Differential Entrainment of Peripheral Clocks in the Rat by Glucocorticoid and Feeding

Abstract

The suprachiasmatic nucleus is the master circadian clock and resets the peripheral clocks via various pathways. Glucocorticoids and daily feeding are major time cues for entraining most peripheral clocks. However, recent studies have suggested that the dominant timing factor differs among organs and tissues. In our current study, we reveal differences in the entrainment properties of the peripheral clocks in the liver, kidney, and lung through restricted feeding (RF) and antiphasic corticosterone (CORT) injections in adrenalectomized rats. The peripheral clocks in the kidney and lung were found to be entrained by a daily stimulus from CORT administration, irrespective of the meal time. In contrast, the liver clock was observed to be entrained by an RF regimen, even if daily CORT injections were given at antiphase. These results indicate that glucocorticoids are a strong zeitgeber that overcomes other entrainment factors regulating the peripheral oscillators in the kidney and lung and that RF is a dominant mediator of the entrainment ability of the circadian clock in the liver. (Endocrinology 153: 2277-2286, 2012) M ost living organisms have developed internal clock mechanisms that generate precise rhythms around a 24-h cycle. One such system, termed the circadian clock, governs daily variations in physiology and behavior. In mammals, the suprachiasmatic nucleus (SCN) is the center of the circadian clock and resides in the hypothalamus (1). The molecular oscillator in the SCN consists of interacting positive and negative transcription/translation feedback loops (2-4). The transcriptional activators CLOCK and BMAL1 form heterodimers and stimulate the transcription of other clock genes, such as the Period (Per) genes (Per1, Per2, and Per3), the Cryptochromes (Cry) (Cry1 and Cry2), retinoid-related orphan receptors (ROR) (ROR␣, ROR␤, and ROR␥) and Rev-erbes (Rev-erb␣ and Rev-erb␤) that bind to the E-box response elements in the promoter regions of these genes. Accumulated PER and CRY proteins form a complex that represses the transcriptional activity of the CLOCK/BMAL1 heterodimer. The ROR transcriptional activators and REV-ERB repressors control the transcriptional regulation of Clock and Bmal1 through their binding to the REV response element (RRE). This autoregulatory loop generates gene expression oscillations of approximately 24 h. In addition, the mammalian SCN can adapt to environmental changes in day/night cycles. Light information from the retinas is delivered to the SCN via the retino-hypothalamic tract and is the most effective time cue for the central clock. Nocturnal light induces the Per1 and Per2 genes, which leads to a resetting of the circadian clock in the SCN (5).The molecular circadian clock operates not only in the SCN but also in peripheral organs and tissues (6, 7). The peripheral clocks are entrained by the central circadian clock in the SCN and express overt circadian rhythms during physiological events (8, 9). Hence, it is commonly assumed that the mammalian circadian system is a complex h...

The Hypersensitive Glucocorticoid Response Specifically Regulates Period 1 and Expression of Circadian Genes

“…It may therefore be that endogenous cortisol acts through PER1 to shift already-established circadian rhythms. A recent study in adrenalectomized rodents supported our hypothesis, showing both that endogenous cortisol was required for circadian expression of rat rPer1 and that daily cortisol administration restored rPer1 expression and entrained circadian rhythms in lung and kidney (58). Combined with our study, these results suggest that GR-mediated responses to low doses of corticosteroids are important for mammalian peripheral circadian physiology.…”

“…Some peripheral clocks can be entrained independent of neuronal signals by restricted feeding times, suggesting additional clock mechanisms (9,58). Researchers have shown that either a serum shock or a DEX shock can induce circadian patterns of gene expression in tissue culture cells (3,4) and that glucocorticoids can also influence circadian rhythms in peripheral tissues (3).…”

“…Numerous studies have shown that long-term and pulsatile glucocorticoids regulate expression of the gene for Period 1 (PER1), a major component of the mammalian circadian clock, in humans and rodents (3,9,14,32,57). Glucocorticoids also regulate PER1 in primary tissues in response to acute physical stress (72) and as part of circadian rhythms (58). We also recently showed that expression of PER1 is sensitive to subnanomolar doses of DEX in the human lung epithelial cell line A549 (50).…”

Mechanism of the circadian clock in physiology

“…It was also shown that hydrocortisone, a glucocorticoid, can synchronize circadian clock gene expression in ex vivo mouse SCN, lung, pineal gland, salivary gland, cornea, and liver (105). Adrenalectomized rats maintain rhythmic oscillation of most clock genes in the liver and kidney, except Per1 (137). The fact that the other clock genes still oscillate suggests that glucocorticoids are not the only synchronization mechanism for the circadian clock.…”

Ghrelin induces clock gene expression in the liver of goldfish in vitro via protein kinase C and protein kinase A pathways

“…However, the food-related signals that entrain the molecular clocks (food-entrainable oscillators, FEOs) in the circadian system remain unknown. In mammals, the oscillators of the circadian system respond to feeding inputs with different sensitivities, the liver being one of the most sensitive peripheral oscillators in these vertebrates (Albrecht, 2012;Damiola et al, 2000;Reddy et al, 2007;Schibler et al, 2015;Schmutz et al, 2012;Sujino et al, 2012). In teleosts, the liver is highly sensitive to the feeding/fasting cycle and food-related signals (Costa et al, 2016;del Pozo et al, 2012;Feliciano et al, 2011;López-Olmeda et al, 2010;Vera et al, 2013;Sánchez-Bretaño et al, 2015b).…”