Review
Interactions of the circadian CLOCK system and the HPA axis

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Organisms have developed concurrent behavioral and physiological adaptations to the strong influence of day/night cycles, as well as to unforeseen, random stress stimuli. These circadian and stress-related responses are achieved by two highly conserved and interrelated regulatory networks, the circadian CLOCK and stress systems, which respectively consist of oscillating molecular pacemakers, the Clock/Bmal1 transcription factors, and the hypothalamic–pituitary–adrenal (HPA) axis and its end-effector, the glucocorticoid receptor. These systems communicate with one another at different signaling levels and dysregulation of either system can lead to development of pathologic conditions. In this review, we summarize the mutual physiologic interactions between the circadian CLOCK system and the HPA axis, and discuss their clinical implications.

Section snippets

Adjustment of internal homeostasis to major changes in circumstance

Virtually all organisms live under the strong influence of day/night cycles created by the 24h rotation of the planet. Organisms sense these regular external changes and synchronize their physical activities, such as behavior, food intake, energy metabolism, sleep, reproductive activity and immune function, to increase their chance for survival [1]. From their early evolution, organisms have developed a highly conserved and sophisticated ubiquitous molecular “clock”, the CLOCK system, which

The circadian CLOCK system

The circadian CLOCK system consists of central and peripheral components. The central component is located in the suprachiasmatic nuclei (SCN) of the hypothalamus and acts as a “master” CLOCK under the strong influence of light/dark input from the eyes, whereas the peripheral components behave as “slave” CLOCKs, functioning virtually in all organs and tissues 1, 2 (Figure 1) (Box 2). The activity of the peripheral CLOCKs is synchronized to that of the central master CLOCK through both humoral

The stress HPA axis

The HPA axis, apart from having circadian activity, also mediates the adaptive response to stressors; it consists of the hypothalamic PVN parvocellular corticotropin-releasing hormone (CRH)- and AVP-secreting neurons, the pituitary corticotrophs, and the adrenal gland cortices. The PVN neurons release CRH and AVP into the hypophyseal portal system located under the median eminence of the hypothalamus in response to stimulatory signals from higher brain regulatory centers. Secreted CRH and AVP

Regulation of the HPA axis by the circadian CLOCK system

Circulating glucocorticoid levels are tightly regulated and fluctuate naturally in a circadian manner, reaching their zenith in the early morning and their nadir in the late evening in diurnal animals, including humans 22, 23. The light-activated central master CLOCK located in the SCN orchestrates this daily rhythmic release of glucocorticoids by influencing the activity of the HPA axis through efferent connections from the SCN to the CRH/AVP-containing neurons of the PVN 6, 18, 24 (Figure 2).

Implications of the CLOCK–HPA axis interaction for the development of metabolic and immune disorders

As evidenced in the previous sections, the CLOCK system and HPA axis influence the activity and function of the CNS and peripheral tissues, whereas the master CLOCK system clearly dictates the circadian activity of the HPA axis. In the following sections, we discuss these mutual interactions and their implications in the development of pathologic conditions, with metabolic and immune disorders as illustrative examples.

Intermediary metabolism handles the turnover of carbohydrates, proteins and

Concluding remarks

The circadian CLOCK and stress systems regulate activity of one another through multilevel interactions to ultimately coordinate homeostasis against the day/night change and various unforeseen random internal and external stressors. As the day/night changes are sterotypic and take place irrevocally, the circadian master CLOCK system controls the stress system, and the stress system adjusts the circadian rhythm of the non-master CNS and peripheral CLOCKs in response to various stressors. Thus,

Acknowledgments

Literary work of this article was funded partly by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

References (64)

  • H. Duez et al.

    Rev-erbα gives a time cue to metabolism

    FEBS Lett.

    (2008)
  • K. Oishi

    CLOCK is involved in obesity-induced disordered fibrinolysis in ob/ob mice by regulating PAI-1 gene expression

    J. Thromb. Haemost.

    (2006)
  • K. Oishi

    PERIOD2 is a circadian negative regulator of PAI-1 gene expression in mice

    J. Mol. Cell. Cardiol.

    (2009)
  • S. Sookoian

    Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity

    Am. J. Clin. Nutr.

    (2008)
  • V. Pilorz

    Age and oestrus cycle-related changes in glucocorticoid excretion and wheel-running activity in female mice carrying mutations in the circadian clock genes Per1 and Per2

    Physiol. Behav.

    (2009)
  • L.A. Segall

    Timed restricted feeding restores the rhythms of expression of the clock protein, Period2, in the oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala in adrenalectomized rats

    Neuroscience

    (2008)
  • J.S. Takahashi

    The genetics of mammalian circadian order and disorder: implications for physiology and disease

    Nat. Rev. Genet.

    (2008)
  • C.H. Ko et al.

    Molecular components of the mammalian circadian clock

    Hum. Mol. Genet.

    (2006)
  • M. Hastings

    Circadian clocks: regulators of endocrine and metabolic rhythms

    J. Endocrinol.

    (2007)
  • G.P. Chrousos

    Stress and disorders of the stress system

    Nat. Rev. Endocrinol.

    (2009)
  • G.P. Chrousos et al.

    Glucocorticoid action networks and complex psychiatric and/or somatic disorders

    Stress

    (2007)
  • A. Kalsbeek

    SCN outputs and the hypothalamic balance of life

    J. Biol. Rhythms

    (2006)
  • N. Cermakian et al.

    Multilevel regulation of the circadian clock

    Nat. Rev. Mol. Cell Biol.

    (2000)
  • R.V. Kondratov

    Post-translational regulation of circadian transcriptional CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES

    Cell Cycle

    (2006)
  • Y.B. Kiyohara

    The BMAL1 C terminus regulates the circadian transcription feedback loop

    Proc. Natl. Acad. Sci. U. S. A.

    (2006)
  • J.A. Ripperger et al.

    Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions

    Nat. Genet.

    (2006)
  • J.H. Meijer et al.

    In search of the pathways for light-induced pacemaker resetting in the suprachiasmatic nucleus

    J. Biol. Rhythms

    (2003)
  • S. Kraves et al.

    A role for cardiotrophin-like cytokine in the circadian control of mammalian locomotor activity

    Nat. Neurosci.

    (2006)
  • K. Mori

    Neuromedin S: discovery and functions

    Results Probl. Cell Differ.

    (2008)
  • S.H. Yoo

    PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • F. Damiola

    Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus

    Genes Dev.

    (2000)
  • P.M. Fuller

    Differential rescue of light- and food-entrainable circadian rhythms

    Science

    (2008)
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