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）：本研究的长期目标是更好地了解导致肥胖发病率和死亡率的骨骼肌（SKM）缺陷。有证据表明，肥胖与SKM脂质氧化能力降低有关，这可能对肌肉胰岛素抵抗和糖尿病的发展至关重要。具体来说，肥胖受试者的SKM线粒体（MitOSKM）氧化长链脂肪酸（LCFA）的能力受损。然而，线粒体外机制对MitOSKM脂肪酸代谢受损的潜在反应尚未得到充分研究。在肝脏中，过氧化物酶体通过将LCFA链缩短为酰基肉碱，在防止细胞脂肪酸过量积累方面发挥着专门的作用，后者被线粒体更有效地氧化。因此，瘦肉动物和肥胖动物肝脏中肝细胞CPT-1（线粒体LCFA进口限速酶）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，因为用降血脂药物治疗的动物显示心肌过氧化物酶体活性明显增加。我们提出过氧化物酶体在SKM脂质代谢中的类似作用，并假设当MitOSKM对脂肪酸的氧化受损时，过氧化物酶体的氧化将增强以补偿。瘦受试者的耐力运动训练（EET）和肥胖受试者的降血脂药物治疗刺激SKM脂肪酸氧化。我们的第二个假设是，肥胖受试者的SKM将对通过提高现有MitOSKM对LCFA完全氧化的过氧化物酶体贡献来提高脂质代谢的治疗有反应。我们的具体目标是：1)确定肥胖与瘦骨骼肌中过氧化物酶体活性对LCFA氧化的贡献；2)确定肥胖与瘦骨骼肌中过氧化物酶体-线粒体氧化能力的代谢灵活性程度。方法:我们将通过以下方法来实现这些目标：1)使用电子显微镜/免疫细胞化学和脂肪酸氧化的放射性同位素评估，量化肥胖和瘦弱受试者后肢（啮齿动物）和腹直肌（人类）肌肉的SKM活检中过氧化物酶体/线粒体对LCFA代谢的贡献；2)确定（在啮齿动物中）EET（8周）和降血脂药物（单独和/或联合EET）的药物治疗（3周）是否可以改善过氧化物酶体和LCFA代谢线粒体代谢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和糖尿病中的作用；(2)帮助确定治疗肥胖和其他血脂异常疾病的新疗法；(3)为我们的学生提供有价值的研究培训；(4)为后续的RO1应用生成数据。

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