Rapid intra-adrenal feedback regulation of glucocorticoid synthesis

Walker, Jamie J.; Spiga, Francesca; Gupta, Rita R.; Zhao, Zidong; Lightman, Stafford L.; Terry, John R.

doi:10.1098/rsif.2014.0875

Cited by 57 publications

(47 citation statements)

References 38 publications

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“…Recent data from our group suggest that, in addition to the well-known CORT-mediated negative feedback at the pituitary and brain regulating HPA axis activity, an intra-adrenal negative feedback involving activation of the GR can rapidly inhibit ACTH-induced glucocorticoid synthesis (17). Consistent with this, there is evidence that glucocorticoids can inhibit the transcription of steroidogenic genes through a mechanism that involves the synergistic association of SF-1 and GR to modulate DAX-1 expression (20).…”

Section: Il-6supporting

confidence: 63%

“…Because of the dynamic nature of steroidogenesis, we developed a mathematical model of the SRN that accounted for regulatory processes occurring at different timescales. Importantly, we also considered an intra-adrenal CORTmediated feedback loop, the effects of which were previously described through mathematical modeling (17). We used our model to predict the time evolution of steroidogenesis following a series of physiological perturbations relevant to stress and inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Effects of cytokines on components of the SRN Immune pathway Mathematical models of CORT dynamics have been developed to study the origin of ultradian oscillations within the HPA axis (4,17) and the inflammatory response at the adrenal level (37). However, these models do not consider the dynamic molecular interactions within adrenocortical cells that occur during steroidogenesis.…”

Section: Il-6mentioning

confidence: 99%

“…These interacting cascades of genomic and nongenomic events work in combination to activate and maintain optimal levels of steroidogenic proteins, ultimately leading to mitochondrial import of cholesterol and CORT synthesis. In addition, our recent mathematical modeling of the CORT response to ACTH suggests that a rapid, intra-adrenal CORT negative feedback loop constitutes an additional control mechanism of steroidogenesis (14)(15)(16)(17). The biological processes underlying this self-inhibition are not known, but the glucocorticoid receptor (GR) is expressed in the adrenal cortex (15,18).…”

mentioning

confidence: 99%

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Dynamic responses of the adrenal steroidogenic regulatory network

Spiga

Zavala

Walker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The hypothalamic-pituitary-adrenal axis is a dynamic system regulating glucocorticoid hormone synthesis in the adrenal glands. Many key factors within the adrenal steroidogenic pathway have been identified and studied, but little is known about how these factors function collectively as a dynamic network of interacting components. To investigate this, we developed a mathematical model of the adrenal steroidogenic regulatory network that accounts for key regulatory processes occurring at different timescales. We used our model to predict the time evolution of steroidogenesis in response to physiological adrenocorticotropic hormone (ACTH) perturbations, ranging from basal pulses to larger stress-like stimulations (e.g., inflammatory stress). Testing these predictions experimentally in the rat, our results show that the steroidogenic regulatory network architecture is sufficient to respond to both small and large ACTH perturbations, but coupling this regulatory network with the immune pathway is necessary to explain the dissociated dynamics between ACTH and glucocorticoids observed under conditions of inflammatory stress. T he hypothalamic-pituitary-adrenal (HPA) axis is a stressresponsive neuroendocrine system that controls circulating levels of the vital glucocorticoid (CORT) hormones corticosterone (in rodents) and cortisol (in humans). These are steroids synthesized by the adrenal gland in response to stimulation by adrenocorticotropic hormone (ACTH), which is secreted by the anterior pituitary in response to corticotrophin-releasing hormone (CRH) and arginine vasopressin released from hypothalamic paraventricular neurons. These neurons receive circadian inputs from the suprachiasmatic nucleus and are activated in response to stress. Via the bloodstream, CORT accesses target tissues where it mediates metabolic, cognitive, and immune responses. CORT also regulates its own production through negative feedback inhibition of ACTH and CRH secretion from the pituitary and hypothalamus, respectively. To mount an effective response to stress, CORT must be secreted rapidly by the adrenal glands. However, because of its lipophilic nature, CORT cannot be prestored in vesicles and must therefore be rapidly synthesized de novo in response to ACTH stimulation.Under basal, unstressed conditions, ACTH and CORT exhibit ultradian oscillations. Although there is some evidence for pulsatility of CRH (1, 2), our recent work suggests that ACTH and CORT pulsatility is predominantly generated by a subhypothalamic oscillator within the pituitary-adrenal system (3, 4). The amplitude of these pulses varies in a circadian manner with larger pulses occurring at the start of the active phase (morning in humans, evening in rodents). Under normal physiological conditions, CORT secretion is tightly correlated with ACTH (5). However, there are a number of conditions where a dynamic dissociation between these hormones occurs (reviewed in ref. 6). For example, there is evidence that proinflammatory cytokines released during inflammation can poten...

