title: HPA axis dysregulation, NR3C1 polymorphisms and glucocorticoid receptor isoforms imbalance in metabolic syndrome.
abstract: Metabolic syndrome (MetS) shares several similarities with hypercortisolism.
  
  
  
  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.
  
  
  
  Prospective study with 40 MetS patients and 40 controls was conducted at the Ribeirão Preto Medical School University Hospital.
  
  
  
  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, IFNγ, TNFα) expression were assessed by quantitative polymerase chain reaction.
  
  
  
  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 GRβ was overexpressed (fold = 100.0; P = .002) and IL4 (fold = -265.0; P < .0001) was underexpressed in MetS.
  
  
  
  MetS patients exhibited decreased HPA sensitivity to glucocorticoid feedback. Moreover, the BclI polymorphism lower frequency, GRβ overexpression, and IL4 underexpression might underlie the molecular mechanism of glucocorticoid resistance in MetS. Thus, HPA axis dysregulation might contribute to MetS pathogenesis.
authors: Department of Internal Medicine - Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors: Clarissa Silva
authors: CS
authors: Martins
authors: Department of Internal Medicine - Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors: Daniel
authors: D
authors: Elias
authors: Department of Internal Medicine - Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors: Leandro Machado
authors: LM
authors: Colli
authors: Department of Internal Medicine - Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors: Carlos Eduardo
authors: CE
authors: Couri
authors: Department of Internal Medicine - Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors: Manoel Carlos L A
authors: MC
authors: Souza
authors: Department of Internal Medicine - Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors: Ayrton C
authors: AC
authors: Moreira
authors: Department of Internal Medicine - Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors: Milton C
authors: MC
authors: Foss
authors: Department of Physiology - Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors: Lucila L K
authors: LL
authors: Elias
authors: Department of Internal Medicine - Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors: Margaret
authors: M
authors: de Castro
mesh_terms: D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D016207:Cytokines; C497713:NR3C1 protein, human; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D006854:Hydrocortisone
keywords: HPA axis; glucocorticoid; glucocorticoid receptor; metabolic syndrome