Interactions of the circadian CLOCK system and the HPA axis

Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Trends in Endocrinology and Metabolism (Impact Factor: 9.39). 05/2010; 21(5):277-86. DOI: 10.1016/j.tem.2009.12.011
Source: PubMed


Organisms have developed concurrent behavioral and physiological adaptations to the strong influence of day/night cycles, as well as to unforeseen, random stress stimuli. These circadian and stress-related responses are achieved by two highly conserved and interrelated regulatory networks, the circadian CLOCK and stress systems, which respectively consist of oscillating molecular pacemakers, the Clock/Bmal1 transcription factors, and the hypothalamic-pituitary-adrenal (HPA) axis and its end-effector, the glucocorticoid receptor. These systems communicate with one another at different signaling levels and dysregulation of either system can lead to development of pathologic conditions. In this review, we summarize the mutual physiologic interactions between the circadian CLOCK system and the HPA axis, and discuss their clinical implications.

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Available from: George Chrousos, Oct 05, 2015
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    • "Hypothalamic PVN receives many axons from various areas of the brains, such as hippocampus, amygdala, prefrontal cortex, and locus ceruleus of the brainstem, and integrates stressful information obtained from peripheral sensory organs and nerves and then assembled in these brain regions (Gold and Chrousos, 2002). In a basal state, the HPA axis demonstrates circadian activity under the control of the circadian rhythm center suprachiasmatic nucleus (SCN) of the hypothalamus, and creates a typical diurnal fluctuation in serum cortisol concentrations, which reaches the zenith in early morning and the nadir at midnight (Nader et al., 2010; Kino, 2012; Nicolaides et al., 2014). When exposed to stressors, the HPA axis escapes from this regular circadian control and secretes massive amounts of glucocorticoids (cortisol in humans and corticosterone in rodents) to adjust the body's functions (Kino, 2012). "
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    ABSTRACT: The hypothalamic-pituitary-adrenal (HPA) axis and its end-effectors glucocorticoid hormones play central roles in the adaptive response to numerous stressors that can be either internal or external. Thus, this system has a strong impact on the brain hippocampus and its major functions, such as cognition, memory as well as behavior, and mood. The hippocampal area of the adult brain contains neural stem cells or more committed neural progenitor cells, which retain throughout the human life the ability of self-renewal and to differentiate into multiple neural cell lineages, such as neurons, astrocytes, and oligodendrocytes. Importantly, these characteristic cells contribute significantly to the above-indicated functions of the hippocampus, while various stressors and glucocorticoids influence proliferation, differentiation, and fate of these cells. This review offers an overview of the current understanding on the interactions between the HPA axis/glucocorticoid stress-responsive system and hippocampal neural progenitor cells by focusing on the actions of glucocorticoids. Also addressed is a further discussion on the implications of such interactions to the pathophysiology of mood disorders.
    Frontiers in Physiology 09/2015; 6:230. DOI:10.3389/fphys.2015.00230 · 3.53 Impact Factor
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    • "The HPA axis, through glucocorticoids, exerts influence on many important biological processes, and glucocorticoids are proposed to have an important synchronizing role on peripheral circadian rhythms [3] [63]. Glucocorticoids have been found to broadly influence gene expression through GR [64]. When activated, the cytoplasmic GR, previously in an inactive complexed state, undergoes conformational changes and, after dimerization, translocates into the nucleus. "
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    ABSTRACT: Many physiological processes and most endocrine functions show fluctuations over the course of the day. These so-called circadian rhythms are governed by an endogenous network of cellular clocks and serve as an adaptation to daily and, thus, predictable changes in the organism’s environment. Circadian clocks have been described in several tissues of the stress axis and in adipose cells where they regulate the rhythmic and stimulated release of stress hormones, such as glucocorticoids, and various adipokine factors. Recent work suggests that both adipose and stress axis clock systems reciprocally influence each other and adrenal-adipose rhythms may be key players in the development and therapy of metabolic disorders. In this review, we summarize our current understanding of adrenal and adipose tissue rhythms and clocks and how they might interact to regulate energy homoeostasis and stress responses under physiological conditions. Potential chronotherapeutic strategies for the treatment of metabolic and stress disorders are discussed.
    International Journal of Endocrinology 05/2015; 2015:1-13. DOI:10.1155/2015/693204 · 1.95 Impact Factor
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    • "Glucocorticoids are mainly related to metabolism and the stress response (Aluru and Vijayan, 2007). The circulating levels of these hormones show a strong circadian rhythm in vertebrates, that seems to be driven by central and peripheral oscillators (Kalsbeek et al., 2012; Nader et al., 2010). Nevertheless, daily fluctuations in glucocorticoids have been suggested also as an input to the circadian system. "
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    ABSTRACT: The circadian system drives daily physiological and behavioral rhythms that allow animals to anticipate cyclic environmental changes. The discovery of the known as "clock genes", which are very well conserved through vertebrate phylogeny, highlighted the molecular mechanism of circadian oscillators functioning, based on transcription and translation cycles (∼24 h) of such clock genes. Studies in goldfish have shown that the circadian system in this species is formed by a net of oscillators distributed at central and peripheral locations, as the retina, brain, gut and liver, among others. In this work we review the existing information about the hepatic oscillator in goldfish due to its relevance in metabolism, and its key role as target of a variety of humoral signals. Different input signals modify the molecular clockwork in the liver of goldfish. Among them, there are environmental cues (photocycle and feeding regime) and different encephalic and peripheral endogenous signals (orexin, ghrelin and glucocorticoids). Per clock genes seem to be a common target for different signals. Thus, this genes family might be important for shifting the hepatic oscillator. The physiological relevance of the crosstalking between metabolic and feeding-related hormones and the hepatic clock sets the stage for the hypothesis that these hormones could act as "internal zeitgebers" communicating oscillators in the goldfish circadian system. Copyright © 2015. Published by Elsevier Inc.
    General and Comparative Endocrinology 05/2015; DOI:10.1016/j.ygcen.2015.05.001 · 2.47 Impact Factor
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