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

大量的证据支持这样的观点，即膳食脂肪的过量供应超过了人体的储存能力。 脂肪组织，并导致异位脂质积聚，导致骨骼肌，肝， 胰腺和可能的其他组织，导致胰岛素抵抗。一个流行的理论是， 骨骼肌脂肪酸氧化（FAO）导致脂质中间体的胞质积累， 与胰岛素信号传导的缺陷直接相关。另一些人报告说，通过高脂肪饮食， 增加粮农组织的程度，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， 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 制造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-/-小鼠的线粒体FAO减少，IMCL增加， 循环游离脂肪酸（FFA）和甘油三酯（TG），以及体力活动和运动减少 耐力然而，CPT-1bm-/-小鼠没有胰岛素抵抗，循环胰岛素减少， 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，缺乏胰岛素抵抗，尽管有标志性的预测因素， 这种疾病与流行的脂毒性理论不一致。事实上，它表明CPT-1bm-/-小鼠经历了 独特的适应，以保持胰岛素敏感性，在面对减少骨骼肌粮农组织。初步 研究揭示了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，以获得更好的 了解线粒体FAO抑制的急性和慢性后果。 具体目的2：评价CPT-1b降低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FAO。 具体目标3：研究能量缺乏信号如何通过营养敏感性 影响胰岛素敏感性的途径。 这些创新的研究将测试脂毒性假说和线粒体超载假说， 以更明确的方式，提供关于CPT-1b和粮农组织在以下方面作用的关键机制信息： 线粒体功能和胰岛素抵抗。

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.