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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

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Autor(es):
Martins, Clarissa Silva ; Elias, Daniel ; Colli, Leandro Machado ; Couri, Carlos Eduardo ; Souza, Manoel Carlos L. A. ; Moreira, Ayrton C. ; Foss, Milton C. ; Elias, Lucila L. K. ; de Castro, Margaret
Número total de Autores: 9
Tipo de documento: Artigo Científico
Fonte: DIABETES-METABOLISM RESEARCH AND REVIEWS; v. 33, n. 3 MAR 2017.
Citações Web of Science: 7
Resumo

Context Metabolic syndrome (MetS) shares several similarities with hypercortisolism. Objectives To evaluate hypothalamic-pituitary-adrenal (HPA) axis sensitivity to dexamethasone (DEX), NR3C1 single nucleotide polymorphisms (SNPs), and expression of glucocorticoid receptor (GR) isoforms and cytokines in peripheral immune cells of MetS patients and controls. Design Prospective study with 40 MetS patients and 40 controls was conducted at the Ribeirao Preto Medical School University Hospital. Methods Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5, and 1 mg of DEX given at 2300 h. In addition, p. N363S (rs6195), p. ER22/23EK (rs6189-6190), and BclI (rs41423247) SNPs were evaluated by quantitative polymerase chain reaction allelic discrimination. Exons 3 to 9 and exon/intron boundaries of NR3C1 were sequenced. GR isoforms and cytokines (IL1B, IL2, IL4, IL6, IL8, IL10, IFN gamma, TNF alpha) expression were assessed by quantitative polymerase chain reaction. Results Plasma and salivary cortisol (nmol/L) after 1-mg DEX were higher in MetS patients compared with controls (PF: 70.2 +/- 17.3 vs 37.9 +/- 2.6, P = .02, and SF: 4.9 +/- 1.7 vs 2.2 +/- 0.3, P <.0001). After all DEX doses, a lower number of MetS patients suppressed plasma and salivary cortisol compared with controls. The BclI genotypic frequencies (%) differed between patients (CC: 56/CG: 44) and controls (CC: 50/CG: 32.5/GG: 17.5) (P = .03). The GR beta was overexpressed (fold = 100.0; P = .002) and IL4 (fold = -265.0; P <.0001) was underexpressed in MetS. Conclusion MetS patients exhibited decreased HPA sensitivity to glucocorticoid feedback. Moreover, the BclI polymorphism lower frequency, GR beta overexpression, and IL4 underexpression might underlie the molecular mechanism of glucocorticoid resistance in MetS. Thus, HPA axis dysregulation might contribute to MetS pathogenesis. (AU)

Processo FAPESP: 05/57033-1 - Avaliação da sensibilidade aos glicocorticóides em indivíduos com síndrome metabólica e correlação com possíveis polimorfismos no gene do receptor de glicocorticóide
Beneficiário:Daniel Elias
Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
Processo FAPESP: 07/58365-3 - Fisiopatologia e etiopatogenia molecular de doenças relacionadas aos eixos corticotrófico, somatotrófico e neurohipofisário
Beneficiário:Margaret de Castro
Modalidade de apoio: Auxílio à Pesquisa - Temático