灵活性是由于线粒体含量的减少，这至少部分是由于无法对诱导线粒体生物合成的条件做出适当的反应，运动训练是显著的例外。这些发现有助于理解这种疾病的潜在生物学，设计有效的治疗方法，以及促进体育活动，作为对严重肥胖症的干预/预防。我们的假设将通过以下目标进行检验。目的1：确定严重肥胖是否改变了骨骼肌线粒体DNA的调控，从而抑制了FAO。A)严重肥胖是否会降低线粒体转录因子A(TFAM)启动子上的NRF-1(核呼吸因子-1)结合位点数？B)TFAM表达的降低是否与TFAM启动子区域的甲基化有关？C)过表达TFAM能改善肥胖患者的代谢表型吗？D)严重肥胖者肌肉中胰岛素诱导的线粒体生物合成是否受损？E)在HSkMC中发现的缺陷在体内是否明显？目的2：探讨严重肥胖症患者线粒体生物合成所需的核基因是否存在协调失调。A)严重肥胖患者是否存在NRF-1靶基因表达的协同降低？B)与线粒体生物合成相关的基因上NRF-1的占有率是否随着严重肥胖而减少？C)NRF-1的过度表达能否挽救严重肥胖所导致的线粒体含量下降、粮农组织和代谢不灵活的现象？目的3：确定运动训练的组成部分是否可以将骨骼肌从严重肥胖明显的代谢表型/程序中拯救出来。A)瘦肉型和严重肥胖型个体的收缩活动是否同样程度地增加了粮农组织和HSkMC的代谢灵活性？B)收缩活动是否能恢复与肥胖相关的TFAM或NRF-1靶基因的减少？C)能源需求的增加会扭转严重肥胖的表型吗？D)运动训练(体内)是否将肌肉从严重肥胖的代谢程序中拯救出来？

DESCRIPTION (provided by applicant): The incidence of severe obesity (BMI > 40 kg/m2) is increasing disproportionately and associated with elevated health care costs. We have reported that fatty acid oxidation (FAO) is depressed in the skeletal muscle of severely obese patients, which may predispose these individuals to ectopic lipid accumulation. Our preliminary findings suggest that this decrement in FAO is due to a reduction in mitochondrial content which is linked with an inability to appropriately induce mitochondrial biosynthesis (metabolic inflexibility). Together, these data are indicative of a "metabolic program" with severe obesity which favors lipid deposition; in contrast exercise training increases FAO and rescues metabolic flexibility in severely obese patients. These findings have led to our central hypothesis that the depressed FAO and metabolic inflexibility evident in the skeletal muscle of severely obese individuals is due to a reduction in mitochondrial content which stems, at least in part, from an inability to respond appropriately to conditions that induce mitochondrial biosynthesis, with the notable exception of exercise training. Findings could aid in understanding the underlying biology of this condition and designing effective treatments as well as promoting physical activity as an intervention/prevention for severe obesity. Our hypothesis will be tested by the following aims. Aim 1: To determine if the regulation of mtDNA in skeletal muscle is altered with severe obesity in a manner that depresses FAO. a) Is occupancy of the NRF-1 (nuclear respiratory factor -1) binding site on the TFAM (mitochondrial transcription factor A) promoter reduced with severe obesity? b) Is the reduction in TFAM expression linked with methylation of the TFAM promoter region? c) Can TFAM overexpression ameliorate the metabolic phenotype evident with obesity? d) Is insulin-induced mitochondrial biosynthesis impaired in the muscle of severely obese individuals? e) Are the defects discerned in HSkMC evident in-vivo? Aim 2: To determine if there is a coordinated dysregulation of nuclear genes required for mitochondrial biosynthesis with severe obesity. a) Is there a coordinated reduction in the expression of NRF-1 target genes with severe obesity? b) Is NRF- 1 occupancy on genes linked with mitochondrial biosynthesis reduced with severe obesity? c) Can NRF-1 overexpression rescue the decrements in mitochondrial content, FAO, and metabolic inflexibility evident with severe obesity? Aim 3: To determine if components of exercise training can rescue skeletal muscle from the metabolic phenotype/program evident with severe obesity. a) Does contractile activity increase FAO and metabolic flexibility to a similar extent in HSkMC from lean and severely obese individuals? b) Does contractile activity restore obesity-related decrements in TFAM or NRF-1 target genes? c) Will an increase in energy demand reverse the severely obese phenotype? d) Does exercise training (in-vivo) rescue muscle from the metabolic program evident with severe obesity?