Katsutaka Oishi (senior research scientist) and Norio Ishida (group leader) of Clock Cell Biology Research Group, the Institute for Biological Resources and Functions (Director: Masahiro Iwakura), the National Institute of Advanced Industrial Science and Technology (President: Hiroyuki Yoshikawa) (hereinafter referred to as AIST), along with Hidenori Shirai (The University of Tsukuba) and Shigenobu Shibata (Waseda University), discovered that it is possible to regulate the circadian clock by fibrate which is a drug used in the treatment of hyperlipemia.

When we bred nocturnal rodents under the daily light-dark cycle, their behavioral activity is usually restricted to the nighttime (dark period). Circadian locomotor activity was phase-advanced about 3 hours in mice given fibrate under light-dark condition. They began activity at the latter half of the daytime (light period).

Fibrate also advanced and normalized the active phase that is delayed in model mice with Delayed Sleep Phase Syndrome (DSPS) due to a circadian clock gene mutation. As fibrates are specific ligands of nuclear receptor PPARα, PPARα could be a potent target of drugs to treat circadian rhythm sleep disorders including DSPS.

Fibrate administration advances the phase of circadian activity rhythm

Various sleep disorders related to round-the-clock society have become serious social problems as well as hereditary sleep disorders. Onset of disease of sleep disorders such as Circadian Rhythm Sleep Disorders is considered to be associated with a biological clock regulated by circadian clock genes, although the detail mechanism is unclear.

Chronobiological intervention such as bright light therapy, as well as the administration of vitamin B₁₂ and melatonin are effective against sleep-onset insomnia in patients with sleep disorders, although a wide individual gap about its effects have been revealed. Therefore, the development of a new sleep disorder treatment with a different functional mechanism from the conventional treatment was looked forward to.

Till now, we have carried out research related to circadian clock and food habits. We found that lipid metabolism is strictly controlled by the circadian clock. On the other hand, it was recently revealed that lipophilic substances are involved in various physiological functions in the human body through their specific nuclear receptors. Previously, AIST revealed that the circadian expression of the PPARα (which plays a central role in the metabolism of fatty acids) is directly regulated by the circadian clock. We started the study of the effects of fibrate (a PPARα agonist) treatment on the circadian rhythm sleep disorders with support from the professor in Waseda University.

Fibrate, a ligand of the nuclear receptor PPARα, is a hypolipidemic drug to treat hyperlipidemia. We demonstrated that the fibrate or other ligands of PPARα are potential therapeutic drugs to treat circadian rhythm sleep disorders by regulating the biological clock.

When we bred the nocturnal mice under the daily light-dark cycle, their activity was usually restricted to the nighttime (dark period). Circadian locomotor activity was gradually phase-advanced for about 3 hours in mice with freely administrated the fibrate under light-dark condition. (Figure 1). As the results, they began activity at the latter half of the light period. In addition, the peak time of the function (mRNA expression levels) of circadian clock gene also advanced about 3 hours.

Figure 1. Fibrate administration advances the phase of circadian activity

 In addition, the fibrate also phase - advanced and normalized the circadian clock gene-mutated delayed sleep phase syndrome (DSPS) model mice (Figure 2). As fibrates are specific ligands of nuclear receptor PPARα, PPARα could be a potent target of drugs to treat circadian rhyhthm sleep disorders including DSPS.

Figure 2. Phase-advancing effect of fibrate in mouse models of Delayed Sleep Phase Syndrome (DSPS)

The action on the central nervous system of fibrates has been hardly reported, and the underlying mechanism of the effects of fibrate on the biological clock is also unclear at present. We aim to elucidate its action site in a brain and identify the target gene controlled by PPARα in the near future.

 On the other hand, even though fibrate is a widely-used medicine administering to patients of hyperlipidemia, effect of fibrate on the circadian clock might be different between rodents and humans. Therefore, it is essential to study the influence of fibrate on the biological clock of the humans.