Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1α:: implications for metabolic disease
Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1α:: implications for metabolic disease
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DOI：
10.1139/h07-083
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发表时间：
2007-10-01
影响因子：
3.4
通讯作者：
Koves, Timothy R.
中科院分区：
文献类型：
--
作者：
Muoio, Deborah M.;Koves, Timothy R.
血脂异常和脂肪酸代谢物的肌内蓄积越来越被认为是肥胖和2型糖尿病的核心特征。新出现的证据表明，对重脂质负荷的正常生理适应取决于广泛的转录调节因子如过氧化物酶体增殖物激活受体（PPARs）和PPARy共激活因子Ia（PGCl α）的协调作用。基于质谱的转录组学和靶向代谢分析工具的应用导致我们发现脂质诱导的胰岛素抵抗是这样一种病症，其中PPAR靶向基因的上调和β-氧化的高速率不受三羧酸（TCA）循环活性的相应上调的支持。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饮食动物的胰岛素敏感性。运动激活的转录辅激活因子PGCl α在协调通过这2个交叉代谢途径的代谢通量中起关键作用，并且其通过过度喂养的抑制可能导致饮食诱导的线粒体功能障碍。我们的新兴模型预测，肌肉胰岛素抵抗是由β-氧化和TCA循环活性之间的线粒体断开引起的。了解这种“断开”及其分子基础可能会导致新的治疗方法来对抗代谢性疾病。
Dyslipidemia and intramuscular accumulation of fatty acid metabolites are increasingly recognized as core features of obesity and type 2 diabetes. Emerging evidence suggests that normal physiological adaptations to a heavy lipid load depend on the coordinated actions of broad transcriptional regulators such as the peroxisome proliferator activated receptors (PPARs) and PPAR gamma coactivator la (PGCl alpha). The application of transcriptomics and targeted metabolic profiling tools based on mass spectrometry has led to our finding that lipid-induced insulin resistance is a condition in which upregulation of PPAR-targeted genes and high rates of (beta-oxidation are not supported by a commensurate upregulation of tricarboxylic acid (TCA) cycle activity. In contrast, exercise training enhances mitochondrial performance, favoring 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 coactivator, PGCl alpha, plays a key role in coordinating metabolic flux through these 2 intersecting metabolic pathways, and its suppression by overfeeding may contribute to diet-induced mitochondrial dysfunction. Our emerging model predicts that muscle insulin resistance arises from a mitochondrial disconnect between (beta-oxidation and TCA cycle activity. Understanding of this "disconnect" and its molecular basis may lead to new therapeutic approaches to combatting metabolic disease.