Mitochondria-Peroxisome Fatty Acid Oxidation in Obesity

肥胖中的线粒体过氧化物酶体脂肪酸氧化

• 批准号: 6701956
• 负责人: RONALD CORTRIGHT
• 金额: $ 20.93万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6701956
• 关键词: biopsy; cell component structure /function; clinical research; combination therapy; diabetes mellitus; electron microscopy; exercise; fatty acid metabolism; human subject; hypoglycemic agents; immunocytochemistry; laboratory rat; lipid metabolism; long chain fatty acid; mitochondria; nonhuman therapy evaluation; obesity; oxidation; peroxisome; pharmacology; radiotracer; striated muscles; thiazoles

DESCRIPTION (provided by applicant): The Iong-term objective of this research is to better understand the defects in skeletal muscle (SKM) that contribute to the morbidity and mortality evident with obesity. There is evidence that obesity is associated with a reduced capacity for SKM lipid oxidation, which could be critical to the development of muscle insulin resistance and diabetes. Specifically, SKM from obese subjects possess an impaired mitochondrial (MitOSKM) capacity to oxidize long-chain fatty acids (LCFA). However, the potential for extra-mitochondrial mechanisms to respond to impaired MitOSKM fatty acid metabolism has been poorly investigated. In the liver, peroxisomes play an obligate role in defending against excess accumulation of cellular fatty acids by chain-shortening LCFA to acyl-carnitines, which are oxidized more efficiently by the mitochondria. In support, chemical inhibition of hepatocyte CPT-1 (rate limiting enzyme in mitochondrial LCFA import) in lean and the livers of obese animals are associated with elevated numbers of peroxisomes. Peroxisomes in extra-hepatic tissues are also responsive to states of altered LCFA metabolism as animals treated with hypolipidemic agents demonstrate clear increases in myocardial peroxisomal activity. We are proposing a similar role for peroxisomes in SKM lipid metabolism, and hypothesize that when MitOSKM oxidation of fatty acids is impaired, peroxisomal oxidation will be enhanced to compensate. Endurance exercise training (EET) in lean subjects and pharmacological treatment with hypolipidemic agents in obese subjects stimulate SKM fatty acid oxidation. Our secondary hypothesis is that SKM from obese subjects will be responsive to treatments that elevate lipid metabolism by elevating peroxisomal contributions toward complete oxidation of LCFA by existing MitOSKM Our Specific Aims are 1) To determine the contributions of peroxisomal activity toward LCFA oxidation in obese vs. lean skeletal muscle and 2) To determine the extent of metabolic flexibility of peroxisomal-mitochondrial oxidative capacity in obese vs. lean SKM. Methods: We will address these aims by 1) quantifying peroxisomal/mitochondrial contributions toward LCFA metabolism in SKM biopsies from hindlimb (rodent) and rectus abdominus (human) muscles of obese vs. lean subjects using electron microscopy/ immunocytochemistry and radioisotope assessment of fatty acid oxidation and 2) determining (in rodents) whether EET (8 weeks) and pharmacological treatment (3 weeks) with hypolipidemic agents (alone and/or in combination with EET) can improve the peroxisomal and MitOSKM capacity to metabolize LCFA. These investigations will 1) further elucidate the role of peroxisomal oxidation in obesity and diabetes 2) aid in the identification of new therapies for the treatment of obesity and other dyslipidemic diseases 3) provide valuable research training for our students and 4) generate data for subsequent RO1 applications.

描述（由申请人提供）：这项研究的IONG期限目的是更好地了解骨骼肌（SKM）的缺陷，这些缺陷导致肥胖症明显的发病率和死亡率。有证据表明，肥胖症与SKM脂质氧化能力降低有关，这对于肌肉胰岛素抵抗和糖尿病的发展至关重要。具体而言，来自肥胖受试者的SKM具有氧化长链脂肪酸（LCFA）的线粒体（Mitoskm）的受损能力。然而，对Mitoskm脂肪酸代谢受损受损的潜在，对MITOSKM脂肪酸代谢受损的可能性很差。在肝脏中，过氧化物酶体在防御过度累积细胞脂肪酸的积累中发挥了强大的作用，通过链链LCFA为酰基肉碱，通过线粒体更有效地氧化了。为了支持，瘦肉和肥胖动物的肝脏中的肝细胞CPT-​​1（线粒体LCFA进口中的速率限制酶）的化学抑制与过氧化物酶体数量升高有关。肝外组织中的过氧化物酶体也对LCFA代谢改变的状态有反应，因为用降脂蛋白药物治疗的动物表明心肌过氧化物酶体活性明显增加。我们提出了过氧化物酶体在SKM脂质代谢中的类似作用，并假设当脂肪酸的mitoskm氧化受损时，会增强过氧化物酶体氧化以补偿。在肥胖受试者和肥胖受试者中降低药物治疗的耐力运动训练（EET）刺激Skm脂肪酸氧化。我们的次要假设是，来自肥胖受试者的SKM将对升高脂质代谢的治疗方法有反应，通过现有Mitoskm提高过氧化物酶体对LCFA完全氧化的贡献，我们的具体目的是1）确定过氧化物酶氧化对Obese viss neceps neks sekeles and sekeles sekecle and 2）的贡献的贡献。肥胖与瘦小SKM中的过氧化物酶体氧化能力。方法：我们将通过1）解决这些目标，以量化肥胖对象与肥胖对象的肥胖对象与肥胖受试者的腹部肌肉（啮齿动物）肌肉（使用电子显微镜/免疫型氧化型（RodeStion Idict）的脂肪酸评估（对肥胖对象的脂肪酸氧化物的肌肉），对LCFA代谢的过氧化物/线粒体对LCFA代谢的贡献和肥胖对象的肌肉（肥胖对象）的脂肪酸氧化物酸度和脂肪酸氧气酸度（Rodistion Iction）的脂肪含量（均为型号）以及对脂肪的评估（对肥胖对象）的脂肪酸的效果（对肥胖的肌肉）的评估（均为摄入量） （8周）和药理学治疗（3周）用降量药（单独和/或与EET结合使用）可以改善过氧化物酶体和Mitoskm代谢LCFA的能力。这些研究将1）进一步阐明过氧化物酶体氧化在肥胖症和糖尿病中的作用2）帮助鉴定新疗法以治疗肥胖症和其他血脂性疾病3）为我们的学生提供有价值的研究培训，以及4）为后续RO1应用提供数据。

项目成果

Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats.

• DOI: 10.1016/j.freeradbiomed.2010.06.022
• 发表时间: 2010-09-15
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Kane, Daniel A.;Anderson, Ethan J.;Price, Jesse W., III;Woodlief, Tracey L.;Lin, Chien-Te;Bikman, Benjamin T.;Cortright, Ronald N.;Neufer, P. Darrell
• 通讯作者: Neufer, P. Darrell