The circadian clock and glucocorticoids – Interactions across many time scales

https://doi.org/10.1016/j.mce.2013.05.012Get rights and content

Highlights

  • The circadian clock regulates endogenous daily rhythms in physiology.

  • Glucocorticoid (GC) signaling is highly dynamic on time scales from seconds to years.

  • Clock mechanisms involve second (transcription) to year (seasonal rhythms) time scales.

  • The circadian clock regulates GC levels by neural, humoral and cell autonomous cues.

  • The circadian clock and GC signaling directly interact in target gene regulation.

Abstract

Glucocorticoids are steroid hormones of the adrenal gland that are an integral component of the stress response and regulate many physiological processes, including metabolism and immune response. Their release into the blood is highly dynamic and occurs in about hourly pulses, the amplitude of which is modulated in a daytime dependent fashion. In addition, in many species seasonal changes in basal glucocorticoid levels have been reported. In their target tissues, glucocorticoids bind to cytoplasmic receptors of the nuclear receptor superfamily. Upon binding, these receptors regulate transcription in a highly dynamic fashion, which involves stochastic binding to regulatory DNA elements on a time scale of seconds and heat shock protein mediated receptor-ligand complex recycling within minutes. The glucocorticoid hormone system interacts with another highly dynamic system, the circadian clock. The circadian clock is an endogenous biological timing mechanism that allows organisms to anticipate regular daily changes in their environment. It regulates daily rhythms of glucocorticoid release by a variety of mechanisms, modulates glucocorticoid signaling and is itself influenced by glucocorticoids. Here, we discuss mechanisms, functions and interactions of the circadian and glucocorticoid systems across time scales ranging from seconds (DNA binding by transcriptional regulators) to years (seasonal rhythms).

Section snippets

The circadian clock

The movements of Earth in the solar system, its yearly path around the sun and daily rotation on its axis, bring about regular changes in the environment for the life inhabiting the planet. Many if not most organisms have developed internal mechanisms that allow them to anticipate these changes. Thus, many birds and mammals possess internal timers to anticipate the changing seasons, allowing them to prepare for yearly migrations and periods of reproduction or hibernation (Gwinner, 2003, Paul et

Glucocorticoid hormones – dynamics on many time scales

Circadian rhythms of hormone release are a prominent aspect of circadian clock output. Circadian changes have been described e.g. for melatonin, growth hormone, thyroid hormone, prolactin, and glucocorticoids (Morris et al., 2012). However, in many cases hormones are also subject to dynamics on additional time scales, such as pulsatile release and seasonal differences. Especially glucocorticoid dynamics have been studied over a large variety of time scales, and the following sections will give

Transcriptional bursts in circadian gene expression

As described above for glucocorticoid signaling, the circadian transcription of clock genes also involves processes occurring on time scales lower than the circadian cycle, with transcription taking place in discrete short bursts (Stratmann et al., 2012, Suter et al., 2011a). Indeed, it has been generally proposed that most genes are transcribed during short activity periods separated by silent phases (reviewed in Suter et al. (2011b)). For the clock genes Bmal1 and Per2 and for the direct

Perspectives

In summary, the glucocorticoid hormone system and the circadian clock appear to interact over many time scales (Fig. 4). While recent work has made great progress notably towards understanding the dynamic molecular mechanisms of transcriptional regulation in both systems and pointed out numerous areas of physiological cross-talk between glucocorticoids and the circadian clock, many open questions remain.

Major future challenges will be to determine the precise molecular mechanisms by which

Acknowledgements

We thank Andrew Cato, Hugues Dardente and Nicolas Diotel for a critical reading of the manuscript.

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