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Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom
Address all correspondence and requests for reprints to: Paul M Stewart, M.D., F.R.C.P., F.Med.Sci., Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom. E-mail: . p.m.stewart{at}bham.ac.uk
Abstract
As exemplified in patients with Cushing’s syndrome, glucocorticoids play an important role in regulating adipose tissue distribution and function, but circulating cortisol concentrations are normal in most patients with obesity. However, human omental adipose stromal cells (ASCs) can generate glucocorticoid locally through the expression of the enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD) type 1 (11ß-HSD1), which, in intact cells, has been considered to be an oxoreductase, converting inactive cortisone (E) to cortisol (F). Locally produced F can induce ASC differentiation, but the relationship between 11ß-HSD1 expression and adipocyte differentiation is unknown. Primary cultures of paired omental (om) and sc ASC and adipocytes were prepared from 17 patients undergoing elective abdominal surgery and cultured for up to 14 d. Expression and activity of 11ß-HSD isozymes were analyzed together with early (lipoprotein lipase) and terminal (glycerol 3 phosphate dehydrogenase) markers of adipocyte differentiation. On d 1 of culture, 11ß-HSD1 activity in intact om ASCs exceeded oxoreductase activity in every patient (78.9 ± 24.9 vs. 15.8 ± 3.7 [mean ± SE] pmol/mg per hour, P < 0.001), and in sc ASCs, relative activities were similar (40.6 ± 12.2 vs. 36.9 ± 8.8). Conversely, in freshly isolated om adipocytes, reductase activity exceeded dehydrogenase activity (23.6 ± 1.5 vs. 6.2 ± 0.8 pmol/mg per hour, P < 0.01). Following 14 d of culture in serum-free conditions with addition of 10 nM insulin (Ctr) or insulin with 100 nM F (+F), lipoprotein lipase/18S RNA levels increased in both the Ctr- and +F-treated ASCs, but glycerol 3 phosphate dehydrogenase increased only in the +F cultures. In both cases, however, 11ß-HSD1 oxoreductase activity exceeded dehydrogenase activity (Ctr: 53.3 ± 9.0 vs. 32.4 ± 10.5, P < 0.05; +F: 65.6 ± 15.6 vs. 37.1 ± 11.5 pmol/mg per hour, P < 0.05), despite no significant changes in 11ß-HSD1 mRNA levels. In sc ASCs, dehydrogenase activity was similar to reductase activity in both Ctr- and +F-treated cells. Type 2 11ß-HSD expression was undetectable in each case. These data show that in intact, undifferentiated om ASCs, 11ß-HSD1 acts primarily as a dehydrogenase, but in mature adipocytes oxoreductase activity predominates. Because glucocorticoids inhibit cell proliferation, we postulate that 11ß-HSD1 activity in uncommitted ASCs may facilitate proliferation rather than differentiation. Once early differentiation is initiated, a "switch" to 11ß-HSD1 oxoreductase activity generates F, thus promoting adipogenesis. Site-specific regulation of the set-point of 11ß-HSD1 activity may be an important mechanism underpinning visceral obesity.
OBESITY IS A prevalent condition; when defined as a body mass index (BMI) greater than 30 kg/m2, 20% of the United Kingdom are obese (1), and the figure is higher for North America (2). The detrimental health effects of obesity are well established, but for any given BMI, it is visceral obesity that confers the greatest risk of diabetes, cardiovascular disease, and premature mortality (3, 4, 5). This has highlighted the need to identify factors that control fat distribution in addition to absolute fat mass. Patients with Cushing’s syndrome emphasize the important and reversible role that glucocorticoids play in regulating the accumulation of visceral adipose tissue (6, 7). Adipogenesis involves the differentiation of fibroblast-like adipose stromal cells (ASCs) or preadipocytes into adipocytes (8); glucocorticoids are known to inhibit ASC proliferation, thereby triggering a cascade of differentiation-dependent genes to facilitate adipogenesis (9, 10). Recently we have proposed a possible mechanism to explain the predilection of glucocorticoids for visceral obesity, which is based on prereceptor regulation of glucocorticoids within adipose tissue itself (11, 12).
