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

The mammalian clock regulates major aspects of energy metabolism, including glucose and lipid homeostasis and mitochondrial oxidative metabolism(1,2). The biochemical basis for coordinated control of the circadian clock and diverse metabolic pathways is not well understood. Here we show that PGC-1 alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism(3-9), is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1 alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erba (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Mice lacking PGC-1 alpha 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-1 alpha-deficient fibroblasts and mice with liver-specific knockdown of PGC-1 alpha indicate that it is required for cell-autonomous clock function. We have thus identified PGC-1 alpha as a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism.