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Lipid Mediators of Insulin Resistance

胰岛素抵抗的脂质介质

基本信息

批准号：
8299139
负责人：
SCOTT A SUMMERS
金额：
$ 32.49万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8299139
关键词：
1,2-diacylglycerol Adaptor Signaling Protein Adipose tissue Anabolism Cardiovascular Diseases Catheters Cells Ceramides Chronic Consensus Consumption Data Deposition Diabetes Mellitus Diglycerides Dose Emulsions Energy-Generating Resources Enzymes Fatty Acids Fatty acid glycerol esters Functional disorder Glucose Goals Health Hormones In Vitro Incubated Inflammation Inflammatory Insulin Insulin Antagonists Insulin Resistance Investigation Laboratories Link Lipids Lipoprotein Binding Liver Malignant Neoplasms Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolism Molecular Mus Muscle Muscle Fibers Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Palmitates Pathway interactions Phenotype Phosphatidic Acid Phospholipids Polyunsaturated Fatty Acids Production Proteins Proto-Oncogene Proteins c-akt Publishing Receptor Signaling Regulation Relative (related person)Resistance Risk Factors Rodent Role Saturated Fatty Acids Signal Pathway Skeletal Muscle Soleus Muscle Sphingolipids System TNF gene Testing Therapeutic Tissues Toll-like receptors Translating Triglycerides Unsaturated Fats Unsaturated Fatty Acids base blood glucose regulation combat cytokine fatty acid metabolism glucose uptake human FRAP1 protein in vivo insight insulin sensitivity insulin signaling lipid mediator mTOR protein new therapeutic target peptide hormone programs protein phosphatase 2A inhibitor 2 resistance mechanism response saturated fat sensor tissue culture uptake

项目摘要

DESCRIPTION (provided by applicant): The peptide hormone insulin stimulates the uptake and storage of glucose and other nutrients into adipose tissue and skeletal muscle while simultaneously repressing glucose efflux from the liver. Insulin resistance occurs when a normal dose of the hormone is incapable of eliciting these anabolic responses, and the condition is a risk factor for cardiovascular disease, type 2 diabetes, and certain forms of cancer. The accumulation of ectopic fat in skeletal muscle has been strongly implicated in insulin resistance, but the mechanism by which excess lipid alters insulin sensitivity is not clear. In particularly, though intramyocellular levels of certain lipid metabolites (e.g., triacylglcyerol and diacylglycerol) correlate with insulin resistance, these molecules don't appear to be active antagonists of insulin action. A long-term goal of our laboratory is to identify the key lipid metabolites which alter insulin sensitivity, and to elucidate the molecular mechanisms by which they inhibit insulin action and disrupt glucose homeostasis. Using experimental systems to deliver exogenous fats to muscle either in vitro or ex vivo, we have determined that the metabolic processing of fatty acids is a key determinant for how they antagonize insulin action. For example, the saturated fatty acid palmitate is almost exclusively reliant on ceramide for its induction of insulin resistance. By contrast, the unsaturated fatty acid linoleate is ceramide-independent, and seems to rely on a glycerolipid intermediate. In the studies proposed herein, we will (a) identify the lipid intermediates which mediate palmitate and linoleate-induced insulin resistance, (b) elucidate the intracellular sensors which link these metabolites to the antagonism of insulin action, and (c) determine how the regulation of fatty acid metabolism by inflammatory factors alters the production of these key lipid metabolites. To obtain this information, we will test the following hypotheses. Aim One: Ceramide, and not a glucosylated ceramide metabolite, links saturated fatty acids to the induction of insulin resistance through the target protein I2PP2A. Aim Two: Phosphatidic acid, and not diacyglycerol, links unsaturated fatty acids to the induction of insulin resistance through the target protein mTOR. Aim Three: Toll like receptors, which are direct effectors of saturated fats, influence insulin sensitivity by diverting incoming fatty acids towards ceramide synthesis. Collectively, these studies could will provide an enhanced understanding of how lipid dysregulation underlies insulin resistance, and could give rise to therapeutic strategies for enhancing insulin sensitivity and combating diabetes. PUBLIC HEALTH RELEVANCE: Excessive deposition of fat in tissues that are not particularly well-suited for fat storage likely contributes to a number of the pathogenic consequences of obesity. However, it is not clear which types of lipid metabolites are deleterious, nor is it understood how these fat derivatives induce cell dysfunction. Using various strategies to alter metabolic pathways controlling fat utilization, we will investigate the role of specific fats in the onset of diabetes.

描述（由申请人提供）：肽激素胰岛素刺激葡萄糖和其他营养物质的摄取和储存进入脂肪组织和骨骼肌，同时抑制葡萄糖从肝脏流出。当正常剂量的激素无法引发这些合成代谢反应时，就会发生胰岛素抵抗，并且这种情况是心血管疾病，2型糖尿病和某些形式的癌症的风险因素。异位脂肪在骨骼肌中的积累与胰岛素抵抗密切相关，但过量脂质改变胰岛素敏感性的机制尚不清楚。特别地，尽管某些脂质代谢物（例如，三酰甘油和二酰甘油）与胰岛素抵抗相关，但这些分子似乎不是胰岛素作用的活性拮抗剂。我们实验室的长期目标是鉴定改变胰岛素敏感性的关键脂质代谢物，并阐明它们抑制胰岛素作用并破坏葡萄糖稳态的分子机制。使用实验系统在体外或离体将外源性脂肪递送到肌肉，我们已经确定脂肪酸的代谢加工是它们如何拮抗胰岛素作用的关键决定因素。例如，饱和脂肪酸棕榈酸酯几乎完全依赖于神经酰胺来诱导胰岛素抗性。相比之下，不饱和脂肪酸亚油酸酯不依赖于神经酰胺，并且似乎依赖于甘油脂质中间体。在本文提出的研究中，我们将（a）鉴定介导棕榈酸和亚麻酸诱导的胰岛素抵抗的脂质中间体，（B）阐明将这些代谢物与胰岛素作用的拮抗作用联系起来的细胞内传感器，和（c）确定炎症因子对脂肪酸代谢的调节如何改变这些关键脂质代谢物的产生。为了获得这些信息，我们将测试以下假设。目标一：神经酰胺，而不是葡萄糖基化的神经酰胺代谢产物，通过靶蛋白I2PP2A将饱和脂肪酸与胰岛素抵抗的诱导联系起来。目标二：磷脂酸，而不是二酰甘油，通过靶蛋白mTOR将不饱和脂肪酸与胰岛素抵抗的诱导联系起来。目标三：Toll样受体是饱和脂肪的直接效应物，通过将进入的脂肪酸转向神经酰胺合成来影响胰岛素敏感性。总的来说，这些研究将提供一个更好的了解如何脂质失调的基础胰岛素抵抗，并可能产生治疗策略，提高胰岛素敏感性和防治糖尿病。公共卫生关系：脂肪在不特别适合脂肪储存的组织中的过度沉积可能导致肥胖症的许多致病后果。然而，目前尚不清楚哪些类型的脂质代谢物是有害的，也不清楚这些脂肪衍生物如何诱导细胞功能障碍。使用各种策略来改变控制脂肪利用的代谢途径，我们将研究特定脂肪在糖尿病发病中的作用。