Effect of dietary fat on diet-induced insulin resistance and vascular dysfunction

膳食脂肪对饮食引起的胰岛素抵抗和血管功能障碍的影响

• 批准号: 8974250
• 负责人: KATHRYN G LAMPING
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974250
• 关键词: Address; Affect; Animal Model; Aorta; Arteries; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Caveolae; Cell membrane; Data; Diet; Dietary Fats; Dietary Fatty Acid; Event; Fat Substitutes; Fatty Acids; Fatty acid glycerol esters; Fish Oils; Goals; Guidelines; Health; Healthcare; High Fat Diet; Individual; Insulin Resistance; Link; Lipids; Measures; Mediating; Membrane; Membrane Lipids; Membrane Microdomains; Menhaden oil; Modeling; Mono-S; Mus; N-3 polyunsaturated fatty acid; NOS3 gene; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Olive oil preparation; Overweight; Phospholipids; Population; Production; Prostaglandin-Endoperoxide Synthase; Proteins; Research; Saturated Fatty Acids; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Sphingolipids; Study models; Testing; Tissues; Unsaturated Fats; Vascular Diseases; Veterans; Work; base; caveolin 1; diabetic; dihydroceramide desaturase; feeding; glucose tolerance; indexing; inhibitor/antagonist; innovation; insulin signaling; lard; mouse model; polyunsaturated fat; prevent; response; saturated fat; sphingosine 1-phosphate; sphingosine kinase; therapeutic target; vascular abnormality

DESCRIPTION (provided by applicant): The alarming increase in overweight and obese individuals in the US is a major healthcare issue since it contributes to higher rates of type 2 diabetes, vascular disease and cardiovascular events. Because dietary saturated fatty acids have been linked to vascular dysfunction and insulin resistance (a prelude to type 2 diabetes), dietary fatty acid manipulation may be an important target for preventing or reversing vascular abnormalities associated with obesity. The focus of this proposal is to address the mechanisms underlying dietary fatty acid-induced vascular dysfunction. We hypothesize two potential mechanisms: high saturated fat diets may produce abnormal membrane lipid composition which 1) affects formation of specialized membrane compartments (lipid rafts) and activation of signaling molecules or 2) promotes unique sphingolipid signaling pathways within vascular tissue. These abnormal membrane effects of saturated fatty acids may be reversed by enriching the diet with monounsaturated (MUFAs) or polyunsaturated (PUFAs) fatty acids. To test our hypothesis, we will use a mouse model of high saturated fat-induced obesity and manipulate dietary fat composition to address the following Specific Aims: Aim 1: To determine whether replacement of a portion of dietary saturated fats with MUFA or n-3 PUFAs restores vascular function to normal by modifying caveolar versus non-caveolar localization of key signaling molecules. Our working hypothesis is that diets enriched in MUFAs and n-3 PUFAs target endothelial nitric oxide synthase (eNOS) and/or cyclooxygenase (Cox) to membrane lipid rafts differently than a high saturated fat diet by altering membrane composition. This shift in localization defines their activation and vascular function. We will measure responses of small gracilis arteries and aorta from mice on diets enriched in saturated fats, MUFA enriched olive oil or n-3 PUFA enriched menhaden oil in conjunction with membrane fatty acid composition and localization of eNOS and Cox within lipid rafts. We will compare the effects of diet on vascular function with localization of signaling pathways using wild type and caveolin-1 (cav-1) deficient mice devoid of vascular caveolae to separate effects on caveolar versus non-caveolar lipid rafts. Aim 2: To determine whether dietary fatty acid saturation affects sphingolipid signaling pathways- specifically sphingosine kinase and sphingosine-1-phosphate (S1P)- to modify vascular function. Our working hypothesis is that dietary fatty acids promote signaling through formation of unique sphingolipid-based proteins that impact vascular function. We will measure responses of small gracilis arteries and aorta from mice on diets enriched in saturated fats, MUFAs or n-3 PUFAs in conjunction with levels of sphingosine kinase and S1P within vascular tissue. We will assess the effects of dietary fatty acids on sphingosine kinase by comparing expression levels and using pharmacological inhibitors and genetically modified mice. High fat feeding of mice is a relevant model for study of vascular complications of diet since mice become obese, develop insulin resistance and abnormal glucose tolerance similar to type 2 diabetics. High fat diets are the greatest cause of obesity in people. These studies are innovative in directly testing the mechanisms involved in effects of dietary fats on vascular function using a mouse model of obesity: abnormal membrane composition and localization of signaling proteins within specific lipid rafts or fatty acid-dependent signaling pathways. The studies are significant because dietary fats are a known therapeutic target but the optimal diet composition for reversing the progression of cardiovascular disease and the mechanisms involved are not clearly defined.

