Circulating levels of glucocorticoids show a circadian rhythm. Obesity is associated with a flattening of the diurnal rhythm; plasma cortisol levels are slightly increased during the trough while they are normal or low in the morning. Studies in humans and in leptin-resistant Zucker rats suggests that tissue-specific alterations in glucocorticoid exposure might play a key role for development of obesity and obesity-associated dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. We hypothesized that there is a circadian rhythm in pre-receptor metabolism of glucocorticoids exerted by 11-hydroxysteroid dehydrogenase type 1 (11HSD1) in brain and/or peripheral tissues (liver, fat and muscle) which might be abrogated in obesity. The present study demonstrates a circadian rhythm in 11HSD1 mRNA expression (35-45% increase at AM vs. PM, P < 0.05) in dentate gyrus granular layer and CA1 subregions of the hippocampus in lean Zucker rats that was lost in the obese rats. Sprague-Dawley rats also revealed a diurnal rhythm in hippocampal 11HSD1 mRNA expression. There was no circadian variation in 11HSD enzyme activity in peripheral tissues, although obese Zucker rats had a decreased enzyme activity in liver and epididymal fat (by 40%, P < 0.05) compared to lean rats. In Sprague-Dawley rats, 11HSD activity in adipose tissue was higher in retroperitoneal and epididymal vs. subcutaneous fat (P < 0.001). In summary, obese Zucker rats lack a circadian rhythm of 11HSD1 gene expression in the hippocampus which may contribute to increased activity of the HPA axis and altered diurnal variation of circulating corticosterone levels.