HPA axis dysregulation, <i>NR3C1</i> polymorphisms and glucocorticoid receptor isoforms imbalance in metabolic syndrome

Martins, Clarissa Silva; Eliáš, Daniel; Colli, Leandro M.; Couri, Carlos Eduardo Barra; Souza, Manoel Carlos L. A.; Moreira, Ayrton Custódio; Foss, Milton César; Elias, Leonardo Abdala; Castro, Margaret de

doi:10.1002/dmrr.2842

Cited by 29 publications

(22 citation statements)

References 52 publications

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“…GC resistance can be ascribed to increased inflammatory state, GRβ overexpression and increased conversion of active/inactive cortisol by 11βHSD2 isoform . As we have previously demonstrated in Metabolic Syndrome, our data in FPLD2 patients also suggest that the increased proinflammatory cytokines might contribute to the HPA axis decreased GC sensitivity. Although no differences on GRα, GRβ, 11βHSD1 and 11βHSD2 expressions were observed in peripheral mononuclear blood cells of FPLD2 patients compared with controls, GRβ overexpression was observed in female FPLD2 patients compared with female controls, which may contribute to decreased HPA axis sensitivity to GC in female FPLD2 patients.…”

Section: Discussionsupporting

confidence: 81%

Phenotypic diversity and glucocorticoid sensitivity in patients with familial partial lipodystrophy type 2

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Martins

Bueno

et al. 2019

Clinical Endocrinology

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Familial partial lipodystrophy type 2 (FPLD2) is characterized by insulin resistance, adipose atrophy of the extremities and central obesity. Due to the resemblance with Cushing's syndrome, we hypothesized a putative role of glucocorticoid in the pathogenesis of metabolic abnormalities in FPLD2. Objective:To evaluate the phenotypic heterogeneity and glucocorticoid sensitivity in FPLD2 patients exhibiting the p.R482W or p.R644C LMNA mutations. Design, patients and measurements:Prospective study with FPLD2 patients (n = 24) and controls (n = 24), who underwent anthropometric, body composition, metabolic profile and adipokines/cytokine plasma measurements. Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5 and 1.0 mg of dexamethasone (DEX) given at 23:00 hours. Glucocorticoid receptor (GR) and 11βHSD isoforms expression were assessed by qPCR.Results: Familial partial lipodystrophy type 2 individuals presented increased waist and neck circumferences, decreased hip circumference, peripheral skinfold thickness and fat mass. Patients presented increased HOMA-IR, triglycerides, TNF-α, IL-1β, IL-6 and IL-10, and decreased adiponectin and leptin plasma levels. FPLD2 patients showed decreased ability to suppress the HPA axis compared with controls after 0.5 mg DEX. The phenotype was more pronounced in patients harbouring the p.R482W LMNA mutation. GRβ overexpression in PBMC was observed in female patients compared with female controls.Conclusions: Familial partial lipodystrophy type 2 patients exhibited anthropometric, clinical and biochemical phenotypic heterogeneity related to LMNA mutation sites and to gender. LMNA mutations affecting both lamin A and lamin C lead to more severe phenotype. FPLD2 patients also showed blunted HPA axis response to DEX, probably due to the association of increased levels of proinflammatory cytokines with GRβ overexpression leading to a more severe phenotype in female. K E Y W O R D Sfamilial partial lipodystrophy type 2, glucocorticoid sensitivity, insulin resistance, metabolic syndrome | 95 RESENDE Et al.

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Section: Discussionsupporting

confidence: 81%

Phenotypic diversity and glucocorticoid sensitivity in patients with familial partial lipodystrophy type 2

Resende

Martins

Bueno

et al. 2019

Clinical Endocrinology

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“…The reduced GRα/GRβ ratio seen in TB patients is compatible with a certain degree of resistance to GC endogenous function. In a recent study, Martins et al reported that GRβ expression levels were dramatically increased in PBMC of patients with the metabolic syndrome compared to lean controls (53). Our present lack of GRβ transcript alterations in control subjects may be explained by considering that their BMI situated below the ones displayed by the group of dysmetabolic Brazilian patients.…”

Section: Discussioncontrasting

confidence: 52%

Evidence for a More Disrupted Immune-Endocrine Relation and Cortisol Immunologic Influences in the Context of Tuberculosis and Type 2 Diabetes Comorbidity

et al. 2020

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Fernández et al. Immune-Endocrine Relation Tuberculosis Diabetes response to Mtb stimulation (increased IL-2 and IFN-γ production), even when exposed to inhibitory cortisol doses. TB+DM patients show a more unbalanced immuno-endocrine relationship, respect the non-diabetic counterparts, with a relative deficiency of cortisol immunomodulatory influences, despite their more favorable microenvironment for cortisol-mediated immune effects.

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“…Finally, transgenic mice overexpressing HSD type 1 (HSD1, see Box 1), a corticosterone-regenerating enzyme, show clinical features of metabolic syndrome (obesity, insulin resistance, dyslipidemia) suggesting a role for glucocorticoids in the pathogenesis of metabolic syndrome [48]. It has been shown that in metabolic syndrome, a NR3C1 polymorphism of the GR predisposes to HPA dysregulation [49]. Metabolic syndrome also impairs vascular reactivity and causes neuroinflammation and oxidative stress in the CNS, providing a substrate for neurodegeneration [26].…”

Section: Hypercorticosteronemia In Experimental Neurodegenerative Dismentioning

confidence: 99%

Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases

Nicola

Meyer

Guennoun

et al. 2020

IJMS

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Glucocorticoids are crucial for stress-coping, resilience, and adaptation. However, if the stress hormones become dysregulated, the vulnerability to stress-related diseases is enhanced. In this brief review, we discuss the role of glucocorticoids in the pathogenesis of neurodegenerative disorders in both human and animal models, and focus in particular on amyotrophic lateral sclerosis (ALS). For this purpose, we used the Wobbler animal model, which mimics much of the pathology of ALS including a dysfunctional hypothalamic–pituitary–adrenal axis. We discuss recent studies that demonstrated that the pathological cascade characteristic for motoneuron degeneration of ALS is mimicked in the genetically selected Wobbler mouse and can be attenuated by treatment with the selective glucocorticoid receptor antagonist (GRA) CORT113176. In long-term treatment (3 weeks) GRA attenuated progression of the behavioral, inflammatory, excitatory, and cell-death-signaling pathways while increasing the survival signal of serine–threonine kinase (pAkt). The action mechanism of the GRA may be either by interfering with GR deactivation or by restoring the balance between pro- and anti-inflammatory signaling pathways driven by the complementary mineralocorticoid receptor (MR)- and GR-mediated actions of corticosterone. Accordingly, GR antagonism may have clinical relevance for the treatment of neurodegenerative diseases.

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HPA axis dysregulation, NR3C1 polymorphisms and glucocorticoid receptor isoforms imbalance in metabolic syndrome

Cited by 29 publications

References 52 publications

Phenotypic diversity and glucocorticoid sensitivity in patients with familial partial lipodystrophy type 2

Phenotypic diversity and glucocorticoid sensitivity in patients with familial partial lipodystrophy type 2

Evidence for a More Disrupted Immune-Endocrine Relation and Cortisol Immunologic Influences in the Context of Tuberculosis and Type 2 Diabetes Comorbidity

Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases

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