Onno C Meijer

Onno C Meijer
Leiden University Medical Centre | LUMC · Department of Endocrinology and General Internal Medicine

PhD

About

238
Publications
24,047
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9,793
Citations
Additional affiliations
January 1999 - March 2012
Leiden University
Position
  • Professor (Assistant)
January 1997 - November 1998
University of California, San Francisco
Position
  • PostDoc Position

Publications

Publications (238)
Article
Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and auto-immune diseases. Unfortunately, their use is hampered by many side effects and therapy resistance. Efforts to find more selective glucocorticoid receptor (GR) agonists and modulators (called SEGRAMs) that are able to separate anti-inflammato...
Preprint
Aims/hypothesis. Pharmacological conditioning, where an association is formed between a drug and a conditioned stimulus (CS, e.g., smell), can influence physiological processes. Evidence exists that it is possible to condition insulin effects in animals and healthy humans but it is unclear whether these effects can be observed in patients as well....
Article
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Glucocorticoids exert their pleiotropic effects by activating the glucocorticoid receptor (GR), which is expressed throughout the body. GR‐mediated transcription is regulated by a multitude of tissue‐ and cell type‐specific mechanisms, including interactions with other transcription factors such as the androgen receptor (AR). We previously showed t...
Article
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The metabolic and cardiovascular clinical manifestations in patients with Cushing’s syndrome (CS) are generally well known. However, recent studies have broadened the perspective of the effects of hypercortisolism, showing that both endogenous and exogenous glucocorticoid excess alter brain functioning on several time scales. Consequently, cognitiv...
Article
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‘You can't roll the clock back and reverse the effects of experiences' Bruce McEwen used to say when explaining how allostasis labels the adaptive process. Here we will for once roll the clock back to the times that the science of the glucocorticoid hormone was honored with a Nobel prize and highlight the discovery of their receptors in the hippoca...
Preprint
Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and auto-immune diseases. Unfortunately, their use is hampered by many side effects and therapy resistance. Efforts to find more selective glucocorticoid receptor (GR) agonists and modulators (called SEGRAMs) that are able to separate anti-inflammato...
Preprint
BACKGROUND The hormone cortisol plays important roles in human circadian and stress physiology and is an interesting target for interventions. Animal studies consistently show that cortisol is affected by pharmacological conditioning, but the results are mixed in humans. Cortisol also varies as part of a diurnal rhythm, showing a sharp increase rig...
Article
Excess glucocorticoid exposure affects emotional and cognitive brain functions. The extreme form, Cushing’s Syndrome, is adequately modeled in the AdKO2.0 mouse, consequential to adrenocortical hypertrophy and hypercorticosteronemia. We previously reported that the AdKO2.0 mouse brain undergoes volumetric changes that resemble closely those of Cush...
Article
Brain mineralocorticoid receptors (MR) mediate effects of glucocorticoid hormones in stress adaptation, and the effects of aldosterone in relation to salt homeostasis. Brain stem MRs respond to aldosterone, while forebrain MRs mediate rapid and delayed glucocorticoid effects in conjunction with the glucocorticoid receptor (GR). MR‐mediated effects...
Article
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Background: Synthetic glucocorticoids like dexamethasone can cause severe neuropsychiatric effects. They preferentially bind to the glucocorticoid receptor (GR) over the mineralocorticoid receptor (MR). High dosages result in strong GR activation, but likely also lower MR activation based on GR-mediated negative feedback on cortisol levels. Therefo...
Article
The pachychoroid disease spectrum (PDS) includes several chorioretinal diseases that share specific choroidal abnormalities. Although their pathophysiological basis is poorly understood, diseases that are part of the PDS have been hypothesized to be the result of venous congestion. Within the PDS, central serous chorioretinopathy is the most common...
Preprint
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The characteristic endogenous circadian rhythm of plasma glucocorticoid concentrations is made up from an underlying ultradian pulsatile secretory pattern. Recent evidence has indicated that this ultradian cortisol pulsatility is crucial for normal emotional response in man. In this study, we investigate the anatomical transcriptional and cell type...
Article
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Introduction The synthetic glucocorticoid dexamethasone can induce serious neuropsychiatric adverse effects. Dexamethasone activates the glucocorticoid receptor (GR) but, unlike endogenous cortisol, not the mineralocorticoid receptor (MR). Moreover, dexamethasone suppresses cortisol production, thereby eliminating its MR binding. Consequently, GR o...
