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

描述(由申请人提供)： 肥胖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，还是其他变化的次要原因尚未确定。到目前为止，还没有报道有脂肪酸氧化(FAO)紊乱的人类受试者患上胰岛素抵抗或糖尿病。粮农组织途径是参与能量生产的一个重要的线粒体过程。我们目前的研究，K01 DK071869脂肪酸氧化紊乱和体重调节，正在调查患有长链粮农组织紊乱的人类的胰岛素抵抗，我们现在建议在超长链酰辅酶A脱氢酶缺乏症(VLCADD)的小鼠模型中检查这种关系。我们假设，与野生型相比，VLCAD基因纯合缺失的小鼠将积累长链酰基肉碱和胞浆脂质中间体，但不会出现饮食诱导的胰岛素抵抗。为了验证这一假设，我们将通过高胰岛素正常血糖钳夹研究比较组织(包括神经酰胺和二酰甘油)、酰肉碱和酮中的脂肪沉积，线粒体功能和氧化应激的标记物，以及胰岛素敏感性，在喂养高脂肪或标准小鼠饲料12周的VLCAD-/-和野生型窝仔中进行。这些实验的数据将有助于确定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，未来的拨款申请将提出研究，通过选择性地恢复胰岛素敏感组织中的VLCAD活性来研究预防饮食诱导的胰岛素抵抗的分子机制。 公共卫生相关性： 肥胖的并发症之一是胰岛素抵抗的发展，导致2型糖尿病。具有线粒体脂肪酸氧化(FAO)遗传缺陷的人，如超长链酰辅酶A脱氢酶缺乏症(VLCADD)，尚未有患胰岛素抵抗或糖尿病的报道。我们建议在VLCADD的小鼠模型中检验这一假设，即FAO途径的阻断可以防止饮食诱导的胰岛素抵抗的发展。

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.