Adrenal peripheral clock controls the autonomous circadian rhythm of glucocorticoid by causing rhythmic steroid production

Abstract

Glucocorticoid (GC) is an adrenal steroid with diverse physiological effects. It undergoes a robust daily oscillation, which has been thought to be driven by the master circadian clock in the suprachiasmatic nucleus of the hypothalamus via the hypothalamuspituitary-adrenal axis. However, we show that the adrenal gland has its own clock and that the peripheral clockwork is tightly linked to steroidogenesis by the steroidogenic acute regulatory protein.Examination of mice with adrenal-specific knockdown of the canonical clock protein BMAL1 reveals that the adrenal clock machinery is required for circadian GC production. Furthermore, behavioral rhythmicity is drastically affected in these animals, together with altered expression of Period1, but not Period2, in several peripheral organs. We conclude that the adrenal peripheral clock plays an essential role in harmonizing the mammalian circadian timing system by generating a robust circadian GC rhythm.adrenal gland ͉ steroidogenic acute regulatory protein ͉ BMAL1

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

“…This is not the case when the animals are supplemented with constant release pellets, indicating that rhythmic glucocorticoid signalling might contribute to rhythm generation [113]. An attenuation of the amplitude (but no effect on the phase) of circadian per1 expression has also been reported in livers of the animals with a clock-less adrenal gland mentioned above, whereas rhythmic per2 expression was unaffected [106]. Together, these findings point to the possibility that tissue specific mechanisms might operate in clock gene regulation via glucocorticoids.…”

“…Finally, tissue specific antisense mediated knock-down of the Bmal1 protein in the adrenal gland abolishes Page 13 of 39 A c c e p t e d M a n u s c r i p t circadian glucocorticoid production under constant conditions (however, under a light dark cycle rhythmic production continues, potentially owing to the neural mechanisms mentioned above) [106]. Another facet of circadian regulation of glucocorticoid production seems to involve clock control of gene transcription in the glucocorticoid synthesis pathway, in addition to that of genes participating in the ACTH signalling pathway [105][106][107].…”

Adrenal peripheral clock disruption leads to altered circadian behavioral responses to voluntary exercise in middle-aged female mice

“…Animals were surgically implanted an E-mitter as described previously (Son et al 2008;Park et al 2012;Yoon et al 2012). After a recovery period of 7 days, half of the animals (4 WT and 4 BMAS animals) were individually housed in cages equipped with a running wheel (12 cm in diameter and 5.4 cm wide).…”

“…Generation of adrenal clock-disrupted mice under C57BL/6J background has been described (Son et al 2008). Middle-aged females of both WT and BMAS genotypes were used in this study.…”

“…We recently established an adrenal clock-disrupted transgenic mouse line (BMAS) where murine BMAL1 antisense RNA is stably expressed under the control of adrenal-specific MC2R promoter (Son et al 2008). The BMAS mice exhibit a loss of GC synthesis rhythm and dampened rhythm of corticosterone secretion as well as reduced amplitude of day/night activity.…”