Two isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) interconvert hormonally active cortisol (F) and inactive cortisone (E) and have been shown to modulate corticosteroid hormone action at an autocrine level in several peripheral tissues. 11ß-HSD2, acting as a dehydrogenase-inactivating cortisol to cortisone, is mainly expressed in mineralocorticoid target tissues, the kidney, and the colon (13, 14) in which it protects the mineralocorticoid receptor from glucocorticoid excess. By contrast, 11ß-HSD1 is a NADP(H)-dependent enzyme (15), demonstrating predominantly 11 oxoreductase activity (E to F conversion) in intact cells (16, 17). In recent studies we have characterized 11ß-HSD isozyme expression in human adipose tissue (11, 18). Only 11ß-HSD1 was expressed, and in paired primary cultures of ASCs, oxoreductase activity was higher at omental (om) compared with sc sites (11). Furthermore, within om ASCs, the differentiation of ASCs to adipocytes following incubation with cortisone could be inhibited using the licorice derivative, glycyrrhetinic acid, a known inhibitor of 11ß-HSD1 (12). Thus, although circulating cortisol concentrations are invariably normal in patients with obesity (19), we have postulated that the autocrine generation of cortisol within om adipose tissue through the expression of 11ß-HSD1 may represent an important therapeutic target in central obesity. In these earlier studies, we evaluated 11ß-HSD1 expression in ASCs cultured to confluence in the presence of serum or in confluent cells cultured in chemically defined medium, both of which would result in adipocyte differentiation. Studies in the mouse 3T3-F442A cell line showed induction of 11ß-HSD1 expression on adipocyte differentiation (20), but the relationship between 11ß-HSD1 expression and adipocyte differentiation in human adipose tissue is unknown. Furthermore, in some of our early experiments on ASC primary cultures, we had observed 11ß-dehydrogenase activity in the absence of 11ß-HSD2. The aim of this work, therefore, was to analyze the site-specific effect of adipocyte differentiation on 11ß-HSD1 expression and set-point of enzyme activity.
Materials and Methods
Isolation of adipose stromal cells and adipocytes
Paired om and sc adipose tissue samples were obtained from a total of 17 patients (mean age 57.4 yr, mean BMI 24.8 kg/m2, 9 females) undergoing elective abdominal surgery. Ethical approval was obtained from the local hospital Ethics Committee, and all patients gave informed consent. ASCs were isolated as previously reported using a modified method of Rodbell (21). Briefly, adipose tissue was cut into small (2 mm3 pieces) (3) and incubated in 2 mg/ml collagenase class 1 (Worthington Biochemical Corp., Freehold, NJ) in HBSS at 37 C in shaking water bath for 1 h. Stromal-vascular fractions were separated from adipocytes by centrifugation at room temperature at 100 g. Adipocytes forming a top layer were subsequently aspirated; ASCs were pelleted at the bottom of the tube. Erythrocytes were lysed as previously described (9), and the resultant ASC fraction was seeded overnight (16 h) in DMEM/F12 supplemented with 15% FCS in 6-well tissue culture dishes. Thereafter in each case, part of the cell culture was washed and cultured in chemically defined medium (9) for 14 d, with insulin at 10 nM (Ctr) or with insulin and F at 100 nM (+F). Medium with freshly added insulin and F was changed every 48 h.
RNA extraction and reverse transcription
Total RNA was isolated according to single-step method of Chomczynski and Sacchi (22) using RNAsol B [AMS Biotechnology (Europe) Ltd., Witney, UK]. Reverse transcription (RT) was performed using 1 µg total RNA and 0.5 µg random hexamers as primers. Reaction was performed in 20 µl total volume with 10 U avian myeloblastosis virus RT, 10 nM each dNTPs, 10 U RNAsin. All reagents were purchased from Promega Corp. (Southampton, UK).
