A glucocorticoid receptor gene marker is associated with abdominal obesity, leptin, and dysregulation of the hypothalamic-pituitary-adrenal axis

Obes Res. 2000 May;8(3):211-8. doi: 10.1038/oby.2000.24.


Objective: Abdominal obesity has a key role in the pathogenesis of prevalent and serious diseases and has been shown to be associated with an altered hypothalamic-pituitary-adrenal (HPA) axis function, which is regulated by endocrine feedback mediated via hippocampal glucocorticoid receptors (GR).

Research methods and procedures: We examined the HPA axis function by repeated salivary samples for the assessment of cortisol, as well as other endocrine, anthropometric, metabolic, and circulatory variables in middle-aged Swedish men (n = 284). With the restriction enzyme BclI, variants of the GR gene (GRL) locus were identified and two alleles with fragment lengths of 4.5 and 2.3 kilobases (kb) were detected.

Results: The observed frequencies were 40.1% for the 2.3- and 2.3-kb, 46.2% for the 4.5- and 2.3-kb, and 13.7% for the 4.5- and 4.5-kb genotypes. The larger allele (4.5 and 4.5 kb) was associated with elevated body mass index (BMI; p < 0.001), waist-to-hip circumference ratio (p = 0.015), abdominal sagittal diameter (p = 0.002), leptin (p < 0.001), and systolic blood pressure (borderline, p = 0.058). The 4.5- and 4.5-kb allele was associated with leptin after adjustment for BMI. Moreover, salivary cortisol values, particularly after stimulation by a standardized lunch (p = 0.040 to 0.086), were elevated in the men with the larger allele.

Discussion: These results indicate that there is an association between a deficient GR function, defined as a poor feedback regulation of the HPA axis activity, and a polymorphic restriction site at the GR gene locus. An abnormal control of HPA axis function due to genetic alterations may contribute to the pathogenesis of abdominal obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / physiopathology
  • Alleles
  • Blood Glucose / analysis
  • Blood Pressure
  • Body Constitution
  • Body Mass Index
  • Cohort Studies
  • DNA / chemistry
  • DNA / isolation & purification
  • Dexamethasone / pharmacology
  • Eukaryotic Initiation Factor-1 / blood
  • Glucocorticoids / pharmacology
  • Humans
  • Hydrocortisone / metabolism
  • Hypothalamo-Hypophyseal System / physiopathology*
  • Insulin / analysis
  • Leptin / blood*
  • Male
  • Middle Aged
  • Obesity / blood
  • Obesity / epidemiology
  • Obesity / genetics*
  • Pituitary-Adrenal System / physiopathology*
  • Polymorphism, Restriction Fragment Length
  • Receptors, Glucocorticoid / chemistry
  • Receptors, Glucocorticoid / genetics*
  • Salivary Glands / metabolism
  • Sweden / epidemiology
  • Testosterone / blood


  • Blood Glucose
  • Eukaryotic Initiation Factor-1
  • Glucocorticoids
  • Insulin
  • Leptin
  • Receptors, Glucocorticoid
  • Testosterone
  • Dexamethasone
  • DNA
  • Hydrocortisone