PPARalpha is a potential therapeutic target of drugs to treat circadian rhythm sleep disorders.
Recent progress at the molecular level has revealed that nuclear receptors play an important role in the generation of mammalian circadian rhythms. To examine whether peroxisome proliferator-activated receptor alpha (PPARalpha) is involved in the regulation of circadian behavioral rhythms in mammals, we evaluated the locomotor activity of mice administered with the hypolipidemic PPARalpha ligand, bezafibrate. Circadian locomotor activity was phase-advanced about 3h in mice given bezafibrate under light-dark (LD) conditions. Transfer from LD to constant darkness did not change the onset of activity in these mice, suggesting that bezafibrate advanced the phase of the endogenous clock. Surprisingly, bezafibrate also advanced the phase in mice with lesions of the suprachiasmatic nucleus (SCN; the central clock in mammals). The circadian expression of clock genes such as period2, BMAL1, and Rev-erbalpha was also phase-advanced in various tissues (cortex, liver, and fat) without affecting the SCN. Bezafibrate also phase-advanced the activity phase that is delayed in model mice with delayed sleep phase syndrome (DSPS) due to a Clock gene mutation. Our results indicated that PPARalpha is involved in circadian clock control independently of the SCN and that PPARalpha could be a potent target of drugs to treat circadian rhythm sleep disorders including DSPS.
Shirai
Hidenori
H
Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8566, Japan.
Oishi
Katsutaka
K
Kudo
Takashi
T
Shibata
Shigenobu
S
Ishida
Norio
N
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001522:Behavior, Animal / Q000187:drug effects; D001629:Bezafibrate / Q000494:pharmacology*; D015152:Blotting, Northern; D018797:Cell Cycle Proteins / Q000235:genetics; D002940:Circadian Rhythm / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics; D004327:Drinking Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D056950:Period Circadian Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012893:Sleep Wake Disorders / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D001629:Bezafibrate; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000960:Hypolipidemic Agents; D009687:Nuclear Proteins; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D047493:PPAR alpha; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C498262:Nr1d1 protein, mouse; C513312:Per2 protein, mouse