Diet-Induced Insulin Resistance in a Murine Fatty Acid Oxidation Disorder

小鼠脂肪酸氧化紊乱中饮食诱导的胰岛素抵抗

• 批准号: 8081734
• 负责人: Melanie B Gillingham
• 金额: $ 7.62万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081734
• 关键词: 1,2-diacylglycerol; Adipose tissue; Animal Model; Applications Grants; Blindness; Body Weight; Cardiomyopathies; Carnitine; Ceramides; Chronic; Data; Defect; Deposition; Development; Diabetes Mellitus; Diet; Diglycerides; Disease; Enzymes; Esters; Euglycemic Clamping; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Future; Genes; Glucose Clamp; Goals; Health; Hepatic; Human; Inborn Genetic Diseases; Individual; Inflammation; Inflammatory Response; Inherited; Insulin; Insulin Resistance; Ketone Bodies; Ketones; Lipids; Literature; Liver; Long-Chain-Acyl-CoA Dehydrogenase; Measures; Metabolic; Mitochondria; Modeling; Molecular; Mus; Muscle; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Stress; Oxidoreductase; Pathogenesis; Pathway interactions; Phenotype; Plasma; Process; Production; Public Health; Reactive Oxygen Species; Recurrence; Regulation; Reporting; Retinitis Pigmentosa; Rhabdomyolysis; Role; Secondary to; Skeletal Muscle; Testing; Tissues; acylcarnitine; base; fatty acid oxidation; feeding; glucose tolerance; human subject; impaired glucose tolerance; improved; insulin sensitivity; insulin signaling; insulin tolerance; long chain fatty acid; oxidation; prevent; research study

DESCRIPTION (provided by applicant): One of the complications of obesity is the development of insulin resistance leading to type 2 diabetes. Recent studies have implicated alterations in mitochondrial function in the pathogenesis of insulin resistance. Whether this is a primary cause of insulin resistance or is secondary to other changes has not been determined. To date no human subject with a fatty acid oxidation (FAO) disorder, inherited defects in mitochondrial FAO, has been reported to develop insulin-resistance or diabetes. The FAO pathway is an essential mitochondrial process involved in energy production. Our current study, K01 DK071869 Fatty Acid Oxidation Disorders and Body Weight Regulation, is investigating insulin resistance in humans with long-chain FAO disorders and we now propose to examine this relationship in a murine model of very long-chain acylCoA dehydrogenase deficiency (VLCADD). We hypothesize that mice with a homozygous deletion of the VLCAD gene will accumulate long-chain acylcarnitines and cytosolic lipid intermediates but will not develop diet-induced insulin resistance compared to wild-type littermates. To test this hypothesis, we will compare lipid deposition in tissues (including ceramide, and diacylglycerols), acylcarnitines, and ketones, markers of mitochondrial function and oxidative stress, and insulin sensitivity by hyperinsulinemic euglycemic clamp studies in VLCAD-/- and wild-type littermates fed either high-fat or standard mouse chow for 12 weeks. Data from these experiments will help define the relationship between FAO and the development of diet-induced insulin resistance. If our hypothesis is true, future grant applications will propose studies to extend the findings by selectively restoring VLCAD activity in insulin sensitive tissues to examining the molecular mechanisms for the protection against diet-induced insulin resistance. PUBLIC HEALTH RELEVANCE: One of the complications of obesity is the development of insulin resistance leading to type 2 diabetes. Humans with inherited defects in mitochondrial fatty acid oxidation (FAO) such as very long-chain acylCoA dehydrogenase deficiency (VLCADD) have not been reported to develop insulin-resistance or diabetes. We propose to test the hypothesis that a block in the FAO pathway prevents the development of diet-induced insulin resistance in a murine model of VLCADD.

描述（由申请人提供）： 肥胖的并发症之一是导致2型糖尿病的胰岛素抵抗的发展。最近的研究暗示了线粒体功能在胰岛素抵抗发病机理中的改变。尚未确定这是胰岛素抵抗的主要原因还是继发于其他变化的原因。迄今为止，据报道，尚无人类受试者的脂肪酸氧化（FAO）障碍，据报道，线粒体粮农组织中的遗传缺陷可以发展出胰岛素抵抗或糖尿病。粮农组织途径是参与能源生产的必不可少的线粒体过程。我们目前的研究，K01 DK071869脂肪酸氧化失调和体重调节，正在研究患有长链FAO疾病的人类的胰岛素抵抗，我们现在建议在非常长链丙基乙酰丙烯量脱氢酶缺乏症（VLCADD）的鼠模型中检查这种关系。我们假设具有纯合缺失的VLCAD基因的小鼠会积累长链酰基肉碱和胞质脂质中间体，但与野生型同意物相比，不会产生饮食诱导的胰岛素抵抗。为了检验这一假设，我们将比较组织（包括神经酰胺和二酰基甘油），酰基苯胺和酮的脂质沉积，线粒体功能和氧化应激的标志物以及胰岛素敏感性以及高胰岛素血液裂解型较高液囊性较高的群 - 和标准型群中的胰岛素质量研究。这些实验的数据将有助于定义粮农组织与饮食诱导的胰岛素抵抗的发展之间的关系。如果我们的假设是正确的，未来的赠款应用将提出研究以选择性恢复胰岛素敏感组织中的VLCAD活性来扩展发现，以检查分子机制，以防止饮食诱导的胰岛素耐药性。 公共卫生相关性： 肥胖的并发症之一是导致2型糖尿病的胰岛素抵抗的发展。线粒体脂肪酸氧化（FAO）中具有遗传缺陷的人类，例如非常长链酰基酰基脱氢酶缺乏症（VLCADD），尚未据报道会产生胰岛素抵抗或糖尿病。我们建议检验以下假设：粮农组织途径中的一个块阻止了在VLCADD的鼠模型中饮食诱导的胰岛素抵抗的发展。