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

相当多的证据支持这样一种观点，即饮食中脂肪的供应过剩超过了食物的储存能力 脂肪组织，并导致异位脂肪堆积，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)导致细胞内脂质中间体的积累，这些中间体是 与胰岛素信号的缺陷直接相关。其他人报告说，通过高脂肪饮食导致的脂肪供应过剩实际上可能 增加粮农组织，使肉碱和三氯乙酸循环中间体受到限制，导致线粒体 骨骼肌异常和胰岛素抵抗。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 交织是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 问题：骨骼肌中FAO的抑制是否会导致胰岛素抵抗？为了解决这个问题，我们 建立肌肉中缺乏肉碱棕榈酰转移酶-1b(CPT-1b-/-)的小鼠。 正如预测的那样，CPT-1bm-/-小鼠线粒体FAO减少，IMCL增加， 循环中的游离脂肪酸(FFA)和甘油三酯(TG)，以及体力活动和锻炼的减少 忍耐力。然而，CPT-1bm-/-小鼠没有胰岛素抵抗，循环胰岛素和 葡萄糖，改善胰岛素和葡萄糖耐量，增加丙酮酸氧化，增加全身 碳水化合物氧化。乍一看，缺乏胰岛素抵抗，尽管有显著的预测因素 这种疾病与流行的脂毒性理论不符。事实上，它表明CPT-1bm-/-小鼠经历了 在骨骼肌萎缩的情况下保持胰岛素敏感性的独特适应。初步 研究表明，潜在的显著变化促进了脂质的吸收和储存，线粒体的生物发生， 增强了粮农组织的过氧化体，并刺激了与mTOR信号级联相关的因子。 具体目标1：在CPT-1bm-/-小鼠中使用饮食和遗传操作来获得更好的 了解粮农组织线粒体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 储存，线粒体的数量和功能，和过氧化物体粮农组织。 具体目标3：研究能量缺乏信号是如何通过营养敏感转导的 影响胰岛素敏感性的途径。 这些创新的研究将检验脂毒假说和线粒体超载假说 更明确的方式，提供关于CPT-1b和粮农组织在 线粒体功能与胰岛素抵抗。

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.