Quantitative PCR
Real-time mRNA quantification of 11ß-HSD1 and 11ß-HSD2 mRNA was carried out using an ABI Prism 7700 sequence detection system (PE Applied Biosystems, Warrington, UK), which employs TaqMan chemistry for highly accurate quantitation of mRNA levels. Briefly, a fluorogenic TaqMan probe consists of an oligonucleotide with a 5' reporter dye with distinctive fluorescent spectra, e.g. FAM or VIC and a 3' quencher dye, TAMRA. Fluorescent quenching of the reporter depends on the spatial proximity of its quencher. PCR amplification releases the reporter into solution, away from its quencher, yielding a signal that can be read by a laser and charge-couple device camera. One such event occurs for each PCR product generated, enabling real-time detection of cDNA amplification. PCR reactions were carried out in 25-µl volumes on 96-well plates, in a reaction buffer containing 2xTaqMan Universal PCR master mix (consisting of 3 mM Mn[Oac]2, 200 µM dNTPs, 1.25 U AmpliTaq gold polymerase, 1.25 U AmpErase UNG), 180 nM TaqMan probe, and 900-nM primers. All reactions were multiplexed with the housekeeping gene 18S rRNA, provided as a preoptimized control probe (PE Applied Biosystems), enabling data to be expressed in relation to an internal reference, to allow for differences in RT efficiency. Measurements were carried at least three times for each sample. All target gene probes were labeled with FAM and the housekeeping gene with VIC. Reactions were as follows: 50 C for 2 min, 95 C for 10 min and then 44 cycles of 95 C for 15 sec and 60 C for 1 min.
Primer sequences for 11ß-HSD1 were: 5'-AGGAAAGCTCATGGGAGGACTAG-3' (antisense, 23 bp), 5'-ATGGTGAATATCATCATGAAAAAGATTC-3' (sense, 28 bp), and 11ß-HSD1 TaqMan probe 5'-CATGCTCATTCTCAACCACATCACCAACA-3' (29 bp). For 11ß-HSD2, primer sequences were: 5'-GGGCCTATGGAACCTCCAA-3' (antisense, 19 bp), 5'-GACCCACGTTTCTCACTGACTCT-3' (sense, 23 bp) and TaqMan Probe 5'-CCGTGGCGCTACTCATGGACACA-3' (23 bp).
According to the manufacturer’s guidelines, data were expressed as Ct values (the cycle number at which logarithmic PCR plots cross a calculated threshold line) and used to determine 
Ct values (Ct = Ct of the target gene minus Ct of the housekeeping gene). To exclude potential bias because of averaging data, which had been transformed through the equation 2-[/
Ct to give a fold-change in gene expression, all statistics were performed with Ct values. (The calculation of Ct involves subtraction from Ct value of the gene of interest average Ct value of the arbitrary constant, e.g. Ct of the control treatment or tissue type.)
Analysis of 11ß-HSD activity
After overnight attachment (d 1), ASCs were washed with HBSS, and 11ß-HSD dehydrogenase and reductase activities measured in serum-free DMEM/F12 using, respectively, F (dehydrogenase) or E (oxoreductase) as substrate at 100-nM concentration with appropriate tritium labeled tracer 3H-F (specific activity 1 mCi/ml, NEN Life Science Products, Hounslow, UK) or 3H-E (50,000 cpm/ml) for 4 h in air/5% CO2 at 37 C. The assays were performed as described previously (12, 14). Identical enzyme activity studies were repeated after 14 d in culture. 11ß-HSD reductase and dehydrogenase activities were also measured in 0.2 ml freshly isolated om adipocytes (100,000 adipocytes/reaction) by incubation in serum-free DMEM/F12 medium (0.8 ml) with 100 nM cortisol or cortisone with appropriate tritiated tracer specific activity) at 37 C for 4 h. After incubation, the medium was transferred to a glass tube, and steroids were extracted using dichloromethane and separated by thin-layer chromatography in chloroform:ethanol (92:8). ASC and adipocyte protein concentrations were quantified according to the Bradford method using reagent (Bio-Rad Laboratories, Inc. GmbH, München, Germany). Conversion of substrate to product was visualized using a 200 Image scanner (Bioscan, Inc., Lablogic, UK) and the fractional conversion of F to E (or E to F) calculated as picomoles of product per milligram of protein per hour. In every experiment, activities were measured in triplicate.
