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Palmitate Metabolism and Insulin Resistance

棕榈酸酯代谢和胰岛素抵抗

基本信息

批准号：
7804331
负责人：
Craig Lawrence Kien
金额：
$ 63.57万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7804331
关键词：
1,2-diacylglycerol Abbreviations Acetyl Coenzyme A Acyl Coenzyme A Address Adenosine Monophosphate Adipose tissue Aerobic Age American Biochemical Biochemical Pathway Body Weight decreased Body mass index Burn injury Carbon Carbon Dioxide Carnitine Carnitine Palmitoyltransferase I Cells Chronic Citrates Citric Acid Cycle Companions Coupled Cross-Over Studies DEXA Data Defect Development Diabetes Mellitus Diet Dietary Fats Dietary Fatty Acid Diglycerides Dual-Energy X-Ray Absorptiometry EMSA Electron Transport Electrophoretic Mobility Shift Assay Exercise Fatty Acids Fatty acid glycerol esters Female Functional disorder GLUT4 gene Gene Expression Generations Hormones Human Incidence Inflammatory Insulin Insulin Resistance Intake Interleukin-6 Intervention Isocitrate Dehydrogenase Lead Lecithin Lesion Lipids Lipopolysaccharides Literature Masks Measures Mediating Membrane Membrane Lipids Messenger RNA Metabolic Metabolism Mitochondria Modeling Molecular Mono-S Monounsaturated Fatty Acids Muscle Muscle Cells Muscle Fibers NADH Non-Insulin-Dependent Diabetes Mellitus North America Northern Europe Nuclear Obesity Oleic Acids Overweight Palmitates Palmitic Acids Palmitoyl Coenzyme A Peripheral Phospholipids Phosphotransferases Physical activity Prevention Production Proteins Reactive Oxygen Species Regimen Relative (related person)Research Research Project Grants Saturated Fatty Acids Series Serum Signal Transduction Skeletal Muscle Skeleton Staging Stearoyl-CoA Desaturase Sum Testing Therapeutic Intervention Tricarboxylic Acids Triglycerides Tumor Necrosis Factor-alpha Tumor Necrosis Factors Tyrosine Phosphorylation Unsaturated Fatty Acids Upper Extremity Urine Variant Woman Work acylcarnitine aged base design fatty acid metabolism fatty acid oxidation fitness glucose uptake glycemic control human subject improved in vivo inhibitor/antagonist insulin receptor substrate 1 protein insulin sensitivity insulin signaling lipid metabolism male monounsaturated fat non-diabetic obesity risk organic acid oxidation prevent protein expression public health relevance receptor response saturated fat trafficking

项目摘要

DESCRIPTION (provided by applicant): Palmitic acid (PA), impairs insulin sensitivity in skeletal muscle, and replacing PA in the diet with oleic acid (OA), a monounsaturated fatty acid (FA), may be beneficial. The first objective of this project is to understand the effects on lipid metabolism and skeletal muscle lipid composition, insulin signaling, and inflammatory signaling of two common variations in FA composition of the diet: (1) The typical intake of North America where PA and OA are present in equal proportions (HI PA diet). (2) The Mediterranean FA composition in which PA is much lower and OA much higher (HI OA diet). PA may induce insulin resistance in skeletal muscle cells via its accumulation in lipids within muscle cells and via activation of inflammatory signaling. The second objective of this project is to assess the hypothesis that a high intake of PA will down-regulate its own one-carbon (initial) oxidation, leading to increased inflammatory signaling and decreased insulin signaling. However, there is literature evidence that FA may induce defects in insulin signaling, if FA are not completely oxidized; therefore, the third objective is to assess the hypotheses that a high PA diet may decrease complete oxidation of FA and possibly accelerate initial FA oxidation. A double-masked, cross-over trial of the effects of a high PA diet versus a high OA/low PA diet in 16 overweight or obese subjects and 16 lean subjects (aged 18 - 40 yr) will be conducted to investigate the following Specific Aims: 1. To test the hypothesis that increased intake of PA will cause a decreased rate of [1-13C]-PA oxidation and will be associated with: (a) increased inflammatory signaling, within the muscle; (b) Decreased insulin signaling as characterized by decreased, whole body, peripheral insulin sensitivity (euglycemic/hyperinsulinemic clamp) and, in skeletal muscle, decreased phospho-AKT (Ser473), increased phospho-IRS-1 (Ser636/Ser639), decreased tyrosine phosphorylation of IRS-1, and decreased membrane content of GLUT4. 2. To test the hypothesis that increased intake of PA will cause less complete mitochondrial fatty acid oxidation, perhaps associated with dysfunction of the TCA cycle and increased reactive oxygen species formation. This hypothesis will be tested by measuring whole body and muscle (upper limb) relative rates of oxidation of [13-13C]-PA and [1-13C]-PA and by determining the serum profile of acylcarnitines, the urine concentrations of organic acids, and muscle concentrations of protein carbonyls. 3. To test the hypothesis that a high PA diet will lead to less complete oxidation of FA, less insulin signaling in skeletal muscle in response to a test meal, less whole body insulin sensitivity, increased dysfunction of the TCA cycle, and greater reactive oxygen species formation compared to the results obtained in obese versus lean humans. PUBLIC HEALTH RELEVANCE: High intakes of saturated fat are associated with diabetes. Our work has shown that the two most common fatty acids in the North American diet, palmitic acid (saturated fat) and oleic acid (monounsaturated fat) are metabolized differently and have opposite effects on fat burning. The proposed study will examine biochemical and molecular mechanisms for how a high saturated fat diet versus a low saturated fat/high monounsaturated fat diet alters the action of the hormone, insulin, in skeletal muscle.

