Glucose down-regulates Per1 and Per2 mRNA levels and induces circadian gene expression in cultured Rat-1 fibroblasts.
In mammals, peripheral circadian clocks are present in most tissues, but little is known about how these clocks are synchronized with the ambient 24-h cycles. By using rat-1 fibroblasts, a model cell system of the peripheral clock, we found that an exchange of the culture medium triggered circadian gene expression that was preceded by slow down-regulation of Per1 and Per2 mRNA levels. This profile contrasts to the immediate up-regulation of these genes often observed for clock resetting. The screening of factor(s) responsible for the down-regulation revealed glucose as a key component triggering the circadian rhythm. The requirement of both glucose metabolism and RNA/protein synthesis for the down-regulation suggests the involvement of gene(s) immediately up-regulated by glucose metabolism. An analysis with high density oligonucleotide microarrays identified >100 glucose-regulated genes. We found among others immediately up-regulated genes encoding transcriptional regulators TIEG1, VDUP1, and HES1, in addition to cooperatively regulated genes that are associated with cholesterol biosynthesis and cell cycle. The immediate up-regulation of Tieg1 and Vdup1 expression was dependent on glucose metabolism but not on protein synthesis, suggesting that the transcriptional regulators mediate the glucose-induced down-regulation of Per1 and Per2 expression. These results illustrate a novel mode of peripheral clock resetting by external glucose, a major food metabolite.
Hirota
Tsuyoshi
T
Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Japan.
Okano
Toshiyuki
T
Kokame
Koichi
K
Shirotani-Ikejima
Hiroko
H
Miyata
Toshiyuki
T
Fukada
Yoshitaka
Y
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002940:Circadian Rhythm; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003609:Dactinomycin / Q000494:pharmacology; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005656:Fungal Proteins / Q000096:biosynthesis; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D009687:Nuclear Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D056950:Period Circadian Proteins; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019289:Pyruvic Acid / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins; D013879:Thioredoxins; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation; D000098825:Oxysterol Binding Proteins
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003513:Cycloheximide; D004268:DNA-Binding Proteins; D003609:Dactinomycin; D005656:Fungal Proteins; D005947:Glucose; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D011500:Protein Synthesis Inhibitors; D019289:Pyruvic Acid; D012313:RNA; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D013879:Thioredoxins; D014157:Transcription Factors; C087902:HES1 protein, S cerevisiae; D000098825:Oxysterol Binding Proteins; C491385:Klf10 protein, rat; C539022:PER1 protein, human; C421902:PER2 protein, human; C539023:Per1 protein, mouse; C539024:Per1 protein, rat; C513312:Per2 protein, mouse; C513311:Per2 protein, rat; C486715:TXNIP protein, human