Abstract

Circadian rhythms are essential to health. Their disruption is associated with metabolic diseases in experimental animals and man [1Turek F.W. Joshu C. Kohsaka A. Lin E. Ivanova G. McDearmon E. Laposky A. Losee-Olson S. Easton A. Jensen D.R. et al.Obesity and metabolic syndrome in circadian Clock mutant mice.Science. 2005; 308: 1043-1045Crossref PubMed Scopus (1746) Google Scholar, 2Karlsson B.H. Knutsson A.K. Lindahl B.O. Alfredsson L.S. Metabolic disturbances in male workers with rotating three-shift work. Results of the WOLF study.Int. Arch. Occup. Environ. Health. 2003; 76: 424-430Crossref PubMed Scopus (232) Google Scholar, 3Hastings M.H. Reddy A.B. Maywood E.S. A clockwork web: circadian timing in brain and periphery, in health and disease.Nat. Rev. Neurosci. 2003; 4: 649-661Crossref PubMed Scopus (891) Google Scholar]. Local metabolic rhythms represent an output of tissue-based circadian clocks [4Reppert S.M. Weaver D.R. Coordination of circadian timing in mammals.Nature. 2002; 418: 935-941Crossref PubMed Scopus (3134) Google Scholar]. Attempts to define how local metabolism is temporally coordinated have focused on gene expression by defining extensive and divergent “circadian transcriptomes” involving 5%–10% of genes assayed [5Akhtar R.A. Reddy A.B. Maywood E.S. Clayton J.D. King V.M. Smith A.G. Gant T.W. Hastings M.H. Kyriacou C.P. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus.Curr. Biol. 2002; 12: 540-550Abstract Full Text Full Text PDF PubMed Scopus (627) Google Scholar, 6Panda S. Antoch M.P. Miller B.H. Su A.I. Schook A.B. Straume M. Schultz P.G. Kay S.A. Takahashi J.S. Hogenesch J.B. Coordinated transcription of key pathways in the mouse by the circadian clock.Cell. 2002; 109: 307-320Abstract Full Text Full Text PDF PubMed Scopus (1768) Google Scholar, 7Storch K.F. Lipan O. Leykin I. Viswanathan N. Davis F.C. Wong W.H. Weitz C.J. Extensive and divergent circadian gene expression in liver and heart.Nature. 2002; 417: 78-83Crossref PubMed Scopus (1175) Google Scholar, 8Ueda H.R. Chen W. Adachi A. Wakamatsu H. Hayashi S. Takasugi T. Nagano M. Nakahama K. Suzuki Y. Sugano S. et al.A transcription factor response element for gene expression during circadian night.Nature. 2002; 418: 534-539Crossref PubMed Scopus (667) Google Scholar]. These analyses are inevitably incomplete, not least because metabolic coordination depends ultimately upon temporal regulation of proteins [9Hanash S. Disease proteomics.Nature. 2003; 422: 226-232Crossref PubMed Scopus (822) Google Scholar, 10Hanash S. Integrated global profiling of cancer.Nat. Rev. Cancer. 2004; 4: 638-644Crossref PubMed Scopus (110) Google Scholar]. We therefore conducted a systematic analysis of a mammalian “circadian proteome.” Our analysis revealed that up to 20% of soluble proteins assayed in mouse liver are subject to circadian control. Many of these circadian proteins are novel and cluster into discrete phase groups so that the liver's enzymatic profile contrasts dramatically between day and night. Unexpectedly, almost half of the cycling proteins lack a corresponding cycling transcript, as determined by quantitative PCR, microarray, or both and revealing for the first time the extent of posttranscriptional mechanisms as circadian control points. The circadian proteome includes rate-limiting factors in vital pathways, including urea formation and sugar metabolism. These findings provide a new perspective on the extensive contribution of circadian programming to hepatic physiology.