Reduced glucocorticoid receptor expression in obese Zucker rats: Protection from the metabolic consequences of obesity?
AJ Drake, ME Cleasby, DEW Livingstone, JR Seckl & BR Walker
Glucocorticoids are potentially important in obesity; recent data suggest both circulating levels and tissue-specific changes in glucocorticoid responsiveness and metabolism may influence their effect. In obese Zucker rats, the phenotype is ameliorated by adrenalectomy, and shows the same pattern of altered glucocorticoid metabolism as in human obesity. However, previous reports suggest hepatic glucocorticoid receptor (GR) binding is impaired. We have now explored expression of GR mRNA in insulin sensitive tissues. Moreover, to distinguish differences intrinsic to the Zucker genotype from those secondary to hyperinsulinaemia, we administered insulin sensitising drugs.
Groups of eight 6-week-old male lean and obese Zucker rats were treated daily with metformin (43 mg/kg), rosiglitazone (1 mg/kg) or vehicle, by gavage. After 3 weeks, the animals were killed; tissues were snap frozen. Total RNA was extracted from liver, quadriceps muscle and subcutaneous fat and used in ribonuclease protection assays with GR and beta-actin probes. Data are mean SEM; comparisons were by two-way ANOVA. GR mRNA levels are expressed as a ratio of GR/Actin protected band fragment intensity x 100.
In obese animals, GR mRNA was decreased in liver (78 plus/minus 5 vs 96 plus/minus 5, p<0.05) and subcutaneous fat (93 plus/minus 4 vs 119 plus/minus 4, p<0.05), but not in muscle (127 plus/minus 16; 150 plus/minus 16, p=0.48). Neither metformin nor rosiglitazone altered GR in either group.
Thus, obese Zucker rats have decreased GR in key glucocorticoid target tissues and, unlike up-regulated GR in dexamethasone-programmed rats, these changes are insensitive to insulin sensitisation. Tissue-specific changes in glucocorticoid metabolism, resulting in lower intra-hepatic and higher intra-adipose glucocorticoid concentrations, may make a more important contribution to differences in glucocorticoid action between lean and obese animals. The down-regulation of GR may, however, represent an important protective mechanism against the metabolic consequences of obesity.