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

• 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
• 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

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.

大量证据支持以下观点：饮食脂肪的过度供应超过 脂肪组织并导致异位脂质积累，导致骨骼肌，肝脏，肝脏中的“代谢应激” 胰腺以及可能导致胰岛素抵抗的其他组织。一个流行的理论是受损 骨骼肌脂肪酸氧化（FAO）导致脂质中间体的胞质积累 直接链接到胰岛素信号中的缺陷。其他人则通过高脂饮食报告说脂质过度供应实际上可以 在肉碱和TCA循环中间体限制的程度上增加粮农组织，导致线粒体 异常和骨骼肌胰岛素抵抗。因此，有证据表明脂肪毒性和 线粒体功能障碍有助于骨骼肌胰岛素抵抗。确定它们是否以及如何是 交织在一起是2型糖尿病研究中最热门的主题之一，这根本重要的问题是 存在：骨骼肌中粮农组织的抑制是否有助于胰岛素抵抗？为了解决这个问题我们 创建了缺乏肌肉中缺乏肉碱棕榈酰转移酶1b（CPT-1B）的小鼠（CPT-1BM - / - ）。 如预测的，CPT-1BM - / - 小鼠的线粒体粮农组织降低，IMCL增加，增加 循环游离脂肪酸（FFA）和甘油三酸酯（TG），体育锻炼和运动减少 耐力。但是，CPT-1BM - / - 小鼠不具有胰岛素耐药性，并且循环胰岛素降低，并且 葡萄糖，改善胰岛素和葡萄糖耐受性，增加丙酮酸氧化并增加了全身 碳水化合物氧化。乍一看，尽管具有标志性预测指标，但缺乏胰岛素抵抗 该疾病与流行的脂肪毒性理论不符。确实，这表明CPT-1BM - / - 小鼠发生 面对减少骨骼肌粮农组织，以保持胰岛素敏感性的独特适应性。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， 增强的过氧化物酶体粮农组织以及与MTOR信号级联有关的因素的刺激。 特定目的1：在CPT-1BM - / - 小鼠中采用饮食和遗传操作以获得更好的 了解线粒体粮农组织抑制的急性和慢性后果。 具体目标2：评估CPT-1B降低对葡萄糖和脂肪酸摄取的影响以及 存储，线粒体数和功能以及过氧化物酶体粮农组织。 特定目的3：研究如何通过营养敏感的方式转导能源信号 影响胰岛素敏感性的途径。 这些创新的研究将检验脂蛋白毒性假设和线粒体超负荷假设 更明确的方式，提供有关CPT-1B和粮农组织作用的关键机理信息 线粒体功能和胰岛素抵抗。