Palmitate Metabolism and Insulin Resistance

棕榈酸酯代谢和胰岛素抵抗

• 批准号: 8055817
• 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
• 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/8055817
• 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

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)，削弱骨骼肌中的胰岛素敏感性，在饮食中用油酸(一种单不饱和脂肪酸(FA))取代PA可能是有益的。本项目的第一个目标是了解饮食中FA组成的两个常见变化对脂代谢和骨骼肌脂组成、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)地中海脂肪酸组成，其中PA较低，而OA较高(HI OA饮食)。PA可能通过聚集在肌细胞内的脂质和激活炎症信号来诱导骨骼肌细胞的胰岛素抵抗。该项目的第二个目标是评估一种假说，即大量摄入PA将下调自身的一碳(初始)氧化，导致炎症信号增加和胰岛素信号减少。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的缺陷；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初始氧化的假说。在16名超重或肥胖者和16名瘦肉型受试者(年龄18-40岁)中，对高PA饮食与高PA/低PA饮食的影响进行了双掩蔽交叉试验，以调查以下特定目的：1.检验PA摄入量增加将导致[1-13C]-PA氧化率降低的假设，并将与：(A)肌肉内炎症信号的增加有关；(B)降低胰岛素信号，表现为全身、外周胰岛素敏感性降低(正常血糖/高胰岛素钳夹)，在骨骼肌中，磷酸化AKT(Ser473)减少，磷酸化IRS-1(Ser636/Ser639)增加，IRS-1酪氨酸磷酸化降低，GLUT4膜含量减少。2.验证PA摄入量增加将导致线粒体脂肪酸氧化不完全的假说，这可能与TCA循环功能障碍和活性氧形成增加有关。这一假说将通过测量全身和肌肉(上肢)[13-13C]-PA和[1-13C]-PA的相对氧化速率，以及通过测定血清中酰基肉碱的含量、尿液中有机酸的浓度和肌肉中蛋白质羰基的浓度来验证。3.与肥胖和瘦人相比，高PA饮食将导致FA氧化不完全，骨骼肌对试餐的胰岛素信号较少，全身胰岛素敏感性降低，TCA循环功能障碍增加，以及更多的活性氧物种形成。 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胰岛素激素的作用的生化和分子机制。