Article
Full-text available
Glucocorticoid stress hormones are powerful modulators of brain function and can affect mood and cognitive processes. The hippocampus is a prominent glucocorticoid target and expresses both the glucocorticoid receptor (GR – Nr3c1) and the mineralocorticoid receptor (MR – Nr3c2). These nuclear steroid receptors act as ligand-dependent transcription...
Article
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Increasing evidence points to a relation between increased glucocorticoid (GC) exposure and weight gain. In support, long-term cortisol measurements using hair analysis revealed that many individuals with obesity appear to have cortisol values in the high physiological range. The mechanisms behind this relationship need to be determined in order to...
Article
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Stress-related neuropsychiatric disorders are often accompanied by dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. In patients suffering from post-traumatic stress disorder (PTSD), increased sensitivity of glucocorticoid negative feedback has regularly been observed. The single prolonged stress (SPS) paradigm was developed to model in...
Preprint
Brain mineralocorticoid receptors (MR) mediate effects of aldosterone in relation to salt homeostasis, and of glucocorticoid stress hormones corticosteroids in the context of stress adaptation. Brain stem MRs respond to aldosterone, while forebrain MRs mediate rapid and delayed MR-mediated glucocorticoids effects in conjunction with the glucocortic...
Article
Full-text available
Glucocorticoid (GC)-induced osteoporosis is a widespread health problem that is accompanied with increased fracture risk. Detrimental effects of anti-inflammatory GC therapy on bone have been ascribed to the excess in GC exposure, but it is unknown whether there is also a role for disruption of the endogenous GC rhythm that is inherent to GC therap...
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Context Central serous chorioretinopathy (CSC) is a severe ocular disease characterized by fluid accumulation under the retina and abnormalities in the underlying vascular layer, the choroid. CSC has a striking prevalence in males of 80-90% of total patients. Corticosteroids are the most pronounced extrinsic risk factor for CSC. Choroidal endotheli...
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We report on a case of a 50-year-old female patient with primary hyperaldosteronism, in whom adrenal venous sampling was required to differentiate between unilateral and bilateral disease. Because of a history of severe allergy to iodinated contrast media, premedication with glucocorticoids was indicated. Exogenous glucocorticoids, however, can aff...
Article
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Responding to different dynamic levels of stress is critical for mammalian survival. Disruption of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) signaling is proposed to underlie hypothalamic-pituitary-adrenal (HPA) axis dysregulation observed in stress-related psychiatric disorders. In this study, we show that FK506-binding prot...
Article
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Physiological circadian (i.e., 24‐hour) rhythms are critical for bone health. Animal studies have shown that genes involved in the intrinsic molecular clock demonstrate potent circadian expression patterns in bone, and that genetic disruption of these clock genes results in a disturbed bone structure and quality. More importantly, circulating marke...
Article
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Glucocorticoids enhance memory consolidation of emotionally arousing events via largely unknown molecular mechanisms. This glucocorticoid effect on the consolidation process also requires central noradrenergic neurotransmission. The intracellular pathways of these two stress mediators converge on two transcription factors: the glucocorticoid recept...
Article
Introduction Remitted Cushing’s disease (RCD)-patients commonly continue to present persistent psychological and cognitive deficits, and alterations in brain function and structure. Assessing cortical thickness and surface area of RCD-patients may offer further insight into the neuroanatomical substrates of Cushing’s disease. Objectives To assess...
Article
Stressful experiences evoke, among others, a rapid increase of brain (nor)epinephrine (NE) levels and a slower increase in glucocorticoid hormones (GCs) in the brain. Microglia are key regulators of neuronal function and contain receptors for NE and GCs. These brain cells may therefore potentially be involved in modulating stress‐effects on neurona...
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Objective Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20β-dihydrocorticosterone (20β-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to the cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediat...
Article
Glucocorticoids regulate numerous processes in human physiology, but deregulated or excessive glucocorticoid receptor (GR) signaling contributes to the development of various pathologies including metabolic syndrome. For this reason, GR antagonists have considerable therapeutic value. Yet, the only GR antagonist that is clinically approved to date...
Article
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Chronic exposure to high circulating levels of glucocorticoids has detrimental effects on health, including metabolic abnormalities, as exemplified in Cushing’s syndrome (CS). Magnetic resonance imaging (MRI) studies have found volumetric changes in gray and white matter of the brain in CS patients during the course of active disease, but also in r...
Article
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Multiple case series have provided evidence for a relatively high incidence of central serous chorioretinopathy (CSC) in patients with active Cushing’s syndrome (CS). We describe the ophthalmological status in detail of consecutive patients with active endogenous CS (either de novo or recurrent active endogenous CS) in this prospective cohort study...
