Identification of Muscle-Specific Biomarkers of Fatty Acid beta-Oxidation

脂肪酸β-氧化的肌肉特异性生物标志物的鉴定

• 批准号: 8118833
• 负责人: Sean Harrison Adams
• 金额: $ 22.53万
• 依托单位: U.S. AGRICULTURAL RESEARCH SERVICE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118833
• 关键词: Acetylcarnitine; Acute; Address; Adipose tissue; Aerobic; Aerobic Exercise; Alleles; Animal Model; Attenuated; Automobile Driving; Beds; Biological Markers; Blood Circulation; Blood Glucose; Body fat; Cardiovascular Diseases; Carnitine; Carrier Proteins; Catabolism; Cell Line; Cells; Chemicals; Consensus; Development; Diabetes Mellitus; Diagnostic; Diet; Dietary Intervention; Disease; Dyslipidemias; Etiology; Event; Exercise; Exons; Fasting; Fatty Acids; Fatty acid glycerol esters; Genetic Polymorphism; Glosso-Sterandryl; Health; Health Status; Human; Hypertension; Impaired fasting glycaemia; In Vitro; Individual; Insulin; Insulin Resistance; Intervention; Kidney; Link; Lipids; Liver; Metabolic; Metabolic Diseases; Mitochondria; Modeling; Molecular; Muscle; Muscle Cells; Muscle Fibers; Muscle Mitochondria; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutritional; Obesity; Organelles; Overweight; Palmitates; Pancreatic Hormones; Pattern; Peripheral; Persons; Pharmacotherapy; Physical activity; Physiological; Plasma; Predisposition; Preparation; Production; Protocols documentation; Purines; RNA Splicing; Regimen; Research; Risk; Sampling; Signal Transduction; Site; Skeletal Muscle; Specificity; System; Testing; Time; Tissues; Training; Transgenic Animals; Transgenic Mice; Up-Regulation; Work; biological systems; clinically relevant; cohort; design; diabetic; diet and exercise; fatty acid metabolism; fatty acid oxidation; fitness; human subject; improved; insulin sensitivity; insulin signaling; lipid metabolism; metabolomics; mitochondrial uncoupling protein 3; outcome forecast; overexpression; oxidation; premature; prognostic; purine; sedentary; tool; uptake; validation studies

DESCRIPTION (provided by applicant): Elevated fat levels within skeletal muscle cells (intramyocellular lipids) are highly correlated with muscle and whole-body insulin resistance, and more prevalent in obesity. The molecular links and metabolic shifts driving this association remain open to debate, but notably, reduced muscle mitochondrial fatty acid (FA) beta-oxidation is more prevalent among insulin-resistant/diabetic persons. Therefore, discovery of biomarkers reflective of the status of an individual's muscle FA beta-oxidation activity or capacity would have tremendous prognostic and diagnostic value in terms of diabetes. Furthermore, characterization of metabolites associated with muscle mitochondrial fat metabolism should uncover candidate signaling factors which tie FA beta-oxidation to insulin signaling. We propose to identify, for the first time, specific biomarkers of muscle FA beta- oxidation using multiple metabolomic analytical platforms to compare metabolite profiles in samples derived from biological systems displaying disparate muscle fat combustion, including: isolated mitochondrial organelles and muscle cells catabolizing FA at different rates, a UCP3 transgenic animal model, and human subjects harboring a UCP3 truncation polymorphism (Aims 1 & 2). Pilot validation studies in Aim 3 will test whether plasma metabolites and/or metabolite signatures that track muscular FA beta-oxidation (as identified in Aims 1 and 2) can be experimentally increased in obese, insulin-resistant subjects via a diet-exercise regimen designed to improve muscle fitness and FA combustion. Aim 1--Identify Metabolite Biomarkers of Muscle Fat Combustion in Organelle, Cell, and Animal Models Displaying Significantly Altered Fatty Acid beta-Oxidation. We will determine how metabolite profiles shift in models displaying increased muscle beta-oxidation (uncoupling protein 3-overexpressing muscle cell line and muscle UCP3-transgenic mice), and hypothesize that profiles in UCP3-overexpressing systems will reflect increased FA beta-oxidation. Complementary studies will identify tissue-specific metabolites generated by mitochondria in the course of palmitate catabolism in vitro, comparing muscle to liver and kidney preparations. Aim 2--Identify Metabolite Biomarkers of Muscle Fat Combustion in Humans Harboring a UCP3 Missense Polymorphic Allele. We predict that subjects with this polymorphism (which yields a truncated UCP3 and 50% decreased whole-body fat combustion) will display a distinctive plasma metabolite profile indicative of reduced muscle FA oxidation, when compared to subjects without the polymorphism. Aim 3--Determine Whether Metabolomic Profiles Reflective of Muscle Fat Combustion Predict Metabolic Health Changes Following Diet & Exercise Intervention in Obese Subjects. We hypothesize that biomarkers reflective of normal to increased muscle beta-oxidation will be increased, and markers indicative of poor muscle fat combustion reduced, in a cohort of sedentary obese subjects undergoing a 4 month diet- exercise protocol which will increase muscle fitness and improve insulin action. PUBLIC HEALTH RELEVANCE: A reduced ability of the pancreatic hormone insulin to trigger tissue uptake of blood sugar is an early event in the course of development of type 2 diabetes mellitus (T2DM), and the muscle beds are important sites for this phenomenon in many people. Relatively poor fat combustion by fasting muscle is often correlated with insulin resistance, even in the pre-diabetic state. Thus, the overarching aim of our research-- identification of clinically-relevant biomarkers of muscle fat metabolism--is critical to help identify at-risk persons, determine etiology of disease, and ultimately thwart development of T2DM through nutritional, physical activity, and pharmacological interventions.

