Lipid metabolism in obesity, weight loss, and exercise

描述（由申请人提供）：严重肥胖（体重指数bbb40 kg/m2）的发病率正在不成比例地增加，并与医疗费用的增加有关。我们已经报道了严重肥胖患者骨骼肌中脂肪酸氧化（FAO）的抑制，这可能使这些人易发生异位脂质积累。我们的初步研究结果表明，粮农组织的这种减少是由于线粒体含量的减少，而线粒体含量的减少与无法适当诱导线粒体生物合成（代谢不灵活性）有关。总之，这些数据表明严重肥胖的“代谢程序”有利于脂质沉积；相反，运动训练增加了粮农组织并挽救了严重肥胖患者的代谢灵活性。这些发现导致了我们的中心假设，即严重肥胖个体骨骼肌中明显的FAO下降和代谢缺乏灵活性是由于线粒体含量减少造成的，至少部分原因是由于无法对诱导线粒体生物合成的条件做出适当反应，运动训练除外。研究结果有助于理解这种情况的潜在生物学原理，设计有效的治疗方法，并促进体育活动作为严重肥胖的干预/预防手段。我们的假设将通过以下目标进行检验。目的1：确定骨骼肌中mtDNA的调节是否因严重肥胖而发生改变，从而使FAO受到抑制。a) TFAM（线粒体转录因子a）启动子上NRF-1（核呼吸因子-1）结合位点的占用是否随着严重肥胖而减少？b) TFAM表达的减少是否与TFAM启动子区域的甲基化有关？c) TFAM过表达是否能改善肥胖的代谢表型？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) HSkMC中发现的缺陷在体内是否明显？目的2：确定是否存在严重肥胖患者线粒体生物合成所需的核基因协调失调。a) NRF-1靶基因的表达是否与严重肥胖相关？b)与线粒体生物合成相关基因上的NRF- 1占用率是否因严重肥胖而降低？c) NRF-1过表达能否挽救严重肥胖患者线粒体含量、FAO和代谢不灵活性明显下降？目的3：确定运动训练的成分是否可以将骨骼肌从严重肥胖的代谢表型/程序中拯救出来。a)在瘦弱和严重肥胖者的HSkMC中，收缩活动增加FAO和代谢灵活性的程度是否相似？b)收缩活动是否能恢复肥胖相关的TFAM或NRF-1靶基因的减少？c)能量需求的增加会逆转严重肥胖表型吗？d)运动训练（体内）是否能将肌肉从严重肥胖的代谢过程中拯救出来？

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?