Adipocyte differentiation
This was determined by analyzing the expression of lipoprotein lipase (LPL) and glycerol-3-phosphate dehydrogenase (G3PDH), representing early and late markers of adipocyte differentiation, respectively (23, 24, 25).
Semiquantitative PCR of adipogenic markers
Quantification of mRNA levels for LPL and G3PDH was determined relative to endogenous RNA standard, define marker (18S rRNA). The commercially available primers for 18S rRNA QuantumRNA [quantitative RT-PCR module, Ambion (Europe) Ltd., Huntingdon, UK] were used together with gene of interest primers in a one-tube reaction. Difficulties arising from the much higher 18S rRNA expression and requirement for both 18S rRNA and 11ß-HSD1 genes to operate in a linear range of amplification were solved through the addition of 18S Competimers (18S primers specifically modified at 3' end, Ambion, Inc.) that inhibit 18S PCR reaction in a ratio-dependent manner. PCR conditions used primers at a concentration of 10 mM, 2 mM MgCl2, 10 mM dNTPs with 0.5 U of Taq DNA polymerase in reaction buffer (50 mM KCl, 10 mM Tris-HCl, pH 9, 1% Triton X-100) in a 20-µl reaction. Primer sequences for LPL were: 5'-AACATCCCATTCACTCTGCC-3' (20 bp) (antisense) and 5'-AATACGCCACATGAAGGAGC-3' (20 bp) (sense), amplifying a fragment of 637 bp. PCR conditions were 32 cycles for 1 min each at 94 C, 60 C (annealing), and 72 C (extension). G3PDH mRNA levels were similarly analyzed using published methodology (12, 26).
G3PDH enzyme assay was carried out according to modifications of published methods (27, 28). Briefly, ASCs were cultured in 6-well tissue culture plates, washed with PBS, and stored at -80 C. Before the G3PDH assay, proteins were extracted into 100 µl protein extraction solution and each well washed with a further 50 µl of the same buffer. G3PDH was assayed using 1–20 µg protein in triethanolamine/NaOH/1% BSA buffer (pH 7.4) with 0.8 mM dihydroxyacetone phosphate (substrate) and 0.2 mM NADH (cofactor). The oxidation of NADH as determined by a decrease in optical density at 340 nm was followed at 5-min intervals for 30 min spectrophotometrically (LKB Spectrophotometer, Pharmacia, Milton Keynes, UK) at 25 C. Unit (U) definition was defined as the amount of enzyme resulting in the conversion of 1 µmole of dihydroxyacetone phosphate to 
-glycerophosphate per minute at 25 C and pH 7.6.
Statistics
Experimental data were graphically presented and statistically analyzed using SigmaPlot and SigmaStat software, respectively (SPSS Science UK Ltd., Woking, UK). All data passed normality and equal variance; thus, the unpaired, parametric t test was used to calculate mean, SE, and P values. The P value cut-off point of 0.05 was accepted as statistically significant.
