PGC-1α deficiency causes multi-system energy metabolic derangements:: Muscle dysfunction, abnormal weight control and hepatic steatosis
PGC-1α deficiency causes multi-system energy metabolic derangements:: Muscle dysfunction, abnormal weight control and hepatic steatosis
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DOI：
10.1371/journal.pbio.0030101
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发表时间：
2005-04-01
期刊：
影响因子：
9.8
通讯作者：
Kelly, DP
中科院分区：
文献类型：
--
作者：
Leone, TC;Lehman, JJ;Kelly, DP
在小鼠中靶向编码转录共激活因子过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1 α）的基因。PGC-1 alpha null（PGC-1 alpha（-/-））小鼠存活。然而，广泛的表型分析显示多系统异常，提示能量代谢表型异常。在PGC-1 alpha（-/-）小鼠中，心脏和慢收缩骨骼肌（线粒体能量需求较高的器官）的产后生长变得迟钝。随着年龄的增长，PGC-1 alpha（-/-）小鼠的体脂异常增加，这是一种在雌性中更为严重的表型。PGC-1 alpha（-/-）小鼠慢颤骨骼肌的线粒体数量和呼吸能力减少，导致肌肉性能和运动能力下降。PGC-1 α（-/-）小鼠表现出心脏功能的适度降低，主要与心率控制异常有关。PGC-1 alpha（-/-）小鼠在暴露于寒冷后无法维持核心体温，这与产热反应的改变一致。在短期饥饿后，PGC-1 α（-/-）小鼠由于线粒体呼吸能力降低和脂肪生成基因表达增加的组合而发生肝脂肪变性。令人惊讶的是，PGC-1 α（-/-）小鼠对饮食诱导的胰岛素抵抗的敏感性低于野生型对照。最后，在PGC-1 α（-/-）小鼠的中枢神经系统中检测到空泡病变。这些结果表明，PGC-1 α是必要的适当适应代谢和生理应激的出生后生活。
The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) was targeted in mice. PGC-1 alpha null (PGC-1 alpha(-/-)) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1 alpha(-/-) mice. With age, the PGC-1 alpha(-/-) mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1 alpha(-/-) mice, leading to reduced muscle performance and exercise capacity. PGC-1 alpha(-/-) mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1 alpha(-/-) mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1 alpha(-/-) mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1 alpha(-/-) mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1 alpha(-/-) mice. These results demonstrate that PGC-1 alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.