Transcriptional coactivator PGC-1alpha 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. The biochemical basis for coordinated control of the circadian clock and diverse metabolic pathways is not well understood. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Mice lacking PGC-1alpha 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-1alpha-deficient fibroblasts and mice with liver-specific knockdown of PGC-1alpha indicate that it is required for cell-autonomous clock function. We have thus identified PGC-1alpha as a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism.
Liu
Chang
C
Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
Li
Siming
S
Liu
Tiecheng
T
Borjigin
Jimo
J
Lin
Jiandie D
JD
D056930:ARNTL Transcription Factors; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics; D001683:Biological Clocks / Q000235:genetics*; D001831:Body Temperature; D002940:Circadian Rhythm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003624:Darkness; D004734:Energy Metabolism / Q000235:genetics*; D005347:Fibroblasts; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics*; D008027:Light; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000235:genetics*
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D004268:DNA-Binding Proteins; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator