This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mattsson, C. Articles by Walker, B. R. Search for Related Content PubMed PubMed Citation Articles by Mattsson, C. Articles by Walker, B. R.

Obese Zucker Rats Have Reduced Mineralocorticoid Receptor and 11ß-Hydroxysteroid Dehydrogenase Type 1 Expression in Hippocampus—Implications for Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in Obesity

Endocrinology Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Prof. Brian R. Walker, Endocrinology Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland, United Kingdom. E-mail: b.walker{at}ed.ac.uk.

Obese Zucker rats have elevated basal corticosterone levels and an increased stress response suggestive of an increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. We hypothesized that altered central expression of glucocorticoid receptors (GR), mineralocorticoid receptors (MR), and/or 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) contribute to these changes.

In brains from young adult male rats, in situ hybridization and Western blotting showed that obese rats had normal hippocampal GR mRNA and protein levels. In contrast, in obese rats, 11ßHSD1 mRNA levels were reduced in a subpopulation of hippocampal cells in the main neuronal layers (by 37–47%, P < 0.05), whereas 11ßHSD1 levels in sparse high-expressing cells did not differ. MR mRNA was decreased in all regions of the hippocampus (by 37–49%, P < 0.05 for CA1–2 and P < 0.01 for dentate gyrus) and in frontal cortex (by 16%, P < 0.05) in obese rats. In whole hippocampal homogenates, however, neither the protein concentration of MR by Western blot nor activity of 11ßHSD1 was measurably different between the phenotypes. To test the functional importance of lower central MR expression, groups of lean and obese rats were given spironolactone before restraint stress. In vehicle-treated animals, obese rats had higher plasma corticosterone levels than lean rats after stress (by ANOVA, P < 0.05). Spironolactone markedly increased the corticosterone response in both groups, but the incremental rise was smaller in the obese rats, so that spironolactone abolished the differences between groups.

We conclude that lower levels of MR, but not GR, contribute to the increased HPA activity in the obese Zucker rats and that this seems more influential during stress than in the basal state. This may be exacerbated by impaired local regeneration of corticosterone by 11ßHSD1. These abnormalities could contribute to the subtle changes in the HPA axis in rodent and human obesity.

This article has been cited by other articles:

				H. E. Bates, A. S. Sirek, M. A. Kiraly, J. T. Y. Yue, D. Goche Montes, S. G. Matthews, and M. Vranic Adaptation to Mild, Intermittent Stress Delays Development of Hyperglycemia in the Zucker Diabetic Fatty Rat Independent of Food Intake: Role of Habituation of the Hypothalamic-Pituitary-Adrenal Axis Endocrinology, June 1, 2008; 149(6): 2990 - 3001. [Abstract] [Full Text] [PDF]

				B. Garcia-Bueno, J. L. M. Madrigal, B. G. Perez-Nievas, and J. C. Leza Stress Mediators Regulate Brain Prostaglandin Synthesis and Peroxisome Proliferator-Activated Receptor-{gamma} Activation after Stress in Rats Endocrinology, April 1, 2008; 149(4): 1969 - 1978. [Abstract] [Full Text] [PDF]

				J. Buren, S.-A. Bergstrom, E. Loh, I. Soderstrom, T. Olsson, and C. Mattsson Hippocampal 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression Has a Diurnal Variability that Is Lost in the Obese Zucker Rat Endocrinology, June 1, 2007; 148(6): 2716 - 2722. [Abstract] [Full Text] [PDF]

				T. W. W. Pace and R. L. Spencer Disruption of mineralocorticoid receptor function increases corticosterone responding to a mild, but not moderate, psychological stressor Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1082 - E1088. [Abstract] [Full Text] [PDF]

				A. J. Drake, D. E. W. Livingstone, R. Andrew, J. R. Seckl, N. M. Morton, and B. R. Walker Reduced Adipose Glucocorticoid Reactivation and Increased Hepatic Glucocorticoid Clearance as an Early Adaptation to High-Fat Feeding in Wistar Rats Endocrinology, February 1, 2005; 146(2): 913 - 919. [Abstract] [Full Text] [PDF]

				J. W. Tomlinson, E. A. Walker, I. J. Bujalska, N. Draper, G. G. Lavery, M. S. Cooper, M. Hewison, and P. M. Stewart 11{beta}-Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response Endocr. Rev., October 1, 2004; 25(5): 831 - 866. [Abstract] [Full Text] [PDF]

				J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393. [Abstract] [Full Text]