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: 8734414
• 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/8734414
• 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

DESCRIPTION (provided by applicant): 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 signaling. Others report lipid oversupply via a high fat iet 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.

描述（由申请人提供）：大量证据支持以下观点：膳食脂肪供应过量超过脂肪组织的储存能力，导致异位脂质蓄积，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的骨骼肌脂肪酸氧化（FAO）导致脂质中间体的胞质积累，所述脂质中间体与胰岛素信号传导中的缺陷直接相关。其他人报告通过高脂肪酸的脂质供应过剩实际上可以增加FAO的程度，肉毒碱和TCA循环中间体是有限的，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都有助于骨骼肌胰岛素抵抗。确定这些是否以及如何交织在一起是2型糖尿病研究中最热门的话题之一，其中最重要的问题是：骨骼肌中FAO的抑制是否有助于胰岛素抵抗？为了解决这个问题，我们创建了肌肉中缺乏肉毒碱棕榈酰转移酶-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）增加，体力活动和运动耐力降低。然而，CPT-1bm-/-小鼠不具有胰岛素抗性，并且具有降低的循环胰岛素和葡萄糖、改善的胰岛素和葡萄糖耐受性、增加的丙酮酸氧化和增加的全身碳水化合物氧化。乍看之下，缺乏胰岛素抵抗，尽管有标志性的预测疾病是不符合流行的脂毒性理论。事实上，这表明CPT-1bm-/-小鼠在骨骼肌FAO下降的情况下经历了独特的适应以维持胰岛素敏感性。初步研究揭示了潜在的重大改变，促进脂质摄取和储存，线粒体生物合成，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：在CPT-1bm-/-小鼠中采用饮食和遗传操作，以更好地了解线粒体FAO抑制的急性和慢性后果。具体目标二：评估CPT-1b降低对葡萄糖和脂肪酸摄取和储存、线粒体数量和功能以及过氧化物酶体FAO的影响。具体目标3：研究能量缺乏信号如何通过营养敏感途径转导以影响胰岛素敏感性。 这些创新研究将以更明确的方式测试脂毒性假说和线粒体过载假说，提供CPT-1b和FAO在线粒体功能和胰岛素抵抗中作用的关键机制信息。