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National Institute of Diabetes and Digestive and Kidney Diseases (R.S.L., S.N., J.B., P.A.P., P.A.T.), National Institutes of Health, Department of Health and Human Services, Phoenix, Arizona 85016; and Endocrinology Unit, Department of Medical Sciences (D.J.W., D.E.W.L., B.R.W.), University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom
Address all correspondence to: P. Antonio Tataranni, M.D., National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, 4212 North 16th Street, Room 541A, Phoenix, Arizona 85016. E-mail: antoniot{at}mail.nih.gov.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We investigated the cross-sectional relationship of adipose 11-HSD1 activity to metabolic variables by assessing enzyme activity, mRNA levels, and tissue cortisol and cortisone levels in adipose biopsies taken from human subjects. We examined the hypotheses that 11-HSD1 activity, mRNA levels, and tissue cortisol levels are positively related to indices of adiposity, insulin resistance, and hyperglycemia. We further assessed whether there are ethnic differences in 11-HSD1 activity by examining these relationships in both Pima Indians, a group with marked propensity to both obesity and type 2 diabetes, and Caucasians.
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Subjects and Methods |
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Pima and Caucasian volunteers were admitted to the metabolic ward of the Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Phoenix, AZ). Subjects were recruited by newspaper advertisement or by community-based recruiters. Although subjects are not formally matched for adiposity, an effort was made to recruit Caucasian subjects across a similar range of adiposity as in the Pima group. All subjects were determined to be in good health by medical history, physical examination, and laboratory screening tests. None were taking medications. Exclusion criteria included smoking, alcohol or drug abuse, and diabetes, according to a 75-g oral glucose tolerance test (11). On admission subjects were placed on a weight-maintenance diet (50% carbohydrate, 30% fat, 20% protein) calculated on the basis of body weight and adjusted to maintain body weight within ± 1%. Body composition, including percentage body fat (%fat) was assessed by dual-energy x-ray absorptiometry (DPX-L; Lunar Corp., Madison, WI) (12). The circumference of the waist was measured supine at the level of the umbilicus. Fat biopsies were obtained after a 12-h overnight fast, between 0830 h and 1000 h. Procedures for biopsy have been described previously (13). In brief, sc abdominal adipose tissue was removed from the periumbilical region by percutaneous needle biopsy under local anesthesia (lidocaine 1%). Biopsies were frozen immediately at -70 C.
The study was approved by the ethics committee of the National Institute of Diabetes and Digestive and Kidney Diseases and the Tribal Council of the Gila River Indian Community. Subjects provided written informed consent.
Analytical measurements
The plasma glucose concentration was measured by the glucose oxidase method (Beckman glucose analyzer; Beckman, Fullerton, CA) and insulin by RIA (Concept 4; ICN Biomedicals, Inc., Costa Mesa, CA). Homeostasis model of assessment insulin resistance index (HOMA-IR) was calculated as previously described (14).
11-HSD1 activity. Fat was thawed, homogenized in Krebs buffer at pH 7.4 and 750 µg/ml protein, and incubated at 37 C with 2 mM nicotinamide adenine dinucleotide phosphate and 100 nM 1,2,6,7-3H-cortisol for 30 h, with samples withdrawn at 3, 6, 20, and 30 h for separation of cortisol and cortisone by HPLC with on-line liquid scintillation detection (4, 5, 6). The 11-HSD1 activity was measured in the dehydrogenase direction (i.e. cortisol to cortisone rather than reductase cortisone to cortisol) because reductase activity is less stable in vitro (1) and the dehydrogenase direction is preferred when the enzyme is liberated from its intracellular environment (15). When driven by excess cofactor, this activity is proportional to total protein, regardless of the direction that the reaction is measured.
11-HSD1 mRNA. Approximately 500 mg fat were homogenized in 1.5 ml Trizol, extracted in chloroform and RNAid matrix (Anachem), washed three times, and precipitated by addition of diethylpyrocarbonate H2O/dithiothreitol/RNAsin. RNA was quantified spectrophotometrically at OD260. RNA integrity was checked by electrophoresis on 1.2% agarose gel. Oligo dT-primed cDNA was synthesized from 0.5 µg of RNA samples. PCR amplification of glyceraldehyde 3-phosphate dehydrogenase transcript using glyceraldehyde 3-phosphate dehydrogenase primers provided in the kit (CLONTECH Laboratories, Inc., Palo Alto, CA) was carried out to confirm successful cDNA synthesis.
