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Hippocampal 11ß-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression Has a Diurnal Variability that Is Lost in the Obese Zucker Rat

Department of Public Health and Clinical Medicine, Umeå University Hospital, SE-901 85 Umeå, Sweden

Address all correspondence and requests for reprints to: Jonas Burén, Ph.D., Department of Public Health and Clinical Medicine, Building 6M, 4th floor, Umeå University Hospital, SE-901 85 Umeå, Sweden. E-mail: jonas.buren{at}medicin.umu.se.

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, although they are normal or low in the morning. Studies in humans and in leptin-resistant Zucker rats suggest 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 axis. We hypothesized that there is a circadian rhythm in prereceptor metabolism of glucocorticoids exerted by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) in brain and/or peripheral tissues (liver, fat, and muscle) that might be abrogated in obesity. The present study demonstrates a circadian rhythm in 11ß-HSD1 mRNA expression (35–45% increase at morning vs. evening, 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 11ß-HSD1 mRNA expression. There was no circadian variation in 11ß-HSD 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 with lean rats. In Sprague Dawley rats, 11ß-HSD activity in adipose tissue was higher in retroperitoneal and epididymal vs. sc fat (P < 0.001). In summary, obese Zucker rats lack a circadian rhythm of 11ß-HSD1 gene expression in the hippocampus, which may contribute to increased activity of the hypothalamic-pituitary-adrenal axis and altered diurnal variation of circulating corticosterone levels.