Article
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Objective Brown adipose tissue (BAT) displays a strong circadian rhythm in metabolic activity, but it is unclear how this rhythm is regulated. As circulating levels of corticosterone coincide with the rhythm of triglyceride-derived fatty acid uptake by BAT, we set out to investigate if corticosterone regulates BAT circadian rhythm. Methods Cortico...
Article
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The biological mechanisms underlying inter-individual differences in human stress reactivity remain poorly understood. We aimed to identify the molecular underpinning of aberrant neural stress sensitivity in individuals at-risk for schizophrenia. Linking mRNA expression data from the Allen Human Brain Atlas to task-based fMRI revealed 201 different...
Article
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Background Learned placebo effects induced by pharmacological conditioning affect immune and endocrine outcomes and may offer new possibilities for clinical applications. Whether or not cortisol is subject to this type of associative learning processes, and whether conditioning may affect responses to stress, is currently unclear. Method A randomi...
Article
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The diversity of actions of the glucocorticoid stress hormones among individuals and within organs, tissues and cells is shaped by age, gender, genetics, metabolism, and the quantity of exposure. However, such factors cannot explain the heterogeneity of responses in the brain within cells of the same lineage, or similar tissue environment, or in th...
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Background Hypothalamic-pituitary-adrenal axis functioning has been related to treatment outcome in posttraumatic stress disorder (PTSD). Previous studies have primarily focused on cortisol levels before and after a course of therapy and findings have not been fully consistent. This study investigated session-related cortisol levels in veterans wit...
Article
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The Single Prolonged Stress protocol is considered a model for PTSD, as it induces long lasting changes in rat behaviour and endocrine regulation. Previous work demonstrated that some of these changes can be prevented by treatment with the glucocorticoid receptor antagonist RU486, administered a week after the stressor. The current study evaluated...
Preprint
Full-text available
The biological mechanisms underlying inter-individual differences in human stress reactivity remain poorly understood. We aimed to identify the molecular underpinning of neural stress sensitivity. Linking mRNA expression data from the Allen Human Brain Atlas to task-based fMRI revealed 201 differentially expressed genes in cortex-specific brain reg...
Article
Full-text available
CADASIL is a NOTCH3-associated cerebral small vessel disease. A pathological ultrastructural disease hallmark is the presence of NOTCH3-protein containing deposits called granular osmiophilic material (GOM), in small arteries. How these GOM deposits develop over time and what their role is in disease progression is largely unknown. Here, we studied...
Article
Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR...
Article
Glucocorticoids are steroid hormones that are of pivotal importance in human physiology. Glucocorticoid signaling is complex in nature and dependent on many interacting factors. As glucocorticoids exhibit sexually dimorphic effects on several key processes including in metabolism, crosstalk with the sex steroid hormones (androgens and estrogens) is...
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Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs early in Alzheimer's disease (AD), associated with elevated circulating glucocorticoids (GC) and glucocorticoid receptors (GR) signaling impairment. However, the precise role of GR in the pathophysiology of AD remains unclear. Using an acute model of AD induced by the intracerebr...
Article
A comprehensive study from Denmark established that the systemic use of glucocorticoids hormones has an annual prevalence of 3% and has been stable from 1999-2014. We comment on the risk of potentially long-lasting adverse effects, dependent on glucocorticoid receptor overactivation, but also mineralocorticoid receptor under-activation. We discuss...
Article
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Early life stress (ELS) is considered a major risk factor for developing psychopathology. Increasing evidence points towards sex-dependent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis as a contributing mechanism. Additionally, clinical studies suggest that the mineralocorticoid receptor (MR) may further confer genetic vulnerabilit...
Article
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Adrenal glucocorticoid hormones are crucial for maintenance of homeostasis and adaptation to stress. They act via the mineralocorticoid (MR) and glucocorticoid receptors (GR), members of the family of nuclear receptors. MR and GR can mediate distinct, sometimes opposite effects of glucocorticoids. Both receptor types can mediate non-genomic steroid...
Article
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Psychotic depression is characterized by elevated circulating cortisol, and high daily doses of the glucocorticoid/progesterone antagonist mifepristone for 1 week are required for significant improvement. Using a rodent model, we find that such high doses of mifepristone are needed because the antagonist is rapidly degraded and poorly penetrates th...