描述(由申请人提供)： 在美国，超重和肥胖人数的惊人增加是一个主要的医疗保健问题，因为它导致了2型糖尿病、血管疾病和心血管事件的更高发生率。由于饮食饱和脂肪酸与血管功能障碍和胰岛素抵抗(2型糖尿病的前奏)有关，饮食脂肪酸操作可能是预防或逆转与肥胖相关的血管异常的重要目标。这项提案的重点是解决膳食脂肪酸导致血管功能障碍的潜在机制。我们假设了两种可能的机制：高饱和脂肪饮食可能产生异常的膜脂组成，1)影响特化膜室(脂筏)的形成和信号分子的激活；2)促进血管组织内独特的鞘磷脂信号通路。通过增加单不饱和脂肪酸(MUFAs)或多不饱和脂肪酸(PUFAs)的饮食，饱和脂肪酸的这些异常的膜效应可能会被逆转。为了验证我们的假设，我们将使用高饱和脂肪诱导的肥胖小鼠模型，并操纵饮食脂肪组成来解决以下特定目标：目标1：确定用MUFA或n-3PUFA取代部分饮食饱和脂肪是否通过改变关键信号分子的凹陷与非凹陷定位来恢复血管功能正常。我们的工作假设是，富含MUFAs和n-3PUFAs的饲料通过改变膜成分，将内皮型一氧化氮合酶(ENOS)和/或环氧合酶(COX)靶向膜脂筏，而不同于高饱和脂肪饲料。这种定位的转变决定了它们的激活和血管功能。我们将测量小鼠股薄肌动脉和主动脉对富含饱和脂肪、MUFA富含橄榄油或n-3PUFA富含薄荷油的饲料的反应，以及膜脂肪酸组成和eNOS和COX在脂筏中的定位。我们将比较饮食对血管功能的影响和信号通路的定位，使用野生型和小窝蛋白-1(Cav-1)缺陷的小鼠，无血管小窝，以区分对小窝和非小窝脂筏的影响。目的2：确定膳食脂肪酸饱和是否影响鞘氨醇信号通路--特别是鞘氨醇激酶和鞘氨醇-1-磷酸(S1P)--从而调节血管功能。我们的工作假设是，饮食中的脂肪酸通过形成独特的基于鞘磷脂的蛋白质来促进信号传递，这些蛋白质影响血管功能。我们将测量小鼠股薄肌小动脉和主动脉对富含饱和脂肪、MUFAs或n-3PUFAs的饮食的反应，以及血管组织中鞘氨醇激酶和S1P的水平。我们将通过比较表达水平以及使用药物抑制剂和转基因小鼠来评估膳食脂肪酸对鞘氨醇激酶的影响。小鼠肥胖，出现胰岛素抵抗和糖耐量异常，类似于2型糖尿病患者，高脂饮食是研究饮食血管并发症的相关模型。高脂肪饮食是人类肥胖的最大原因。这些研究在利用肥胖小鼠模型直接测试饮食脂肪对血管功能影响的机制方面具有创新性：在特定的脂筏或脂肪酸依赖的信号通路中，信号蛋白的膜成分和定位异常。这些研究意义重大，因为饮食脂肪是已知的治疗目标，但逆转心血管疾病进展的最佳饮食结构和涉及的机制尚未明确定义。