Results
Following overnight culture in DMEM/F12 with 15% FCS, 11ß-HSD activity studies conducted on intact cells indicated the presence of both dehydrogenase and reductase activities. In om ASCs, dehydrogenase activity exceeded reductase activity in all 11 patients studied (Fig. 1A
) despite the lack of 11ß-HSD2 expression as assessed by quantitative PCR (2.2 ± 0.3 vs. 337.0 ± 8.0 for 11ß-HSD1 mRNA; Fig. 1B). This could not be attributed to any serum effect because, in separate experiments, identical results were observed when cells were cultured for a further 24 h in serum-free medium (data not shown). Conversely, in intact adipocytes, analyzed immediately upon isolation, 11ß-HSD activity was predominantly reductase in nature (23.6 ± 1.5 vs. 6.2 ± 0.8 pmol/mg per hour, mean ± SE, n = 3, P < 0.05; Fig. 1C).
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). This was mediated by a significant reduction in dehydrogenase activity from d 1 to d 14 (P < 0.001) and a concomitant increase in oxoreductase activity (P < 0.05).
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ASC cultured in chemically defined medium supplemented with insulin (Ctr) underwent early, but not terminal, differentiation into adipocytes as assessed by the expression of LPL and G3PDH (Fig. 4, A and B, respectively). Thus, insulin alone significantly increased LPL mRNA/18S rRNA expression from 23.3 ± 0.7 to 55.5 ± 7.7 (n = 4, P < 0.05), and this induction was more pronounced in ASCs treated with insulin and 100 nM F (165.0 ± 15.1, P < 0.01, n = 4) (Fig. 4A). Induction of G3PDH expression was observed only following incubation with +F. G3PDH activity was 6.0 ± 2.1 U/mg on d 1, 16.6 ± 4.5 U/mg on d 14 in cells treated with insulin alone and 197.0 ± 58.6 U/mg on d 14 in cells treated with insulin and cortisol (Fig. 4B).
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In freshly isolated om ASCs, we have demonstrated predominant 11ß-HSD dehydrogenase activity (cortisol to cortisone conversion). Conversely, in freshly isolated adipocytes, activity was oxoreductase in nature (cortisone to cortisol conversion). At both sites, activity was associated with abundant expression of 11ß-HSD1 mRNA but not 11ß-HSD2 mRNA. Following 14 d of culture in carefully controlled conditions to monitor adipocyte differentiation, a switch in the set-point of 11ß-HSD1 activity occurred in om, but not sc, ASCs with a marked fall in dehydrogenase activity and concomitant increase in oxoreductase activity. This was not associated with any change in 11ß-HSD1 mRNA expression and was dependent on early but not terminal adipocyte differentiation in that it also occurred in the context of induction of LPL before any increase in G3PDH mRNA or activity. Glucocorticoids inhibit ASC proliferation (10); 11ß-HSD1 dehydrogenase activity, by inactivating F to E, may represent an autocrine protective mechanism that facilitates proliferation rather than differentiation. However, once the differentiation process is initiated, the set-point of the enzyme changes, with oxoreductase activity generating active cortisol, thereby promoting adipocyte differentiation (12, 29, 30). Thus, a relatively high concentration of glucocorticoid is maintained in maturing adipocytes through 11ß-HSD1 oxoreductase activity, but ASCs may protect themselves against cortisol excess by converting active cortisol to inactive cortisone. This process appears to be depot specific because, in contrast to om ASCs, sc ASCs had similar 11ß-HSD activities in both directions on both d 1 and d 14 of culture.
A switch in 11ß-HSD1 activity has been reported in rat Leydig cells but in this case from reductase to dehydrogenase (31). During pubertal development, oxoreductase activity of 11ß-HSD1 ensures an adequate exposure of Leydig cells to glucocorticoids. On maturation, the set-point of 11ß-HSD1 activity switches to dehydrogenase, thereby protecting Leydig cells from the inhibitory effect of glucocorticoids on T production (32). The basis for this switch in activity in rat Leydig cells may relate to the effects of culture media on 11ß-HSD1 dehydrogenase/reductase ratios (33). Thus, dehydrogenase activity exceeded reductase activity in Leydig cells cultured in DMEM; yet the opposite was found in cells cultured in DMEM/F12 media, probably because of a 4-fold increase in ATP levels in the latter. However, this scenario is unlikely to explain our data because the same DMEM/F12 media was used throughout the whole experiment and in both om and sc ASC preparations. Furthermore, the addition of serum to the primary cultures for the first 16 h had no effect on the initial and contrasting set-point activity data observed in om and sc ASCs.
