Peripheral circadian clocks are diversely affected by adrenalectomy

Abstract

Glucocorticoids are considered to synchronize the rhythmicity of clock genes in peripheral tissues; however, the role of circadian variations of endogenous glucocorticoids is not well defined. In the present study, we examined whether peripheral circadian clocks were impaired by adrenalectomy. To achieve this, we tested the circadian rhythmicity of core clock genes (Bmal1, Per1-3, Cry1, RevErbα, Rora), clock-output genes (Dbp, E4bp4) and a glucocorticoid- and clock-controlled gene (Gilz) in liver, jejunum, kidney cortex, splenocytes and visceral adipose tissue (VAT). Adrenalectomy did not affect the phase of clock gene rhythms but distinctly modulated clock gene mRNA levels, and this effect was partially tissue-dependent. Adrenalectomy had a significant inhibitory effect on the level of Per1 mRNA in VAT, liver and jejunum, but not in kidney and splenocytes. Similarly, adrenalectomy down-regulated mRNA levels of Per2 in splenocytes and VAT, Per3 in jejunum, RevErbα in VAT and Dbp in VAT, kidney and splenocytes, whereas the mRNA amounts of Per1 and Per2 in kidney and Per3 in VAT and splenocytes were up-regulated. On the other hand, adrenalectomy had minimal effects on Rora and E4bp4 mRNAs. Adrenalectomy also resulted in decreased level of Gilz mRNA but did not alter the phase of its diurnal rhythm. Collectively, these findings suggest that adrenalectomy alters the mRNA levels of core clock genes and clock-output genes in peripheral organs and may cause tissue-specific modulations of their circadian profiles, which are reflected in changes of the amplitudes but not phases. Thus, the circulating corticosteroids are necessary for maintaining the high-amplitude rhythmicity of the peripheral clocks in a tissue-specific manner.

Multimodal Regulation of Circadian Glucocorticoid Rhythm by Central and Adrenal Clocks

“…Similarly, a large number of genes with circadian expression in muscular tissue were also identified as GC-responsive genes [ 109 ]. Furthermore, cyclic expression of canonical circadian clock genes in visceral adipose tissue is drastically attenuated in adrenalectomized rats, suggesting that normal molecular rhythms in adipocytes are highly dependent on circulating GC rhythm [ 110 ]. It can thus be postulated that the circulating GC rhythm may contribute to the circadian control of metabolic processes by acting on metabolic tissues either directly or indirectly through local clockworks in those tissues.…”

Mechanistic Multi—Tissue Modeling of Glucocorticoid-Induced Leucine Zipper Regulation: Integrating Circadian Gene Expression with Receptor-Mediated Corticosteroid Pharmacodynamics

“…The GILZ mRNA displays circadian oscillations, which is under the complex regulation of CST as well as the peripheral circadian clock gene loop present in tissues (Ayyar et al, 2015;Soták et al, 2016). Circadian rhythms in GILZ mRNA expression in tissues were modeled using an IDR model with a time-dependent synthesis rate [k s,GILZm(t) ], described by a single harmonic function and degraded by a first-order rate constant (k d,GILZm ) as: where a i and b i are Fourier coefficients associated with the harmonic oscillations.…”

Stress affects expression of the clock gene Bmal1 in the suprachiasmatic nucleus of neonatal rats via glucocorticoid‐dependent mechanism

“…The insensitivity may protect the stability of the clock mechanism from unexpected fluctuations in GC levels in response to various stressors. In this respect, the SCN differs from peripheral clocks that are highly responsive to GC in a time‐dependent manner and use the circadian cycle in GC levels as an efficient signal for their entrainment . The mechanism of how GC entrain the peripheral clocks is mostly based on their binding to GREs on the promoters of some clock genes, namely Per1 , Per2 and Nr1d1 , but other mechanisms are also plausible …”