Glucocorticoids and the circadian clock

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   Figure 2

   Neural pathways in circadian control of glucocorticoid release. See text for details. Arrows: black arrows: neural projections targeting the HPA axis. Blue arrows: neural projections via the autonomic nervous system. Purple arrow: projection from the DMH to the ‘autonomic PVN’ distinct from the SCN–adrenal gland pathway. Also the subPVZ projects into this region. Open arrows: humoral transport through the vasculature. Clocks symbolise autonomous pacemakers. Abbreviations: Regions of the nervous system: SCN, suprachiasmatic nucleus; subPVZ, subparaventricular zone; DMH, dorsomedial hypothalamus; PVN, paraventricular nucleus; mpPVN, medioparvocellular division of the PVN; I, interneuron of the PVN; C, corticotrope cell of the pituitary; IML, intermediolateral column of the spinal cord. Hormones and neurotransmitters: AVP, arginine vasopressine; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone.
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   Figure 1

   The molecular clock mechanism. ‘Core loop’: The bHLH transcription factors CLOCK and BMAL1 heterodimerise and bind to E-box enhancer elements. This activates transcription of period and cryptochrome genes, the products of which also heterodimerise and, after translocation to the nucleus, inhibit the activity of the CLOCK/BMAL1 dimer. This shuts down transcription of their own genes. Posttranscriptional and posttranslational modifications (not shown) delay nuclear accumulation of PER and CRY, thereby leading to the approximate 24 h rhythm of activation and repression on the per and cry promoters. ‘Accessory loop’: The CLOCK/BMAL1 dimer also binds E-boxes in the promoter of the REV-ERBα and RORA genes. RORA in turn binds a RORE element in the promoter of bmal1 and activates its transcription. REV-ERBα competes with RORA for the RORE binding site and inhibits transcription of bmal1. The resulting cyclical transcription of bmal1 is thought to enhance the core feedback loop. Glucocorticoids (GC) might modulate transcription of certain clock genes by binding to glucocorticoid response elements (GRE) in their promoters. Thus, a positive GRE element appears to mediate per1 induction by glucocorticoids (Yamamoto et al. 2005), whereas the promoter of rev-erbα has been proposed to contain a negative GRE (nGRE) that mediates glucocorticoid induced repression (Torra et al. 2000).
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   Figure 3

   Working models for circadian regulation of glucocorticoid secretion. (A) Rhythms in the HPA axis drive circadian ACTH release, which then stimulates glucocorticoid secretion. (B) The autonomic nervous system, perhaps together with other unknown cues, entrains the circadian clock of the adrenal gland. The clock in turn regulates circadian glucocorticoid production and release. (C) The adrenal gland clock, perhaps together with the autonomic nervous system, gates sensitivity of the gland to ACTH in a circadian manner. Abbreviations: ANS, autonomic nervous system; GC, glucocorticoids; SCN, suprachiasmatic nucleus; ACTH, adrenocorticotropic hormone.
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   Figure 4

   Working models for circadian regulation by glucocorticoids. (A) Rhythms in glucocorticoid concentrations drive circadian output rhythms in the target tissue. (B) Glucocorticoid changes entrain peripheral circadian clocks, which in turn control circadian rhythms in the tissue. (C) Peripheral clocks gate the glucocorticoid input to physiological processes in a circadian manner. (D) Glucocorticoids are required as permissive agents for circadian clock control to operate in rhythmic tissue processes. GC, glucocorticoids.
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   Figure 5

   Hypothetical intracellular mechanisms of circadian modulation of glucocorticoid signalling. I) HSD11B1 (11β, green) catalyses conversion of inactive keto-glucocorticoids (O=) to their active hydroxyforms (OH-). Its mRNA is under circadian regulation in certain tissues. II) Heat shock proteins (HSPs, H, blue) form complexes with the glucocorticoid receptor (GR, red) in the cytoplasm, before GR binding of glucocorticoids and subsequent nuclear translocation. Expression of many HSPs shows circadian dynamics. III) The mRNA of the GR itself shows circadian cycling in some tissues. IV) Transcriptional cofactors (C, pink) for nuclear receptors, such as PGC1α, can be regulated in a circadian fashion. V) The glucocorticoid receptor can interact with various signalling pathways at the level of the promoter of its target genes. This may include: Va) other transcription factors which are subject to circadian regulation at the level of their mRNAs (X, turquoise, e.g. HNF4A), Vb) targets of other signalling pathways subject to circadian changes in their activity (Y, brown) and Vc) the core clock components themselves (yellow and orange, Fig. 1).

• © 2009 Society for Endocrinology