The 11ß-HSD1 isozyme, although bidirectional in some tissue homogenates, is exclusively reductase in intact hepatocytes (16, 17) and pulmonary cells (34). In other cell systems, such as Leydig cells (31), skin fibroblasts (35), and rat pituitary GH3 cells (36), dehydrogenase activity is reported. Furthermore in several in vitro systems, both 11ß-HSD1 dehydrogenase and reductase activities have been reported (37, 38), but the explanation for this has remained elusive. Could the observed dehydrogenase activity reflect expression of a putative third 11ß-HSD isozyme as postulated from studies conducted on sheep and porcine kidney (39)? Characterization of such an isozyme, notably in human tissues, has been lacking, and this study does not seem to support this hypothesis; 11ß-HSD1 mRNA levels did not change between d 1 and d 14 in om ASCs despite the change of the set-point from dehydrogenase to oxoreductase.
The most plausible explanation to account for differences in the set-point of 11ß-HSD1 activity probably relates to subcellular redox potentials within peripheral tissues. In earlier studies we showed that expression of glucose-6-phosphate dehydrogenase (the first enzyme in the pentose phosphate pathway generating cytosolic NADPH:NADP ratio) could not account for differences in om and sc 11ß-HSD1 expression (12). 11ß-HSD1, however, is tightly bound to microsomes (40), and a key factor in determining enzyme set-point in ASC and differentiated adipocytes may be an alteration in the microsomal NADPH:NADP+ ratio. Formation of microsomal NADPH is dependent on the enzyme hexose-6-phosphate dehydrogenase (H6PDH) (41), distinct from cytosolic glucose-6-phosphate dehydrogenase. Early immunohistochemical studies localized H6PDH to the liver, theca, and testicular cells (42, 43), tissues that also express 11ß-HSD1 (44, 45). Loss of 11ß-HSD1 reductase activity in tissue homogenates and colocalization of H6PDH and 11ß-HSD1 enzymes to the lumen of endoplasmic reticulum (40, 46) imply a close affiliation between them. Because H6PDH is expressed in sc and om ASCs (our unpublished data) and its activity in rat liver microsomes can be altered by fasting or diet (47, 48), further studies are required to assess any interaction between 11ß-HSD1 and H6PDH and its role in human adipogenesis.
In summary, we have demonstrated that the overall expression of 11ß-HSD1 within adipose tissue is not dependent on adipocyte differentiation. However, within om adipose tissue, there exists a marked difference in the set-point of 11ß-HSD1 activity with dehydrogenase activity predominating in preadipocytes and oxoreductase activity in adipocytes. This switch in activity occurs at an early stage in the differentiation process. 11ß-HSD1 dehydrogenase activity in om ASCs by inactivating cortisol may sustain a pool of proliferating ASCs that may then enter a committed state to undergo differentiation. On initiation of differentiation, the oxoreductase activity of 11ß-HSD1 ensures the autocrine generation of cortisol, which will further induce adipocyte differentiation.
It is exciting to speculate that the observed interindividual differences in 11ßHSD1 activity within om ASCs may regulate individual om preadipocyte pools and adipocyte differentiation. The intracellular regulation of cortisol concentrations in human ASCs at different stages of differentiation and in particular the set-point of 11ß-HSD1 activity within om adipose tissue may be a crucial factor in the pathogenesis of central obesity.
Acknowledgments
We thank the Medical Research Council (MRC) for the financial support (P.M.S. is an MRC Senior Clinical Fellow) and the surgeons and theater staff of the Queen Elizabeth and Women’s Hospitals in Birmingham for their help in collecting tissue samples.
