Defects in adaptive energy metabolism with CNS-Linked hyperactivity in PGC-1α null mice
Defects in adaptive energy metabolism with CNS-Linked hyperactivity in PGC-1α null mice
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DOI：
10.1016/j.cell.2004.09.013
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发表时间：
2004-10-01
期刊：
影响因子：
64.5
通讯作者：
Spiegelman, BM
中科院分区：
文献类型：
--
作者：
Lin, JD;Wu, PH;Spiegelman, BM
PGC-1 α是核受体和其他转录因子的共激活因子，调节几种代谢过程，包括线粒体生物发生和呼吸，肝细胞再生和肌纤维类型转换。我们在这里表明，虽然缺乏PGC-1 α的肝细胞是有缺陷的，在程序中的肝细胞刺激hepatocyte eogenesis，小鼠组成性激活hepatocyte eogenesis基因表达是完全不敏感的正常喂养控制。C/EBP β在这些小鼠的肝脏中升高，并以PGC-1 α非依赖性方式激活致癌基因。尽管线粒体功能降低，但PGC-1 α基因敲除小鼠却出奇地瘦，并且对饮食诱导的肥胖有抵抗力。这在很大程度上是由于无效动物表现出的极度活跃，并且与控制运动的大脑纹状体区域的病变有关。这些数据说明了PGC-1 α在控制能量代谢中的核心作用，但也揭示了新的全身代偿机制和能量稳态受损的致病作用。
PGC-1alpha is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1alpha are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPbeta is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1alpha-independent manner. Despite having reduced mitochondrial function, PGC-1alpha null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1alpha in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.