Entrainment of peripheral clock genes by cortisol

Abstract

Circadian rhythmicity in mammals is primarily driven by the suprachiasmatic nucleus (SCN), often called the central pacemaker, which converts the photic information of light and dark cycles into neuronal and hormonal signals in the periphery of the body. Cells of peripheral tissues respond to these centrally mediated cues by adjusting their molecular function to optimize organism performance. Numerous systemic cues orchestrate peripheral rhythmicity, such as feeding, body temperature, the autonomic nervous system, and hormones. We propose a semimechanistic model for the entrainment of peripheral clock genes by cortisol as a representative entrainer of peripheral cells. This model demonstrates the importance of entrainer's characteristics in terms of the synchronization and entrainment of peripheral clock genes, and predicts the loss of intercellular synchrony when cortisol moves out of its homeostatic amplitude and frequency range, as has been observed clinically in chronic stress and cancer. The model also predicts a dynamic regime of entrainment, when cortisol has a slightly decreased amplitude rhythm, where individual clock genes remain relatively synchronized among themselves but are phase shifted in relation to the entrainer. The model illustrates how the loss of communication between the SCN and peripheral tissues could result in desynchronization of peripheral clocks.

Circadian characteristics of permissive and suppressive effects of cortisol and their role in homeostasis and the acute inflammatory response

“…Introduction of intercellular variability leads to a distribution of phases, amplitudes and periods for each peripheral cell. We have previously [42] discussed that cortisol’s rhythmic secretion synchronize the population of peripheral cells in order to maintain a narrow distribution of periods and phases that is further mediated to cytokine rhythm (Figure 2B). The average of single cell responses is optimized in order to be in accordance with available experimental data (Figure 2A, 2B) [47].…”

“…The average of single cell responses is optimized in order to be in accordance with available experimental data (Figure 2A, 2B) [47]. In particular, parameters of the Equations 3,6,16-21 were estimated based on the available experimental evidence of cortisol and pro-inflammatory cytokines, whereas the rest of the parameters values were adopted from our previous publications [25, 42]. However, similar to our previous modeling efforts, the dynamics observed in this work do not represent parameter-specific responses but are rather indicative of dynamics present at a larger parameter regime and are highly based on model structure and underlying assumptions.…”

“…Furthermore, experiments in human peripheral blood mononuclear cells (PBMCs) and fibroblasts [39-41] have indicated that glucocorticoids can be particularly interesting putative entrainers of PCGs. In the present work, in accordance with our previous modeling efforts [42], we incorporate the entrainment of peripheral immune cells by cortisol by considering the binding of glucocorticoid/receptor complex to the GRE present at the promoter region of Per and Cry clock genes (Equation 9, last additive term) [43, 44]. By this we aim to further investigate the translation of PCGs rhythmicity to pro-inflammatory cytokine expression [45].…”

On the analysis of complex biological supply chains: From process systems engineering to quantitative systems pharmacology

“…Interestingly, and as explored in (Pierre et al, 2016), neurons in the hypothalamus show a more synchronized firing activity during the short winter days, resulting in increased ensemble amplitude (Meijer et al, 2010; Rohling et al, 2006). The issue of periodic signals increasing synchronization and entrainment, and by extension acting as an implicit signal strengthening mechanism, is a concept also explored in our earlier work discussing the importance of maintaining robust rhythmic (circadian) patterns in circulating hormones (Mavroudis et al, 2012). In all cases, the intrinsic dynamics of the control elements, greatly impacted by exogenous factors, elminates the ability of the system to respond to a disturbance.…”

“…The relay of circadian inputs from the hypothalamic circadian clock in the suprachiasmatic nucleus (SCN) to peripheral circadian clocks in tissues such as the liver, adipose tissue and heart by cortisol is well known. By incorporating network models of the peripheral clocks, we were able to highlight the importance of the entrainer (cortisol) circadian characteristics in modulating the synchronization of circadian clocks in peripheral tissues (Mavroudis et al, 2012). We have also extended our model of circadian rhythms of cortisol to elucidate the observed time-of-day dependence in host susceptibility to inflammatory stimuli by incorporating a more detailed description of glucocorticoid modulation of the inflammatory response; whereby depending on its dynamic state, cortisol can both support and inhibit the inflammatory response (Mavroudis et al, 2014, 2015).…”