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Section: Il-6supporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Il-6mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Dynamic responses of the adrenal steroidogenic regulatory network

Spiga

Zavala

Walker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Targeted experimental studies have for many years been unsuccessful in identifying the anatomical origin of ultradian rhythms [84]. However, recent work suggests that an additional level of glucocorticoid autoregulation may exist within the adrenal glands [85], further strengthening the view that birhythmic oscillatory changes in blood glucocorticoid levels reflect the integrated activity of pulsatile hypothalamic forcing on an endogenously rhythmic pituitary-adrenal system.…”

Section: Methodsmentioning

confidence: 99%

Corticosterone oscillations during mania induction in the lateral hypothalamic kindled rat—Experimental observations and mathematical modeling

Abulseoud

Choi

et al. 2017

PLoS ONE

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Changes in the hypothalamic-pituitary-adrenal (HPA) axis activity constitute a key component of bipolar mania, but the extent and nature of these alterations are not fully understood. We use here the lateral hypothalamic-kindled (LHK) rat model to deliberately induce an acute manic-like episode and measure serum corticosterone concentrations to assess changes in HPA axis activity. A mathematical model is developed to succinctly describe the entwined biochemical transformations that underlay the HPA axis and emulate by numerical simulations the considerable increase in serum corticosterone concentration induced by LHK. Synergistic combination of the LHK rat model and dynamical systems theory allows us to quantitatively characterize changes in HPA axis activity under controlled induction of acute manic-like states and provides a framework to study in silico how the dynamic integration of neurochemical transformations underlying the HPA axis is disrupted in these states.

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Rhythms Within Rhythms: The Importance of Oscillations for Glucocorticoid Hormones

Lightman

2016

Research and Perspectives in Endocrine Interactions

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The circadian activity of the hypothalamic-pituitary-adrenal (HPA) axis is made up from an underlying oscillatory rhythm of ACTH and glucocorticoid pulses that vary in amplitude but not frequency over the 24 h. This oscillatory activity is not the result of a hypothalamic oscillator but emerges as a natural consequence of the feedforward:feedback interaction between the pituitary corticotropes and the glucocorticoid-secreting cells of the adrenal cortex. This oscillatory activity has resulted in adaptations in the way tissues read their 'digital' ligand signal. The adrenal cortex is relatively insensitive to constant signals of ACTH but responds briskly to the equivalent amount of ACTH administered in a pulsatile manner. Similarly glucocorticoid-responsive tissues such as the brain and the liver are able to read the oscillating signals of cortisol or corticosterone secretion, with differential biochemical and functional responses to different patterns of ligand presentation. During a prolonged acute stress there is a major change in the pituitary-adrenal relationship, with a marked increase in the sensitivity of the adrenal to small changes in ACTH, so that following cardiac surgery small oscillations in ACTH result in massive swings in cortisol. This response appears to be due to a change both in the ACTH signalling pathway and in the endogenous activators and inhibitors of glucocorticoid synthesis.

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Rapid intra-adrenal feedback regulation of glucocorticoid synthesis

Cited by 57 publications

References 38 publications

Dynamic responses of the adrenal steroidogenic regulatory network

Dynamic responses of the adrenal steroidogenic regulatory network

Corticosterone oscillations during mania induction in the lateral hypothalamic kindled rat—Experimental observations and mathematical modeling

Rhythms Within Rhythms: The Importance of Oscillations for Glucocorticoid Hormones

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