Inhibition of CPT-1b in muscle: effects on glucose homeostasis

肌肉中 CPT-1b 的抑制：对葡萄糖稳态的影响

基本信息

批准号：
8632087
负责人：
Randall Lee Mynatt
金额：
$ 32.19万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-17 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8632087
关键词：
1,2-diacylglycerol Accounting Acute Address Adipose tissue Adverse effects Biogenesis Carbohydrates Carnitine Carnitine O-Palmitoyltransferase Ceramides Chronic Citric Acid Cycle Data Defect Development Diabetes Mellitus Diet Dietary Fats Diglycerides Disease Epidemic Exercise FGF21 gene Fatty Acids Fatty acid glycerol esters Glucose Glycogen Grant Health Expenditures In Vitro Insulin Insulin Resistance Intervention Link Lipids Liver Maintenance Metabolic stress Mitochondria Morbidity - disease rate Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nutrient Obesity Pancreas Pathway interactions Physical activity Prevalence Pyruvate Rattus Reporting Research Role Signal Transduction Skeletal Muscle Tamoxifen Testing Tetanus Helper Peptide Tissues Triglycerides United States Work base blood glucose regulation etomoxir fatty acid oxidation fatty acid transport feeding genetic manipulation glucose tolerance glucose uptake human FRAP1 protein improved inhibitor/antagonist innovation insulin sensitivity insulin signaling insulin tolerance long chain fatty acid mitochondrial dysfunction mortality novel oxidation public health relevance research study theories uptake

项目摘要

Considerable evidence supports the idea that oversupply of dietary fat exceeds the storage capacity of adipose tissue and leads to ectopic lipid accumulation resulting in "metabolic stress" in skeletal muscle, liver, pancreas and possibly other tissues, leading to insulin resistance. One prevailing theory is that impaired skeletal muscle fatty acid oxidation (FAO) leads to the cytosolic accumulation of lipid intermediates that are directly linked to defects in insulin signalin. Others report lipid oversupply via a high fat diet can actually increase FAO to the extent that carnitine and TCA cycle intermediates are limiting, leading to mitochondrial abnormalities and skeletal muscle insulin resistance. Thus, evidence exists that both lipotoxicity and mitochondrial dysfunction contribute to skeletal muscle insulin resistance. Determining if and how these are intertwined is one of the hottest topics in type 2 diabetes research, with the fundamentally important question being: Does inhibition of FAO in skeletal muscle contribute to insulin resistance? To address this question we created mice lacking Carnitine Palmitoyltransferase-1b (CPT-1b) in muscle (CPT-1bm-/-). As predicted, CPT-1bm-/- mice have decreased mitochondrial FAO, increased IMCL, increased circulating free fatty acids (FFA) and triglycerides (TG), and decreased physical activity and exercise endurance. However, CPT-1bm-/- mice are not insulin resistant and have decreased circulating insulin and glucose, improved insulin and glucose tolerance, increased pyruvate oxidation, and increased whole body carbohydrate oxidation. At first glance, the lack of insulin resistance in spite of having hallmark predictors of the disease is at odds with prevailing lipotoxic theories. Indeed, it indicates that CPT-1bm-/- mice undergo unique adaptations to maintain insulin sensitivity in the face of decreased skeletal muscle FAO. Preliminary studies reveal potentially significant alterations promoting lipid uptake and storage, mitochondrial biogenesis, enhanced peroxisomal FAO, and stimulation of factors linked to the mTor signaling cascade. Specific Aim 1: Employ dietary and genetic manipulations in CPT-1bm-/- mice to gain a better understanding of acute and chronic consequences of mitochondrial FAO inhibition. Specific Aim 2: To evaluate the effects of decreased CPT-1b on glucose and fatty acid uptake and storage, mitochondrial number and function, and peroxisomal FAO. Specific Aim 3: To investigate how energy deficit signals are transduced through nutrient sensitive pathways to influence insulin sensitivity. These innovative studies will test the lipotoxic hypothesis and the mitochondrial overload hypothesis in a more definitive manner, providing critical mechanistic information on the role of CPT-1b and FAO in mitochondrial function and insulin resistance.

大量证据支持这样的观点：膳食脂肪供应过剩超过了脂肪的储存能力。脂肪组织并导致异位脂质积累，导致骨骼肌、肝脏、胰腺和可能的其他组织，导致胰岛素抵抗。一种流行的理论是，受损骨骼肌脂肪酸氧化（FAO）导致细胞质中脂质中间体的积累，这些中间体是与胰岛素信号缺陷直接相关。其他人报告说，高脂肪饮食导致的脂质供应过剩实际上可以增加FAO到肉碱和TCA循环中间体受到限制的程度，导致线粒体异常和骨骼肌胰岛素抵抗。因此，有证据表明脂毒性和线粒体功能障碍导致骨骼肌胰岛素抵抗。确定这些是否以及如何相互交织是 2 型糖尿病研究中最热门的话题之一，其中一个根本性的重要问题是：抑制骨骼肌中的FAO是否会导致胰岛素抵抗？为了解决这个问题我们创建了肌肉中缺乏肉碱棕榈酰转移酶-1b (CPT-1b) 的小鼠 (CPT-1bm-/-)。正如预测的那样，CPT-1bm-/-小鼠线粒体FAO减少，IMCL增加，循环游离脂肪酸（FFA）和甘油三酯（TG），以及体力活动和锻炼减少耐力。然而，CPT-1bm-/- 小鼠不具有胰岛素抵抗性，并且循环胰岛素减少，并且葡萄糖，改善胰岛素和葡萄糖耐量，增加丙酮酸氧化，并增加全身碳水化合物氧化。乍一看，尽管有胰岛素抵抗的标志性预测因素，但缺乏胰岛素抵抗这种疾病与流行的脂毒性理论不一致。事实上，这表明 CPT-1bm-/- 小鼠经历了面对骨骼肌减少，保持胰岛素敏感性的独特适应FAO。初步的研究揭示了促进脂质摄取和储存、线粒体生物发生的潜在显着改变，增强过氧化物酶体FAO，并刺激与mTor信号级联相关的因子。具体目标 1：对 CPT-1bm-/- 小鼠进行饮食和基因操作以获得更好的结果了解线粒体FAO抑制的急性和慢性后果。具体目标 2：评估 CPT-1b 减少对葡萄糖和脂肪酸摄取的影响储存、线粒体数量和功能以及过氧化物酶体。具体目标 3：研究如何通过营养敏感信号转导能量不足信号影响胰岛素敏感性的途径。这些创新研究将检验脂毒性假说和线粒体超载假说以更明确的方式提供有关 CPT-1b 和粮农组织在线粒体功能和胰岛素抵抗。