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Understanding the Role of Glucocorticoids in Obesity: Tissue-Specific Alterations of Corticosterone Metabolism in Obese Zucker Rats¹

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

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

	Abstract

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The role of glucocorticoids in obesity is poorly understood. Observations in obese men suggest enhanced inactivation of cortisol by 5-reductase and altered reactivation of cortisone to cortisol by 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1). These changes in glucocorticoid metabolism may influence corticosteroid receptor activation and feedback regulation of the hypothalamic-pituitary-adrenal axis (HPA). We have compared corticosterone metabolism in vivo and in vitro in male obese and lean Zucker rats, aged 9 weeks (n = 8/group). Steroids were measured in 72-h urine and 0900 h trunk blood samples. 5-Reductase type 1 and 11ßHSD activities were assessed in dissected tissues. Obese animals were hypercorticosteronemic and excreted more total corticosterone metabolites (2264 ± 623 vs. 388 ± 144 ng/72 h; P = 0.003), with a greater proportion being 5-reduced or 11-oxidized. 11-Dehydrocorticosterone was also elevated in plasma (73 ± 9 vs. 18 ± 2 nM; P = 0.001) and urine (408 ± 111 vs. <28 ng/72 h; P = 0.01). In liver of obese rats, 5-reductase type 1 activity was greater (20.6 ± 2.7% vs. 14.1 ± 1.5%; P < 0.04), but 11ßHSD1 activity (maximum velocity, 3.43 ± 0.56 vs. 6.57 ± 1.13 nmol/min/mg protein; P = 0.01) and messenger RNA levels (0.56 ± 0.08 vs. 1.03 ± 0.15; P = 0.02) were lower. In contrast, in obese rats, 11ßHSD1 activity was not different in skeletal muscle and sc fat and was higher in omental fat (36.4 ± 6.2 vs. 19.2 ± 6.6; P = 0.01), whereas 11ßHSD2 activity was higher in kidney (16.7 ± 0.6% vs. 11.3 ± 1.5%; P = 0.01).

We conclude that greater inactivation of glucocorticoids by 5-reductase in liver and 11ßHSD2 in kidney combined with impaired reactivation of glucocorticoids by 11ßHSD1 in liver may increase the MCR of glucocorticoids and decrease local glucocorticoid concentrations at these sites. By contrast, enhanced 11ßHSD1 in omental adipose tissue may increase local glucocorticoid receptor activation and promote obesity.

	Introduction

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INCREASED SECRETION of glucocorticoids (e.g. in Cushing’s syndrome) is associated with obesity, and cortisol secretion is increased in subjects with idiopathic obesity, especially of central distribution (1). However, peak plasma cortisol levels are not elevated in idiopathic obesity (2), suggesting that peripheral metabolism of cortisol may be enhanced. We recently reported that inactivation of cortisol to 5-tetrahydrocortisol is enhanced in obese humans (3). Alternatively, increased activation of glucocorticoid receptors in obesity could result from raised local, rather than systemic, glucocorticoid concentrations. We and others have suggested that obesity is exaggerated because of increased reactivation of inactive cortisone into cortisol in adipose tissue by 11ß-hydroxy-steroid dehydrogenase type 1 (11ßHSD1) (3, 4).

Obese Zucker rats are leptin resistant due to a homozygous point mutation in the leptin receptor gene (5). Glucocorticoids seem to be important in the development of their obesity, as adrenalectomy or glucocorticoid receptor antagonists attenuate weight gain and associated metabolic abnormalities (6, 7). Because of their relevance to local glucocorticoid levels and MCR, we have now examined glucocorticoid-metabolizing enzymes in Zucker rats. Specifically, we have measured inactivation of corticosterone by the enzymes 5-reductase type 1 in liver and 11ßHSD type 2 in kidney. We have also assessed reactivation of corticosterone by 11ßHSD1.

