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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：
8254436
负责人：
Craig Lawrence Kien
金额：
$ 49.83万
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/8254436
关键词：
1,2-diacylglycerol Abbreviations Acetyl Coenzyme A Acyl Coenzyme A Address Adenosine Monophosphate Adipose tissue Aerobic 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 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 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 Proto-Oncogene Proteins c-akt 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 TNF gene Testing Therapeutic Intervention Tricarboxylic Acids Triglycerides Tumor Necrosis Factor-alpha 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 mRNA Expression 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（由申请人提供）：棕榈酸 (PA) 会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 可能是有益的。该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成分、胰岛素信号和炎症信号的影响：(1) PA 和 OA 比例相等的北美典型摄入量（HI PA 饮食）。 (2) 地中海 FA 组成，其中 PA 较低，OA 较高（HI OA 饮食）。 PA 可能通过其在肌肉细胞内脂质中的积累和炎症信号的激活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以下假设：大量摄入 PA 会下调其自身的一碳（初始）氧化，从而导致炎症信号增加和胰岛素信号减少。然而，有文献证据表明，如果 FA 没有完全氧化，FA 可能会导致胰岛素信号传导缺陷；因此，第三个目标是评估高 PA 饮食可能减少 FA 完全氧化并可能加速 FA 初始氧化的假设。将在 16 名超重或肥胖受试者和 16 名瘦受试者（年龄 18 - 40 岁）中进行一项双盲、交叉试验，比较高 PA 饮食与高 OA/低 PA 饮食的影响，以研究以下具体目标： 1. 检验以下假设：增加 PA 摄入量将导致 [1-13C]-PA 氧化率降低，并与以下因素相关： (a) 肌肉内炎症信号增加； (b) 胰岛素信号传导减少，其特征是全身、外周胰岛素敏感性降低（正常血糖/高胰岛素钳），并且在骨骼肌中，磷酸-AKT (Ser473) 减少，磷酸-IRS-1 (Ser636/Ser639) 增加，IRS-1 酪氨酸磷酸化减少，以及 GLUT4 膜含量减少。 2. 检验以下假设：增加 PA 摄入量会导致线粒体脂肪酸氧化不太完全，这可能与 TCA 循环功能障碍和活性氧形成增加有关。该假设将通过测量全身和肌肉（上肢）[13-13C]-PA 和 [1-13C]-PA 的相对氧化率以及确定酰基肉碱的血清谱、尿液中的有机酸浓度和肌肉中的蛋白质羰基浓度来检验。 3. 测试以下假设：与肥胖人群和瘦人群中获得的结果相比，高 PA 饮食将导致 FA 氧化不完全、骨骼肌中响应测试餐的胰岛素信号减弱、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更多。公众健康相关性：大量摄入饱和脂肪与糖尿病有关。我们的研究表明，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。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作用的生化和分子机制。