描述（由申请人提供）：骨骼肌细胞内的脂肪水平升高（细胞内脂质）与肌肉和全身胰岛素抵抗高度相关，并且在肥胖症中更为普遍。驱动这种关联的分子联系和代谢转移仍然对辩论开放，但尤其是，在耐胰岛素/糖尿病患者中，肌肉线粒体脂肪酸（FA）β-氧化更为普遍。因此，发现生物标志物反映了个体的肌肉FAβ-氧化活性或能力的状态将具有巨大的预后和诊断价值。此外，与肌肉线粒体脂肪代谢相关的代谢物的表征应揭示候选信号传导因子，将FAβ-氧化与胰岛素信号传导联系起来。 We propose to identify, for the first time, specific biomarkers of muscle FA beta- oxidation using multiple metabolomic analytical platforms to compare metabolite profiles in samples derived from biological systems displaying disparate muscle fat combustion, including: isolated mitochondrial organelles and muscle cells catabolizing FA at different rates, a UCP3 transgenic animal model, and human subjects harboring a UCP3 truncation多态性（目标1和2）。 AIM 3中的试验验证研究将测试在肥胖的，抗胰岛素耐药的受试者中，是否可以通过设计旨在改善肌肉健身和FA摄取剂的饮食疗法方案来测试追踪肌肉FAβ-氧化（AIM 1和2中确定的）是否可以在实验上增加肌肉FAβ-氧化（如AIM 1和2中确定的）的试验验证研究。 AIM 1-识别细胞器，细胞和动物模型中肌肉脂肪燃烧的代谢产物生物标志物，表现出明显改变脂肪酸β-氧化。我们将确定如何在显示出增加肌肉β氧化的模型中的代谢产物轮廓（解偶联蛋白3过表达的肌肉细胞系和肌肉UCP3-转基因小鼠），并假设UCP3超过表达系统中的曲线将反映FAβ-β-氧化剂的增加。互补研究将在体外在棕榈酸酯分解代谢过程中确定线粒体产生的组织特异性代谢产物，将肌肉与肝脏和肾脏制剂进行比较。 AIM 2-识别具有UCP3错义多态等位基因的人类中肌肉脂肪燃烧的代谢物生物标志物。我们预测，与没有多态性的受试者相比，这种多态性受试者（产生截短的UCP3和50％减少全身脂肪燃烧）将显示出独特的血浆代谢物谱，指示降低肌肉FA氧化。目标3确定性是否反映了肌肉脂肪燃烧的代谢谱是否可以预测肥胖受试者的饮食和运动干预后代谢健康的变化。我们假设生物标志物将增加反映肌肉β-氧化的肌肉氧化，并且在一系列久坐的肥胖受试者中，表明肌肉脂肪抑制不良的标记减少了，他们接受了4个月的饮食运动方案，这将增加肌肉适应性并改善胰岛素的作用。 公共卫生相关性：胰腺激素胰岛素触发血糖摄取组织的能力降低是在2型糖尿病（T2DM）发展过程中的早期事件，而肌肉床是许多人的重要场所。禁食肌肉相对较差的脂肪燃烧通常与胰岛素抵抗相关，即使在糖尿病前也是如此。因此，我们的研究的总体目的 - 鉴定肌肉脂肪代谢的临床相关的生物标志物 - 至关重要，对于帮助识别危险人士，确定疾病的病因以及最终通过营养，体育活动和药理干预措施来阻止T2DM的发展至关重要。