	Materials and Methods

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Animals
Groups of eight 5-week-old male obese and lean Zucker rats (Harlan Orlac, Bicester, UK) were characterized by phenotype, maintained under controlled conditions of light (lights on, 0800–2000 h) and temperature (21 C) and allowed free access to standard rat chow (Special Diet Services, Witham, UK) and drinking water. At 8 weeks of age, animals were acclimatized in metabolic cages for 4 days before 72-h urine collection. At 9 weeks of age, they were decapitated between 0900–1100 h, and trunk blood was collected. Tissues were dissected, and whole adrenals were blotted dry and weighed. Portions of other tissues were snap-frozen on dry ice or mechanically homogenized in Krebs-Ringer buffer (118 mM NaCl, 3.8 mM KCl, 1.19 mM KH₂PO₄, 2.54 mMCaCl₂, 1.19 mM MgSO₄, and 25 mM NaHCO₃, pH 7.4).

Measurement of endogenous steroids
Plasma corticosterone and 11-dehydrocorticosterone were measured in trunk blood by RIAs. Urinary steroids were extracted and derivatised from a 10-ml aliquot for each animal using methods previously described for human urine (8), except that epicorticosterone and epitetrahydrocorticosterone (Steraloids, Newport, RI) were used as internal standards and 2-g/12-cc Sep-Pak cartridges (Waters Corp., Herts, UK) were used. Steroids were quantified using a Voyager gas chromatograph-mass spectrometer (Finnigan, Manchester, UK) in electron impact mode fitted with a EC-5 capillary column (30 m; id, 0.25 mm; film thickness, 0.25 µm; Alltech, Carnforth, UK).

Measurement of enzyme activities
In vivo 11ßHSD1 is a reductase, converting inactive 11-dehydrocorticosterone to corticosterone. However, in vitro dehydrogenase activity predominates, so we quantified 11ßHSD1 activity by conversion of corticosterone to 11-dehydrocorticosterone. Hepatic 11ßHSD1 kinetics were determined by preparing microsomes from tissue homogenate (by centrifugation; 14,000 x g for 20 min, supernatant was removed and centrifuged at 100,000 x g for 60 min, pellet was resuspended in Krebs-Ringer buffer). The protein concentration was determined colorimetrically. Microsomal preparations (15 µg/ml protein) were incubated in duplicate at 37 C in Krebs-Ringer buffer containing 0.2% glucose, NADP (2 mM), [³H]corticosterone (50 nM), and unlabeled corticosterone (0.3–10 µM). After 10 min, steroids were extracted with ethyl acetate, the organic phase was evaporated under nitrogen, and extracts were resuspended in mobile phase (20% methanol, 30% acetonitrile, and 50% water). Steroids were separated by HPLC using a reverse phase µ-Bondapak C₁₈ column (Phenomenex, Cheshire, UK) and were quantified by on-line liquid scintillation counting.

11ßHSD1 activity was also measured in homogenates of liver (10 µg/ml protein), quadriceps skeletal muscle (1.5 mg/ml), sc lumbar fat (0.5 mg/ml), and omental fat (1 mg/ml) by the same method, except that incubations were performed for 60 min in the presence of 100 nM [³H]corticosterone. Conditions were optimized for each tissue to ensure first order kinetics. 11ßHSD activity was measured in kidney homogenates by the same method (50 µg/ml protein). In addition, to detect 11ßHSD type 2 rather than type 1 activity, incubations were performed with NAD (2 mM) rather than NADP as cofactor and 10 nM [³H]corticosterone.

5-Reductase type 1 activity was assessed in liver, as previously described in prostate (9), by measuring the metabolism of testosterone to 5-dihydrotestosterone. Liver homogenate (0.5 mg/ml protein) was incubated in duplicate at 37 C in orthophosphate buffer (40 mM Na₂HPO_4, pH 7.5) with NADPH (1 mM) and [³H]testosterone (50 nM) as a substrate. After 10 min, steroids were extracted with ethyl acetate, the organic phase was evaporated under nitrogen, and extracts were resuspended in ethanol with unlabeled testosterone and 5-dihydrotestosterone and separated by TLC. Fractions containing testosterone and 5-dihydrotestosterone were identified with phosphomolybdic acid, scraped from plates, and counted in Cocktail T liquid scintillant (BDH, Dorset, UK).

