Lipid-induced metabolic dysfunction in skeletal muscle.
Lipid-induced metabolic dysfunction in skeletal muscle.
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DOI：
10.1002/9780470985571.ch4
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发表时间：
2007-11
影响因子：
--
通讯作者：
D. Muoio;T. Koves
中科院分区：
文献类型：
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作者：
D. Muoio;T. Koves
胰岛素抵抗是2型糖尿病的标志，通常在其他能量紧张的环境中观察到，如肥胖，饥饿，不活动和衰老。血脂异常和“脂毒性”--脂质代谢物的组织蓄积--越来越被认为是胰岛素抵抗状态的重要驱动因素。越来越多的证据表明，骨骼肌中脂质诱导的代谢功能障碍在很大程度上是由干扰胰岛素信号转导的应激激活的丝氨酸激酶介导的。然而，将脂质过度供应与应激激酶激活和葡萄糖耐受不良联系起来的代谢和分子事件尚不清楚。转录组学和基于靶向质谱的代谢组学工具的应用使我们发现胰岛素抵抗是一种肌肉线粒体持续承受重脂质负荷的状况。因此，高速率的β-氧化超过了通过TCA循环的代谢通量，导致不完全氧化的酰基-肉毒碱中间体的积累。相比之下，运动训练增强线粒体性能，有利于β-氧化和TCA循环之间的更紧密耦合，并伴随着恢复长期高脂肪饮食动物的胰岛素敏感性。运动激活的转录辅激活因子PGC 1 α在协调通过这两个交叉代谢途径的代谢流中起着关键作用，过度喂养对其的抑制可能导致肥胖相关的线粒体功能障碍。我们的新兴模型预测，肌肉胰岛素抵抗是由线粒体脂质应激和β-氧化与TCA循环活性之间的脱节引起的。了解这种“断开”及其分子基础可能会导致新的治疗目标，以打击代谢疾病。
Insulin resistance is a hallmark of type 2 diabetes and commonly observed in other energy-stressed settings such as obesity, starvation, inactivity and ageing. Dyslipidaemia and 'lipotoxicity'--tissue accumulation of lipid metabolites-are increasingly recognized as important drivers of insulin resistant states. Mounting evidence suggests that lipid-induced metabolic dysfunction in skeletal muscle is mediated in large part by stress-activated serine kinases that interfere with insulin signal transduction. However, the metabolic and molecular events that connect lipid oversupply to stress kinase activation and glucose intolerance are as yet unclear. Application of transcriptomics and targeted mass spectrometry-based metabolomics tools has led to our finding that insulin resistance is a condition in which muscle mitochondria are persistently burdened with a heavy lipid load. As a result, high rates of beta-oxidation outpace metabolic flux through the TCA cycle, leading to accumulation of incompletely oxidized acyl-carnitine intermediates. In contrast, exercise training enhances mitochondrial performance, favouring tighter coupling between beta-oxidation and the TCA cycle, and concomitantly restores insulin sensitivity in animals fed a chronic high fat diet. The exercise-activated transcriptional co-activator, PGC1alpha, plays a key role in co-ordinating metabolic flux through these two intersecting metabolic pathways, and its suppression by overfeeding may contribute to obesity-associated mitochondrial dysfunction. Our emerging model predicts that muscle insulin resistance arises from mitochondrial lipid stress and a resultant disconnect between beta-oxidation and TCA cycle activity. Understanding this 'disconnect' and its molecular basis may lead to new therapeutic targets for combating metabolic disease.