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Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism


The mammalian clock regulates major aspects of energy metabolism, including glucose and lipid homeostasis and mitochondrial oxidative metabolism1,2. The biochemical basis for coordinated control of the circadian clock and diverse metabolic pathways is not well understood. Here we show that PGC-1α (Ppargc1a), a transcriptional coactivator that regulates energy metabolism3,4,5,6,7,8,9, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1α stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbα (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Mice lacking PGC-1α show abnormal diurnal rhythms of activity, body temperature and metabolic rate. The disruption of physiological rhythms in these animals is correlated with aberrant expression of clock genes and those involved in energy metabolism. Analyses of PGC-1α-deficient fibroblasts and mice with liver-specific knockdown of PGC-1α indicate that it is required for cell-autonomous clock function. We have thus identified PGC-1α as a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism.

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Figure 1: Regulation of clock genes by PGC-1α.
Figure 2: Regulation of Bmal1 gene transcription by PGC-1α and ROR.
Figure 3: Disruption of clock function in PGC-1α null mice.
Figure 4: Cell-autonomous role of PGC-1α in clock regulation.

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We thank J. Hogenesch and T. Sato for Bmal1-luc, RORα and Rev-erb plasmids; S. Reppert for the E-box luciferase constructs; J. Takahashi for the Bmal1 and Clock expression plasmids; and M. Montminy for PGC-1α RNAi adenovirus. We also thank A. Saltiel and B. Spiegelman for comments on the manuscript and P.-H. Wu for discussions. This work is supported by NIDDK (J.D.L.) and the University of Michigan BSSP program (J.D.L.).

Author Contributions C.L., S.L., J.B. and J.D.L. designed the research. C.L., S.L., T.L., and J.D.L. performed the experiments. C.L., S.L., T.L., J.B. and J.D.L. analysed the data. J.D.L. wrote the paper.

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Correspondence to Jiandie D. Lin.

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Liu, C., Li, S., Liu, T. et al. Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Nature 447, 477–481 (2007).

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