Radiolabeled steroids were obtained from Amersham Pharmacia Biotech (Aylesbury, UK). Solvents were HPLC glass-distilled grade from Rathburn Chemicals (Walkerburn, UK). Other chemicals were purchased from Sigma (Poole, UK).

Quantification of messenger RNA (mRNA) by Northern blot
Total mRNA was extracted from snap-frozen liver samples, and 20 µg were separated by electrophoresis. The RNA was blotted onto a Bio-Rad Laboratories, Inc. Zeta-Probe nylon membrane (Richmond, CA), and 11ßHSD1 mRNA was identified as previously described (10). Hybridized probe was quantified using a Fuji Photo Film Co., Ltd. FLA2000 fluorescent image analyzer (Tokyo, Japan). Membranes were rehybridized with a glyceraldehyde-3-phosphate dehydrogenase probe using the same method, to control for differences in mRNA loading and transfer.

	Results

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In obese rats, plasma corticosterone concentrations and total urinary corticosterone metabolites were elevated compared with those in lean Zucker rats (Table 1). Obese rats exhibited a larger difference in excretion of metabolites of 11-dehydrocorticosterone (>10-fold higher) than of corticosterone (3- to 5-fold higher), and a more substantial difference in 5-reduced rather than 5ß-reduced metabolites of corticosterone compared with lean rats. Adrenal glands were heavier in obese animals, but this was not statistically significant after correction for body weight.

View larger version (22K): [in this window] [in a new window]   Figure 1. Data are the mean ± SEM for eight lean (open symbols) and eight obese (closed symbols) Zucker rats. P values are for Mann-Whitney U tests. A shows 11ßHSD activity in homogenates of each tissue incubated with NADP, except where indicated. B shows Line-weaver-Burke plots for summarized data from lean and obese liver microsomes. Km values (2.15 ± 0.55 µM in lean vs. 1.80 ± 0.53 µM in obese; P = 0.31) and maximum velocity (Vmax) values (6.57 ± 1.13 nmol/min·mg protein in lean vs. 3.43 ± 0.56 nmol/min·mg protein in obese; P = 0.01) were calculated for each individual animal.

	Discussion

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There are two isozymes of 5-reductase, but only the type 1 isozyme is expressed in rat liver (13). This isozyme reduces most ^4,5 unsaturated steroids with similar efficiency, in contrast to the type 2 isozyme, which modulates androgen receptor activation by converting testosterone to active 5-dihydrotestosterone (14). In obese Zucker rats we found an increase in urinary excretion of 5-reduced corticosterone metabolites and increased activity of 5-reductase in liver.

Interconversion of active corticosterone with inactive 11-dehydrocorticosterone (or cortisol and cortisone, respectively, in man) is catalyzed by the isozymes of 11ßHSD. 11ßHSD type 2 is NAD dependent, catalyzes the dehydrogenase (inactivating) reaction, and is expressed in tissues such as distal nephron, where it protects mineralocorticoid receptors from inappropriate activation by glucocorticoids (15). In obese Zucker rats, we found higher renal NAD-dependent 11ßHSD activity in vitro, predicting enhanced inactivation of corticosterone. 11ßHSD type 1 is NADP(H) dependent and is expressed in a wider range of tissues, including liver, adipose tissue, and skeletal muscle, where it is usually a reductase, reactivating glucocorticoids and maintaining local activation of glucocorticoid receptors (16). 11ßHSD1 activity and mRNA levels were decreased in liver of obese animals, whereas affinity for corticosterone was not different. By contrast with liver, 11ßHSD1 activity was higher in omental adipose tissue from obese rats, but was not different in skeletal muscle and sc adipose tissue. The overall balance between 11ßHSD activities in different tissues was assessed by excretion of corticosterone metabolites in urine. In obese Zucker rats we found differences in urinary metabolites consistent with an alteration in overall balance of whole body 11ßHSDs toward inactive 11-dehydrocorticosterone, suggesting that decreased hepatic 11ßHSD1 and increased renal 11ßHSD2 predominate over changes in other tissues.

