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

描述（由申请人提供）： 肥胖症的并发症之一是胰岛素抵抗的发展，导致2型糖尿病。最近的研究表明，线粒体功能的改变与胰岛素抵抗的发病机制有关。这是胰岛素抵抗的主要原因还是继发于其他变化尚未确定。迄今为止，还没有报道患有脂肪酸氧化（FAO）障碍（线粒体FAO中的遗传缺陷）的人类受试者发展成胰岛素抵抗或糖尿病。FAO途径是参与能量生产的重要线粒体过程。我们目前的研究，K 01 DK 071869脂肪酸氧化障碍和体重调节，正在调查胰岛素抵抗的人与长链FAO疾病，我们现在建议在非常长链酰基辅酶A脱氢酶缺乏症（VLCADD）的小鼠模型中检查这种关系。我们假设，与野生型同窝小鼠相比，VLCAD基因纯合缺失的小鼠将积累长链酰基肉毒碱和胞质脂质中间体，但不会发展饮食诱导的胰岛素抵抗。为了验证这一假设，我们将比较组织中的脂质沉积（包括神经酰胺和二酰基甘油），酰基肉毒碱和酮，线粒体功能和氧化应激的标志物，以及通过高胰岛素正葡萄糖钳夹研究在VLCAD-/-和野生型同窝出生仔中喂养高脂肪或标准小鼠食物12周的胰岛素敏感性。这些实验的数据将有助于确定FAO和饮食诱导的胰岛素抵抗的发展之间的关系。如果我们的假设是真的，未来的资助申请将提出研究，通过选择性恢复胰岛素敏感组织中的VLCAD活性来扩展研究结果，以检查防止饮食诱导的胰岛素抵抗的分子机制。 公共卫生相关性： 肥胖症的并发症之一是胰岛素抵抗的发展，导致2型糖尿病。线粒体脂肪酸氧化（FAO）遗传缺陷的人，如极长链酰基辅酶A脱氢酶缺乏症（VLCADD），尚未报告发生胰岛素抵抗或糖尿病。我们建议测试的假设，在FAO途径的块阻止饮食诱导的胰岛素抵抗的发展在VLCADD的小鼠模型。

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.