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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
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Abstract |
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-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.
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Introduction |
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-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.
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Materials and Methods |
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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 Na2HPO4, 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.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). 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.
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-reductase type 1 activity was increased
(20.6 ± 2.7% in obese vs. 14.1 ± 1.5% in lean;
P < 0.04). Hepatic 11ßHSD1 activity (Fig. 1) and mRNA levels
(11ßHSD1/glyceraldehyde-3-phosphate dehydrogenase ratio, 0.56 ±
0.08 in obese vs. 1.03 ± 0.15 in lean;
P = 0.02) were also markedly lower in obese rats, but
there was no difference in Km for corticosterone
(Fig. 1). However, 11ßHSD1 activity was not different between groups
in skeletal muscle or sc fat and was higher in omental fat from obese
rats (Fig. 1). In the kidney, both NADP-dependent (11ßHSD1)
and NAD-dependent (11ßHSD2) 11ßHSD activities were greater in obese
rats (Fig. 1).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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.
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Acknowledgments |
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Footnotes |
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Received July 12, 1999.
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References |
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USA 90:9359–9363-reductase:
two genes/two enzymes. Annu Rev Biochem 63:25–61[Medline]
and interleukin 1ß enhance the
cortisone/cortisol shuttle. J Exp Med 186:189–198This article has been cited by other articles:
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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]
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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]
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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]
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 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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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 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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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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]
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 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]
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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]
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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]
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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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