The combination of increased 5-reductase, increased renal 11ßHSD2, and decreased hepatic 11ßHSD1 activities predict an increased glucocorticoid MCR. In normal circumstances this would result in a compensatory increase in corticosterone production (17). This mechanism could contribute to activation of the hypothalamic-pituitary-adrenal axis (HPA) and adrenocortical hypertrophy in obesity. However, it does not explain why trough plasma corticosterone levels are elevated in obese rats. Abnormalities of central control of the HPA have been sought previously in these animals, but responses to glucocorticoid feedback and stressful stimuli have been variably reported as normal, increased, or decreased (18, 19, 20). Moreover, it remains unclear whether leptin resistance alone could explain activation of the HPA, as there may be opposing effects of increased neuropeptide Y and decreased POMC expression (21, 22, 23). If obese rats have similarly reduced 11ßHSD1 expression in brain and pituitary, this may explain central HPA activation. Mice with transgenic disruption of the 11ßHSD1 gene (16) have increased plasma corticosterone levels, which have been attributed to decreased 11ßHSD1 (and hence local corticosterone levels) in sites responsible for negative feedback (hippocampus, hypothalamus, and anterior pituitary).

The observed changes in glucocorticoid metabolism also predict changes in peripheral corticosteroid receptor activation. Enhanced inactivation (5-reductase) and impaired reactivation (11ßHSD1) of glucocorticoids in the liver predict lower intracellular corticosterone concentrations. Decreased glucocorticoid exposure would normally be associated with enhanced insulin sensitivity and decreased gluconeogenesis, as in 11ßHSD1 knockout mice (16), so it may be that reduced hepatic glucocorticoid exposure in the obese Zucker rat represents a compensatory mechanism that limits the metabolic complications of obesity. By contrast, 11ßHSD1 activity was normal in other glucocorticoid targets (skeletal muscle and sc adipose tissue) in obese rats, so the proposed compensatory mechanism may not operate in all tissues. Moreover, 11ßHSD1 activity was elevated in omental fat in obese rats, and this predicts higher local glucocorticoid receptor activation and may promote obesity.

The current study does not address the mechanism of dysregulation of 5-reductase and 11ßHSD activities in obesity. With respect to 11ßHSD1 we have shown that there is no difference in affinity for corticosterone in obese Zucker rats, and that hepatic mRNA levels are reduced, suggesting that gene transcription is altered in obese animals. It is unlikely that the altered 11ßHSD activities are secondary to activation of the HPA, as chronic glucocorticoid excess is associated with up-regulation (not down-regulation) of hepatic 11ßHSD1 activity and expression (24). 11ßHSD1 is regulated by many other factors, including some that are altered in obesity, such as GH, insulin, tumor necrosis factor-, and gonadal steroids (25, 26, 27). By contrast, 5-reductase type 1 and 11ßHSD type 2 do not appear to be highly regulated enzymes. Further studies will be required to elucidate these mechanisms.

Finally, the differences in metabolism of glucocorticoids in obese Zucker rats mirror observations in obese humans. We and others have reported that obese men and women excrete more cortisol as 5-reduced metabolites (3, 28). Detailed dynamic tests and arteriovenous sampling have shown that hepatic 11ßHSD1 activity is impaired in obese men (29), but adipose 11ßHSD1 is either maintained or marginally increased in obesity (30). The present studies demonstrate that the obese Zucker rat will be a useful model in which to explore the mechanisms of disrupted glucocorticoid metabolism, its impact on body weight regulation, and its potential for therapeutic manipulation.

	Acknowledgments

 
We are grateful to Dr. F. Habib for advice.

	Footnotes

 
¹ This work was supported by fellowships from the University of Edinburgh Faculty of Medicine (to D.E.W.L.), the Wellcome Trust (to G.C.J), and the British Heart Foundation (to B.R.W.) and by grants from the Scottish Hospitals Endowment Research Trust to (to K.S.) and the Medical Research Council (to C.J.K.).