Article
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Corticosteroid hormones act in the brain to support adaptation to stress via binding to mineralocorticoid and glucocorticoid receptors (MR and GR). These receptors act in large measure as transcription factors. Corticosteroid effects can be highly divergent, depending on the receptor type, but also on brain region, cell type, and physiological cont...
Article
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Background: Stressors activate a wide spectrum of interacting hormonal and neuronal systems resulting in behavioral and physiological responses, with consequences for the development of psychopathology. Several recent studies demonstrated that treatment with the glucocorticoid receptor (GR) antagonist RU486 during adulthood normalized effects of e...
Article
Full-text available
Brain mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) respond to the same glucocorticoid hormones, but can have differential effects on cellular function. Several lines of evidence suggest that MR‐specific target genes must exist, and might underlie distinct effects of the receptors. Our goal was to identify MR‐specific target...
Article
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Mineralocorticoid receptor (MR)-mediated signaling in the brain has been suggested as a protective factor in the development of psychopathology, in particular mood disorders. We recently identified genomic loci at which either MR or the closely related glucocorticoid receptor (GR) binds selectively, and found members of the NeuroD transcription fac...
Article
Full-text available
Glucocorticoid hormones have important effects on brain function in the context of acute and chronic stress. Many of these are mediated by the glucocorticoid receptor (GR). GR has a transcriptional activity which is highly context-specific and differs between tissues and even between cell types. The outcome of GR-mediated transcription depends on t...
Article
Full-text available
Regulatory factors that control gene transcription in multicellular organisms are assembled in multicomponent complexes by combinatorial interactions. In this context, nuclear receptors provide well-characterized and physiologically relevant systems to study ligand-induced transcription resulting from the integration of cellular and genomic informa...
Article
In contrast to classical conditioning of physiological responses such as immune responses and drug effects, only a limited number of studies investigated classical conditioning of endocrine responses. The present paper is the first systematic review that integrates evidence from animal and human trials regarding the possibility to condition the end...
Article
Full-text available
Purpose: To isolate, culture, and characterize primary human choroidal endothelial cells, and to assess their responsiveness to corticosteroids, in order to enable knowledge gain on the pathogenesis of central serous chorioretinopathy. Methods: Choroidal endothelial cells were isolated from cadaveric human donors. Magnetic-activated cell sorting...
Article
Non-alcoholic fatty liver disease (NAFLD) medication is an unmet need. Glucocorticoid stress hormones (GC) drive fat metabolism in the liver, but both full blockade and full stimulation of GC signaling aggravate NAFLD pathology. We investigated the efficacy of selective glucocorticoid receptor (GR) modulator CORT118335, that recapitulates only a su...
Article
Glucocorticoid signaling is context-dependent, and in certain scenarios glucocorticoid receptors (GR) are able to engage with other members of the nuclear receptor subfamily. Glucocorticoid signaling can exert sexually dimorphic effects, suggesting a possible interaction with androgen sex hormones. We therefore set out to determine the crosstalk be...
Article
Full-text available
Metabolic status impacts on the emotional brain to induce behavior that maintains energy balance. While hunger suppresses the fear circuitry to promote explorative food-seeking behavior, satiety or obesity may increase fear to prevent unnecessary risk-taking. Here we aimed to unravel which metabolic factors, that transfer information about the acut...
Conference Paper
Introduction: Glucocorticoids (GCs) are widely used anti-inflammatory medications that cause many metabolic side effects. Long-term treatment with GCs causes obesity and induces insulin resistance in many metabolic tissues, including adipose tissue and muscle. Factors secreted by adipose tissue, so-called adipokines, including leptin and adiponecti...
Article
The glucocorticoid hormone cortisol acts throughout the body to support circadian processes and adaptation to stress. The glucocorticoid receptor is the target of cortisol and of synthetic glucocorticoids, which are used widely in the clinic. Both agonism and antagonism of the glucocorticoid receptor may be beneficial in disease, but given the wide...
Article
Many favorable metabolic effects have been attributed to thermogenic activity of brown adipose tissue (BAT). Yet, time of day has rarely been considered in this field of research. Here, we show that a diurnal rhythm in BAT activity regulates plasma lipid metabolism. We observed a high-amplitude rhythm in fatty acid uptake by BAT that synchronized w...
Article
Full-text available
Bruce McEwen's discovery of receptors for corticosterone in the rat hippocampus introduced higher brain circuits in the neuroendocrinology of stress. Subsequently, these receptors were identified as mineralocorticoid receptors (MRs) that are involved in appraisal processes, choice of coping style, encoding and retrieval. The MR-mediated actions on...