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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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 11beta-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 11beta-HSD1 mRNA expression. There was no circadian variation in 11beta-HSD enzyme activity in peripheral tissues, although obese Zucker rats had a decreased enzyme activity in liver and epididymal fat (by approximately 40%, P < 0.05) compared with lean rats. In Sprague Dawley rats, 11beta-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 11beta-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.

Original publication

DOI

10.1210/en.2006-0897

Type

Journal article

Journal

Endocrinology

Publication Date

06/2007

Volume

148

Pages

2716 - 2722

Keywords

11-beta-Hydroxysteroid Dehydrogenase Type 1, Animals, Cerebral Cortex, Circadian Rhythm, Corticosterone, Gene Expression Regulation, Enzymologic, Hippocampus, Male, Obesity, RNA, Messenger, Rats, Rats, Sprague-Dawley, Rats, Zucker