Received July 12, 1999.

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				K. L. McCormick, X. Wang, and G. J. Mick Evidence That the 11 {beta}-Hydroxysteroid Dehydrogenase (11 {beta}-HSD1) Is Regulated by Pentose Pathway Flux: STUDIES IN RAT ADIPOCYTES AND MICROSOMES J. Biol. Chem., January 6, 2006; 281(1): 341 - 347. [Abstract] [Full Text] [PDF]

				J. M. Paterson, J. R. Seckl, and J. J. Mullins Genetic manipulation of 11{beta}-hydroxysteroid dehydrogenases in mice Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R642 - R652. [Abstract] [Full Text] [PDF]

				L. M. Watts, V. P. Manchem, T. A. Leedom, A. L. Rivard, R. A. McKay, D. Bao, T. Neroladakis, B. P. Monia, D. M. Bodenmiller, J. X.-C. Cao, et al. Reduction of Hepatic and Adipose Tissue Glucocorticoid Receptor Expression With Antisense Oligonucleotides Improves Hyperglycemia and Hyperlipidemia in Diabetic Rodents Without Causing Systemic Glucocorticoid Antagonism Diabetes, June 1, 2005; 54(6): 1846 - 1853. [Abstract] [Full Text] [PDF]

				E. Velkoska, T. J. Cole, and M. J. Morris Early dietary intervention: long-term effects on blood pressure, brain neuropeptide Y, and adiposity markers Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1236 - E1243. [Abstract] [Full Text] [PDF]

				R. Andrew, J. Westerbacka, J. Wahren, H. Yki-Jarvinen, and B. R. Walker The Contribution of Visceral Adipose Tissue to Splanchnic Cortisol Production in Healthy Humans Diabetes, May 1, 2005; 54(5): 1364 - 1370. [Abstract] [Full Text] [PDF]

				E. E. Kershaw, N. M. Morton, H. Dhillon, L. Ramage, J. R. Seckl, and J. S. Flier Adipocyte-Specific Glucocorticoid Inactivation Protects Against Diet-Induced Obesity Diabetes, April 1, 2005; 54(4): 1023 - 1031. [Abstract] [Full Text] [PDF]

				T. C. Sandeep, R. Andrew, N. Z.M. Homer, R. C. Andrews, K. Smith, and B. R. Walker Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone Diabetes, March 1, 2005; 54(3): 872 - 879. [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]

				K. Kannisto, K. H. Pietilainen, E. Ehrenborg, A. Rissanen, J. Kaprio, A. Hamsten, and H. Yki-Jarvinen Overexpression of 11{beta}-Hydroxysteroid Dehydrogenase-1 in Adipose Tissue Is Associated with Acquired Obesity and Features of Insulin Resistance: Studies in Young Adult Monozygotic Twins J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4414 - 4421. [Abstract] [Full Text] [PDF]

				R. Basu, R. J. Singh, A. Basu, E. G. Chittilapilly, C. M. Johnson, G. Toffolo, C. Cobelli, and R. A. Rizza Splanchnic Cortisol Production Occurs in Humans: Evidence for Conversion of Cortisone to Cortisol Via the 11-{beta} Hydroxysteroid Dehydrogenase (11{beta}-HSD) Type 1 Pathway Diabetes, August 1, 2004; 53(8): 2051 - 2059. [Abstract] [Full Text] [PDF]

				N. M. Morton, L. Ramage, and J. R. Seckl Down-Regulation of Adipose 11{beta}-Hydroxysteroid Dehydrogenase Type 1 by High-Fat Feeding in Mice: A Potential Adaptive Mechanism Counteracting Metabolic Disease Endocrinology, June 1, 2004; 145(6): 2707 - 2712. [Abstract] [Full Text] [PDF]