Footnotes
Abbreviations: ASC, Adipose stromal cell; 11ß-HSD, 11ß-hydroxysteroid dehydrogenase; BMI, body mass index; Ct values, cycle number at which logarithmic PCR plots cross a calculated threshold line; Ctr, addition of 10 nM insulin; Ct, Ct of the target gene minus Ct of the housekeeping gene; E, inactive cortisone; F, cortisol; +F, addition of insulin with 100 nM F; G3PDH, glycerol-3-phosphate dehydrogenase; H6PDH, hexose-6-phosphate dehydrogenase; LPL, lipoprotein lipase; om, omental; RT, reverse transcription.
Received September 7, 2001.
Accepted November 26, 2001.
References
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 M. Eijken, M. Hewison, M. S. Cooper, F. H. de Jong, H. Chiba, P. M. Stewart, A. G. Uitterlinden, H. A. P. Pols, and J. P. T. M. van Leeuwen 11{beta}-Hydroxysteroid Dehydrogenase Expression and Glucocorticoid Synthesis Are Directed by a Molecular Switch during Osteoblast Differentiation Mol. Endocrinol., March 1, 2005; 19(3): 621 - 631. [Abstract] [Full Text] [PDF]
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K. Blouin, S. Blanchette, C. Richard, P. Dupont, V. Luu-The, and A. Tchernof Expression and activity of steroid aldoketoreductases 1C in omental adipose tissue are positive correlates of adiposity in women Am J Physiol Endocrinol Metab, February 1, 2005; 288(2): E398 - E404. [Abstract] [Full Text] [PDF]
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M. Quinkler, B. Sinha, J. W Tomlinson, I. J Bujalska, P. M Stewart, and W. Arlt Androgen generation in adipose tissue in women with simple obesity - a site-specific role for 17{beta}-hydroxysteroid dehydrogenase type 5 J. Endocrinol., November 1, 2004; 183(2): 331 - 342. [Abstract] [Full Text] [PDF]
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J. P. Girod and D. J. Brotman Does altered glucocorticoid homeostasis increase cardiovascular risk? Cardiovasc Res, November 1, 2004; 64(2): 217 - 226. [Abstract] [Full Text] [PDF]
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 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]
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G. Valsamakis, A. Anwar, J. W. Tomlinson, C. H. L. Shackleton, P. G. McTernan, R. Chetty, P. J. Wood, A. K. Banerjee, G. Holder, A. H. Barnett, et al. 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity in Lean and Obese Males with Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4755 - 4761. [Abstract] [Full Text] [PDF]
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C. Frick, A. G. Atanasov, P. Arnold, J. Ozols, and A. Odermatt Appropriate Function of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in the Endoplasmic Reticulum Lumen Is Dependent on Its N-terminal Region Sharing Similar Topological Determinants with 50-kDa Esterase J. Biol. Chem., July 23, 2004; 279(30): 31131 - 31138. [Abstract] [Full Text] [PDF]
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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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K. Blouin, C. Richard, C. Belanger, P. Dupont, M. Daris, P. Laberge, V. Luu-The, and A. Tchernof Local Androgen Inactivation in Abdominal Visceral Adipose Tissue J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5944 - 5950. [Abstract] [Full Text] [PDF]
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D. Tiosano, I. Eisentein, D. Militianu, G. P. Chrousos, and Z.'e. Hochberg 11{beta}-Hydroxysteroid Dehydrogenase Activity in Hypothalamic Obesity J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 379 - 384. [Abstract] [Full Text] [PDF]
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M. Friedberg, E. Zoumakis, N. Hiroi, T. Bader, G. P. Chrousos, and Z.'e. Hochberg Modulation of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Mature Human Subcutaneous Adipocytes by Hypothalamic Messengers J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 385 - 393. [Abstract] [Full Text] [PDF]
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) and reductase (
) activities in isolated intact om adipocytes (n = 3).
) (n = 7) on d 1 and 14 using real-time RT-PCR. B, Table showing calculated 
