The role of glucocorticoid receptor polymorphisms and glucocorticoid sensitivity in human obesity
Creators: name: Syed, Akheel
Publisher: name: figshare
Year: 2024
Subjects: classificationCode: 320208
subject: Endocrinology
classificationCode: 420208
subject: Nutritional epidemiology
classificationCode: 310509
subject: Genomics

description: AbstractIt has been recognized that obesity and the metabolic syndrome share clinical similarities with Cushing’s syndrome. This has led to speculation of the role of glucocorticoids in the internal obesogenic milieu. Glucocorticoid effects are mediated by the glucocorticoid receptor, alteration of which may result in either enhanced or depressed responsiveness to endogenous glucocorticoids, leading to either an increase or a decrease in glucocorticoid-driven obesogenic characteristics. As single nucleotide polymorphisms of the glucocorticoid receptor gene could potentially alter receptor function, this work explored the relationship of several well-characterised and some less well characterized polymorphisms with obesity and obesity-related characteristics in a northeast England study population. The N363S polymorphism (rs6195), a single nucleotide change in exon 2 that occurs not uncommonly in White populations, had a low prevalence in south Asian people. The A3669G polymorphism (rs6198) in exon 9β has been shown to result in increased stability of the β isoform of the glucocorticoid receptor, a dominant negative inhibitor of the functional α isoform. In this study, it associated with reduced central adiposity in White women; a similar effect, albeit not reaching statistical significance, was observed in south Asian women. The rs2918419 polymorphism in intron 2 associated with higher fasting insulin concentration and greater prevalence of insulin resistance in White men. The Bcl1 polymorphism in intron 2, contrary to earlier reports, did not associate with hyperinsulinaemia on its own, but was in linkage disequilibrium with rs2918419. This may account for the former’s association with hyperinsulinaemia in earlier studies. The rs852980 and rs258813 polymorphisms appeared to contribute to obesogenic characteristics. However, rs10482682 appeared to be protective against obesogenic factors; women with variant alleles had a lower prevalence of insulin resistance, and smaller waist-to-hip ratios. In a parallel study, glucocorticoid sensitivity in vivo and in vitro was examined in a highly selected sample of 12 obese people with cushingoid features in the absence of Cushing’s syndrome compared to 6 slim control participants. To study GC-sensitivity in vitro, skin biopsies were taken and dose-response studies of dexamethasone-induced suppression of IL-6 secretion in skin fibroblast cultures were performed. Seven obese subjects were normosensitive and 5 subjects hypersensitive to GCs in vitro. A low dose (0.25 mg) overnight dexamethasone suppression test resulted in a median suppression of cortisol from baseline of 32% in normosensitive and 60% in hypersensitive obese subjects (P &lt; 0.004). No other clinical or biochemical measures were discriminatory between these two groups. These data from two independent measures of glucocorticoid sensitivity suggest that enhanced GC-sensitivity may characterize a substantial proportion of obese people with cushingoid appearance. In conclusion, these studies demonstrate the considerable impact of glucocorticoid homeostasis on the degree and distribution of adiposity and related characteristics, which is influenced by polymorphisms in the glucocorticoid receptor locus and by tissue sensitivity to glucocorticoids.