				K. J. McInnes, C. J. Kenyon, K. E. Chapman, D. E. W. Livingstone, L. J. Macdonald, B. R. Walker, and R. Andrew 5{alpha}-Reduced Glucocorticoids, Novel Endogenous Activators of the Glucocorticoid Receptor J. Biol. Chem., May 28, 2004; 279(22): 22908 - 22912. [Abstract] [Full Text] [PDF]

				S. E. la Fleur, S. F. Akana, S. L. Manalo, and M. F. Dallman Interaction between Corticosterone and Insulin in Obesity: Regulation of Lard Intake and Fat Stores Endocrinology, May 1, 2004; 145(5): 2174 - 2185. [Abstract] [Full Text] [PDF]

				N. M. Morton, J. M. Paterson, H. Masuzaki, M. C. Holmes, B. Staels, C. Fievet, B. R. Walker, J. S. Flier, J. J. Mullins, and J. R. Seckl Novel Adipose Tissue-Mediated Resistance to Diet-Induced Visceral Obesity in 11{beta}-Hydroxysteroid Dehydrogenase Type 1-Deficient Mice Diabetes, April 1, 2004; 53(4): 931 - 938. [Abstract] [Full Text] [PDF]

				K. R. Steffensen and J.-A. Gustafsson Putative Metabolic Effects of the Liver X Receptor (LXR) Diabetes, February 1, 2004; 53(90001): S36 - 42. [Abstract] [Full Text]

				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]

				P. Alberts, C. Nilsson, G. Selen, L. O. M. Engblom, N. H. M. Edling, S. Norling, G. Klingstrom, C. Larsson, M. Forsgren, M. Ashkzari, et al. Selective Inhibition of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Improves Hepatic Insulin Sensitivity in Hyperglycemic Mice Strains Endocrinology, November 1, 2003; 144(11): 4755 - 4762. [Abstract] [Full Text] [PDF]

				J. Westerbacka, H. Yki-Jarvinen, S. Vehkavaara, A.-M. Hakkinen, R. Andrew, D. J. Wake, J. R. Seckl, and B. R. Walker Body Fat Distribution and Cortisol Metabolism in Healthy Men: Enhanced 5{beta}-Reductase and Lower Cortisol/Cortisone Metabolite Ratios in Men with Fatty Liver J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4924 - 4931. [Abstract] [Full Text] [PDF]

				D. J. Wake, E. Rask, D. E. W. Livingstone, S. Soderberg, T. Olsson, and B. R. Walker Local and Systemic Impact of Transcriptional Up-Regulation of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue in Human Obesity J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3983 - 3988. [Abstract] [Full Text] [PDF]

				C. Mattsson, M. Lai, J. Noble, E. McKinney, J. L. Yau, J. R. Seckl, and B. R. Walker Obese Zucker Rats Have Reduced Mineralocorticoid Receptor and 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression in Hippocampus--Implications for Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in Obesity Endocrinology, July 1, 2003; 144(7): 2997 - 3003. [Abstract] [Full Text] [PDF]

				R. S. Lindsay, D. J. Wake, S. Nair, J. Bunt, D. E. W. Livingstone, P. A. Permana, P. A. Tataranni, and B. R. Walker Subcutaneous Adipose 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity and Messenger Ribonucleic Acid Levels Are Associated with Adiposity and Insulinemia in Pima Indians and Caucasians J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2738 - 2744. [Abstract] [Full Text] [PDF]

				B. R. Walker and R. Andrew Cortisol Metabolism in Type 2 Diabetes J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2951 - 2952. [Full Text] [PDF]

				Y. Liu, Y. Nakagawa, Y. Wang, R. Li, X. Li, T. Ohzeki, and T. C. Friedman Leptin Activation of Corticosterone Production in Hepatocytes May Contribute to the Reversal of Obesity and Hyperglycemia in Leptin-Deficient ob/ob Mice Diabetes, June 1, 2003; 52(6): 1409 - 1416. [Abstract] [Full Text] [PDF]

				D. E. W. Livingstone and B. R. Walker Is 11beta -Hydroxysteroid Dehydrogenase Type 1 a Therapeutic Target? Effects of Carbenoxolone in Lean and Obese Zucker Rats J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 167 - 172. [Abstract] [Full Text]

