PGC-1α-induced improvements in skeletal muscle metabolism and insulin sensitivity
PGC-1α-induced improvements in skeletal muscle metabolism and insulin sensitivity
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DOI：
10.1139/h09-008
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发表时间：
2009-06-01
影响因子：
3.4
通讯作者：
Bonen, Arend
中科院分区：
文献类型：
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作者：
Bonen, Arend
过氧化物酶体增殖物激活受体γ（PPAR γ）辅激活因子1 α（PGC-1 α）是一种核编码的转录辅激活因子，可增加骨骼肌中许多基因的表达，包括与脂肪酸氧化和氧化磷酸化相关的基因。运动增加PGC-1 α的表达，运动诱导的许多基因上调部分归因于PGC-1 α的先前激活和上调。事实上，PGC-1 α过表达，就像运动训练一样，增加了运动表现。在2型糖尿病中观察到人类PGC-1 α减少，而在细胞系中，PGC-1 α模拟运动诱导的胰岛素敏感性改善。然而，出乎意料的是，在哺乳动物肌肉中，PGC-1 α过表达有助于饮食诱导的胰岛素抵抗的发展。这可能与PGC-1 α的大量过表达有关，PGC-1 α诱导脂肪酸转运蛋白FAT/CD 36上调，导致肌内脂质增加，从而干扰胰岛素信号传导。相比之下，当PGC-1 α在生理限度内适度过表达时，线粒体脂肪酸氧化增加，GLUT 4表达上调，胰岛素刺激的葡萄糖转运增加。最近，已经观察到肥胖Zucker大鼠的胰岛素抵抗骨骼肌中类似的PGC-1 α诱导的改善。这些研究表明，大量PGC-1 α过表达，而不是生理性PGC-1 α过表达，诱导有害的代谢效应，并且运动诱导的胰岛素敏感性改善部分是由运动诱导的PGC-1 α上调诱导的。
The peroxisome proliferator-activated receptor gamma (PPAR gamma) coactivator 1 alpha (PGC-1 alpha), a nuclear encoded transcriptional coactivator, increases the expression of many genes in skeletal muscle, including those involved with fatty acid oxidation and oxidative phosphorylation. Exercise increases the expression of PGC-1 alpha, and the exercise-induced upregulation of many genes is attributable, in part, to the preceding activation and upregulation of PGC-1 alpha. Indeed, PGC-1 alpha overexpression, like exercise training, increases exercise performance. PGC-1 alpha reductions in humans have been observed in type 2 diabetes, while, in cell lines, PGC-1 alpha mimics the exercise-induced improvement in insulin sensitivity. However, unexpectedly, in mammalian muscle, PGC-1 alpha overexpression contributed to the development of diet-induced insulin resistance. This may have been related to the massive overexpression of PGC-1 alpha which induced the upregulation of the fatty acid transporter FAT/CD36 and led to an increase in intramuscular lipids, which interfere with insulin signalling. In contrast, when PGC-1 alpha was overexpressed modestly, within physiological limits, mitochondrial fatty acid oxidation was increased, GLUT4 expression was upregulated, and insulin-stimulated glucose transport was increased. More recently, similar PGC-1 alpha-induced improvements in the insulin-resistant skeletal muscle of obese Zucker rats have been observed. These studies suggest that massive PGC-1 alpha overexpression, but not physiologic PGC-1 alpha overexpression, induces deleterious metabolic effects, and that exercise-induced improvements in insulin sensitivity are induced, in part, by the exercise-induced upregulation of PGC-1 alpha.