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

基本信息

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
项目类别：
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

项目摘要

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产生胰岛素抵抗，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。这是否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，尚无患有脂肪酸氧化（FAO）疾病（线粒体FAO遗传缺陷）的人类受试者出现胰岛素抵抗或糖尿病的报道。 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 K01 DK071869 脂肪酸氧化紊乱和体重调节正在调查患有长链脂肪酸紊乱的人类的胰岛素抵抗，我们现在建议在极长链酰基辅酶 A 脱氢酶缺乏症 (VLCADD) 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会积累长链酰基肉碱和胞质脂质中间体，但不会出现饮食诱导的胰岛素抵抗。为了检验这一假设，我们将通过在 VLCAD-/- 和野生型中进行高胰岛素正常血糖钳夹研究来比较组织中的脂质沉积（包括神经酰胺和二酰基甘油）、酰基肉碱和酮、线粒体功能和氧化应激的标志物以及胰岛素敏感性。同窝小鼠喂食高脂肪或标准小鼠饲料 12 周。这些实验的数据将有助于确定FAO与饮食引起的胰岛素抵抗的发展之间的关系。如果我们的假设成立，未来的拨款申请将提出研究，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，以检查防止饮食引起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产生胰岛素抵抗，导致 2 型糖尿病。尚无报道称患有线粒体脂肪酸氧化 (FAO) 遗传缺陷（例如极长链酰基辅酶 A 脱氢酶缺乏症 (VLCADD)）的人类会出现胰岛素抵抗或糖尿病。我们建议在 VLCADD 小鼠模型中检验以下假设：FAO 途径的阻断可防止饮食诱导的胰岛素抵抗的发展。