				R. C. Andrews, O. Rooyackers, and B. R. Walker Effects of the 11{beta}-Hydroxysteroid Dehydrogenase Inhibitor Carbenoxolone on Insulin Sensitivity in Men with Type 2 Diabetes J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 285 - 291. [Abstract] [Full Text] [PDF]

				C. Wotus and W. C. Engeland Differential regulation of adrenal corticosteroids after restriction-induced drinking in rats Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R183 - R191. [Abstract] [Full Text] [PDF]

				R. C. Andrews, O. Herlihy, D. E. W. Livingstone, R. Andrew, and B. R. Walker Abnormal Cortisol Metabolism and Tissue Sensitivity to Cortisol in Patients with Glucose Intolerance J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5587 - 5593. [Abstract] [Full Text] [PDF]

				J. W. Tomlinson, B. Sinha, I. Bujalska, M. Hewison, and P. M. Stewart Expression of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue Is Not Increased in Human Obesity J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5630 - 5635. [Abstract] [Full Text] [PDF]

				N. Draper, S. M. Echwald, G. G. Lavery, E. A. Walker, R. Fraser, E. Davies, T. I. A. Sorensen, A. Astrup, J. Adamski, M. Hewison, et al. Association Studies between Microsatellite Markers within the Gene Encoding Human 11{beta}-Hydroxysteroid Dehydrogenase Type 1 and Body Mass Index, Waist to Hip Ratio, and Glucocorticoid Metabolism J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4984 - 4990. [Abstract] [Full Text] [PDF]

				T. M. Stulnig, U. Oppermann, K. R. Steffensen, G. U. Schuster, and J.-A. Gustafsson Liver X Receptors Downregulate 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression and Activity Diabetes, August 1, 2002; 51(8): 2426 - 2433. [Abstract] [Full Text] [PDF]

				E. Rask, B. R. Walker, S. Soderberg, D. E. W. Livingstone, M. Eliasson, O. Johnson, R. Andrew, and T. Olsson Tissue-Specific Changes in Peripheral Cortisol Metabolism in Obese Women: Increased Adipose 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3330 - 3336. [Abstract] [Full Text] [PDF]

				K. E. Sheppard and D. J. Autelitano 11{beta}-Hydroxysteroid Dehydrogenase 1 Transforms 11-Dehydrocorticosterone into Transcriptionally Active Glucocorticoid in Neonatal Rat Heart Endocrinology, January 1, 2002; 143(1): 198 - 204. [Abstract] [Full Text] [PDF]

				H. Masuzaki, J. Paterson, H. Shinyama, N. M. Morton, J. J. Mullins, J. R. Seckl, and J. S. Flier A Transgenic Model of Visceral Obesity and the Metabolic Syndrome Science, December 7, 2001; 294(5549): 2166 - 2170. [Abstract] [Full Text] [PDF]

				J. W. Tomlinson, J. Moore, M. S. Cooper, I. Bujalska, M. Shahmanesh, C. Burt, A. Strain, M. Hewison, and P. M. Stewart Regulation of Expression of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue: Tissue-Specific Induction by Cytokines Endocrinology, May 1, 2001; 142(5): 1982 - 1989. [Abstract] [Full Text]

				J. R. Seckl and B. R. Walker Minireview: 11{beta}-Hydroxysteroid Dehydrogenase Type 1-- A Tissue-Specific Amplifier of Glucocorticoid Action Endocrinology, April 1, 2001; 142(4): 1371 - 1376. [Abstract] [Full Text]

				N. M. Morton, M. C. Holmes, C. Fievet, B. Staels, A. Tailleux, J. J. Mullins, and J. R. Seckl Improved Lipid and Lipoprotein Profile, Hepatic Insulin Sensitivity, and Glucose Tolerance in 11beta -Hydroxysteroid Dehydrogenase Type 1 Null Mice J. Biol. Chem., October 26, 2001; 276(44): 41293 - 41300. [Abstract] [Full Text] [PDF]

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