描述（申请人提供）：棕榈酸（PA）损害骨骼肌的胰岛素敏感性，用油酸（OA）（一种单不饱和脂肪酸（FA））替代饮食中的PA可能有益。本项目的第一个目标是了解饮食中FA组成的两种常见变化对脂质代谢和骨骼肌脂质组成、胰岛素信号传导和炎症信号传导的影响：（1）北美的典型摄入量，其中PA和OA以相等的比例存在（HI PA饮食）。(2)地中海FA组成，其中PA低得多，OA高得多（HI OA饮食）。PA可能通过其在肌细胞内脂质中的积累和通过激活炎症信号传导而诱导骨骼肌细胞中的胰岛素抵抗。该项目的第二个目标是评估高PA摄入量将下调其自身的一碳（初始）氧化，导致炎症信号增加和胰岛素信号减少的假设。然而，有文献证据表明，如果FA没有完全氧化，FA可能会诱导胰岛素信号传导缺陷;因此，第三个目标是评估高PA饮食可能会减少FA的完全氧化并可能加速初始FA氧化的假设。将在16名超重或肥胖受试者和16名瘦受试者（年龄18 - 40岁）中进行高PA饮食与高OA/低PA饮食的效果的双盲、交叉试验，以研究以下具体目的：为了检验PA摄入量增加将导致[1- 13 C]-PA氧化速率降低并与以下因素相关的假设：（a）肌肉内炎症信号增加;（B）胰岛素信号传导降低，其特征在于全身外周胰岛素敏感性降低（正常血糖/高胰岛素钳夹），并且在骨骼肌中，磷酸化AKT（Ser 473）减少，磷酸化IRS-1增加（Ser 636/Ser 639），降低IRS-1的酪氨酸磷酸化，并降低GLUT 4的膜含量。2.为了验证PA摄入量增加将导致线粒体脂肪酸氧化不完全的假设，可能与TCA循环功能障碍和活性氧形成增加有关。将通过测量[13- 13 C]-PA和[1- 13 C]-PA的全身和肌肉（上肢）相对氧化速率以及通过测定酰基肉毒碱的血清谱、有机酸的尿液浓度和蛋白质羰基的肌肉浓度来检验该假设。3.为了检验以下假设：与肥胖与瘦人相比，高PA饮食将导致FA的不完全氧化、骨骼肌对试验餐的胰岛素信号传导减少、全身胰岛素敏感性降低、TCA循环功能障碍增加以及活性氧形成增加。公共卫生相关性：饱和脂肪的高摄入量与糖尿病有关。我们的工作表明，北美饮食中最常见的两种脂肪酸，棕榈酸（饱和脂肪）和油酸（单不饱和脂肪）的代谢方式不同，对脂肪燃烧有相反的影响。这项拟议的研究将研究高饱和脂肪饮食与低饱和脂肪/高单不饱和脂肪饮食如何改变骨骼肌中激素胰岛素的作用的生化和分子机制。