The Functional and Clinical Significance of the 24-Hour Rhythm of Circulating Glucocorticoids

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ESSENTIAL POINTS

The daily rhythmicity of plasma glucocorticoid (GC) levels is a strong modulator of many physiological and psychological processes, although its functional significance is poorly understood.
The suprachiasmic nuclei of the hypothalamus have been shown to harbor a molecular clock mechanism generating circadian rhythmicity in mammals, but the same mechanism is present in many peripheral tissues and elsewhere in the brain.
Mineralocorticoid receptors and glucocorticoid receptors mediate the action of naturally occurring GC in complementary fashion.
Optimal physiological effects of GC occur when the central signal that controls the rhythm of GC release and the peripheral rhythms in tissues expressing GC receptors are aligned.
New studies suggest that misalignment of central and peripheral oscillators may increase the risk of disease, with adverse effects on the immune system, cardiovascular system and metabolism, among others prominent.
Chronopharmacological strategies that attempt to normalize the rhythm of circulating GCs have potential to improve the treatment of a wide variety of physical and mental conditions.

Abstract

Adrenal glucocorticoids are major modulators of multiple functions, including energy metabolism, stress responses, immunity, and cognition. The endogenous secretion of glucocorticoids is normally characterized by a prominent and robust circadian (around 24 hours) oscillation, with a daily peak around the time of the habitual sleep-wake transition and minimal levels in the evening and early part of the night. It has long been recognized that this 24-hour rhythm partly reflects the activity of a master circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus. In the past decade, secondary circadian clocks based on the same molecular machinery as the central master pacemaker were found in other brain areas as well as in most peripheral tissues, including the adrenal glands. Evidence is rapidly accumulating to indicate that misalignment between central and peripheral clocks has a host of adverse effects. The robust rhythm in circulating glucocorticoid levels has been recognized as a major internal synchronizer of the circadian system. The present review examines the scientific foundation of these novel advances and their implications for health and disease prevention and treatment.

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Disruption of the Clock Components CLOCK and BMAL1 Leads to Hypoinsulinemia and Diabetes

Biliana Marcheva, Kathryn Moynihan Ramsey, Ethan D Buhr … (2010)

The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night1–3. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis, and while rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes4, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism, and insulin signaling is delayed in circadian mutant mice, and both Clock 5,6 and Bmal1 7 mutants exhibit impaired glucose tolerance, reduced insulin secretion, and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival, and synaptic vesicle assembly. Remarkably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective β-cell function at the very latest stage of stimulus-secretion coupling. These results demonstrate a role for the β-cell clock in coordinating insulin secretion with the sleep-wake cycle, and reveal that ablation of the pancreatic clock can trigger onset of diabetes mellitus.

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Stress and the individual. Mechanisms leading to disease.

E STELLAR, B McEwen (1993)

This article presents a new formulation of the relationship between stress and the processes leading to disease. It emphasizes the hidden cost of chronic stress to the body over long time periods, which act as a predisposing factor for the effects of acute, stressful life events. It also presents a model showing how individual differences in the susceptibility to stress are tied to individual behavioral responses to environmental challenges that are coupled to physiologic and pathophysiologic responses. Published original articles from human and animal studies and selected reviews. Literature was surveyed using MEDLINE. Independent extraction and cross-referencing by us. Stress is frequently seen as a significant contributor to disease, and clinical evidence is mounting for specific effects of stress on immune and cardiovascular systems. Yet, until recently, aspects of stress that precipitate disease have been obscure. The concept of homeostasis has failed to help us understand the hidden toll of chronic stress on the body. Rather than maintaining constancy, the physiologic systems within the body fluctuate to meet demands from external forces, a state termed allostasis. In this article, we extend the concept of allostasis over the dimension of time and we define allostatic load as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenge that an individual reacts to as being particularly stressful. This new formulation emphasizes the cascading relationships, beginning early in life, between environmental factors and genetic predispositions that lead to large individual differences in susceptibility to stress and, in some cases, to disease. There are now empirical studies based on this formulation, as well as new insights into mechanisms involving specific changes in neural, neuroendocrine, and immune systems. The practical implications of this formulation for clinical practice and further research are discussed.

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Resetting of circadian time in peripheral tissues by glucocorticoid signaling.

F Tronche, A Balsalobre, G Schütz … (2000)

In mammals, circadian oscillators reside not only in the suprachiasmatic nucleus of the brain, which harbors the central pacemaker, but also in most peripheral tissues. Here, we show that the glucocorticoid hormone analog dexamethasone induces circadian gene expression in cultured rat-1 fibroblasts and transiently changes the phase of circadian gene expression in liver, kidney, and heart. However, dexamethasone does not affect cyclic gene expression in neurons of the suprachiasmatic nucleus. This enabled us to establish an apparent phase-shift response curve specifically for peripheral clocks in intact animals. In contrast to the central clock, circadian oscillators in peripheral tissues appear to remain responsive to phase resetting throughout the day.

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Author and article information

Journal

Journal ID (nlm-ta): Endocr Rev

Journal ID (iso-abbrev): Endocr. Rev

Journal ID (pmc): edrv

Journal ID (publisher-id): edrv

Title: Endocrine Reviews

Publisher: Endocrine Society (Washington, DC )

ISSN (Print): 0163-769X

ISSN (Electronic): 1945-7189

Publication date Collection: 01 February 2017

Publication date (Electronic): 17 October 2016

Volume: 38

Issue: 1

Pages: 3-45

Affiliations

Medical Department I (H.O., V.O.), University of Lübeck, 23562 Lübeck, Germany; Institute for Cellular and Integrative Neuroscience (E.C.), Centre National de la Recherche Scientifique (CNRS) UPR 3212, University of Strasbourg, 67084 Strasbourg, France; Division of Endocrinology, Diabetology and Metabolism (E.A.), Department of Internal Medicine, University of Turin, 10043 Turin, Italy; Department of Endocrinology and Metabolic Disease (E.R.d.K.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; Surrey Sleep Research Center (D.-J.D.), Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XP, United Kingdom; Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (S.L.), University of Bristol, Bristol BS8 1TH, United Kingdom; Sleep Research and Treatment Center (A.V.), Department of Psychiatry, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; and Sleep, Metabolism, and Health Center (E.V.C.), Department of Medicine, University of Chicago, Chicago, Illinois 60637

Author notes

[*]

H.O. and E.C. shared the responsibilities of lead authorship equally.

Address all correspondence and requests for reprints to: Eve Van Cauter, PhD, The University of Chicago, 5841 S. Maryland Avenue, MC1027, Chicago, IL 60637. E-mail: evcauter@ 123456medicine.bsd.uchicago.edu .

Article

Publisher ID: ER_151080

DOI: 10.1210/er.2015-1080

PMC ID: 5563520

PubMed ID: 27749086

License:

This article has been published under the terms of the Creative Commons Attribution License (CC BY; https://creativecommons.org/licenses/by/4.0/).

The Functional and Clinical Significance of the 24-Hour Rhythm of Circulating Glucocorticoids

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Most cited references 347

Disruption of the Clock Components CLOCK and BMAL1 Leads to Hypoinsulinemia and Diabetes

Stress and the individual. Mechanisms leading to disease.

Resetting of circadian time in peripheral tissues by glucocorticoid signaling.

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