Transcript level quantification for 11-HSD1 was performed with real-time PCR primer-probe sets using the ABI PRISM 7700 sequence detection system (Applied Biosystems, Foster City, CA) using primers 5'GGAATATTCAGTGTCCAGGGTCAA3'(F), 5'TGATCTCCAGGGCACATTCCT3'(R), and 5'-6-FAM-CTTGGCCTCATAGACACAGAAACAGCCA-BHQ-3', respectively. Human cyclophilin (Applied Biosystems) was used to normalize the 11-HSD1 transcript levels. A standard curve for each primer-probe set was generated by serial dilution of cDNA from a healthy subject done in triplicate. Each sample was run in duplicate and the mean values of the duplicates were used to calculate transcript level.
Tissue cortisol and cortisone. Following homogenization in Trizol, the infranatant from the RNA extraction protocol (see above) was used to extract steroids. Approximately 0.3 pmol/ml (<1% final tissue concentrations) of 1,2,6,7-3H4-cortisone and 1,2,6,7-3H4-cortisol (Amersham, Little Chalfont, Buckinghamshire, UK) were added to the homogenate to correct for steroid extraction and HPLC efficiency. Samples was centrifuged to remove the fat layer and extracted on a sep-pak (Waters C18 cartridges, Elstree, Hertfordshire, UK), further purified with hexane, reextracted with ethyl acetate, and reconstituted in mobile phase for HPLC separation of cortisone and cortisol fractions as previously described (16). Fractions were counted for recovery of tracer 3H-steroid (mean, 61 ± 12%) and assayed in triplicate for endogenous cortisol and cortisone by RIAs (16). Final steroid concentrations are expressed per gram of wet weight of adipose tissue after adjustment for extraction efficiency.
Statistical analysis
All values are represented as mean ± SD unless otherwise indicated. Statistical analyses were performed using the procedures of the SAS Institute, Inc. (Cary, NC). Relationships between 11-HSD1 activity and adipose or metabolic variables were assessed either by Pearson correlation (using area under the curve for the 11-HSD1 reaction) or, where multiple covariates were assessed, by general linear modeling. Where appropriate, variables (fasting insulin, 11-HSD1 mRNA, tissue cortisol) were log transformed to approach a normal distribution. Where 11-HSD1 activity is modeled as the dependent variable, separate time points of the 11-HSD1 assay (3, 6, 20, and 30 h) were fitted in a single model with a repeated measures design.
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Results |
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Measures of adiposity [body mass index (BMI), %fat, waist circumference)], fasting plasma glucose, and insulin were comparable between the Pima and Caucasian groups (Table 1
). Neither fasting plasma insulin nor HOMA-IR differed between Pimas and Caucasians, even after adjustment for sex, %fat, or BMI (data not shown). Ten subjects (Caucasian, two males and one female; Pima, three males and four females) had impaired glucose tolerance (IGT) (11). All other subjects were normal glucose tolerant (NGT). Although glucose at 2 h was higher in those with IGT, other baseline variables were similar (%fat, BMI, waist, all P > 0.5 vs. NGT) including fasting glucose (NGT 87 ± 7 mg/dl; IGT 92 ± 11; P = 0.2).
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; r = 0.51, P = 0.003). This relationship was consistent across all time points of the activity assay (3, 6, 20, and 30 h; r = 0.47, 0.49, 0.56, 0.60, respectively; P < 0.01 for all). When considered separately the relation of 11-HSD1 activity and mRNA levels was present in both Pima Indians (r = 0.58, P = 0.01) and Caucasians (r = 0.69, P = 0.02).
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Relationship of adipose 11-HSD1 to obesity and metabolic variables
In all subjects, 11-HSD1 activity was significantly associated with BMI, %fat, waist circumference, fasting plasma glucose, fasting plasma insulin, and HOMA-IR (Table 2, Fig. 2). When Pima Indians and Caucasians were considered separately, positive associations of BMI, %fat, waist, fasting plasma glucose, fasting plasma insulin, and HOMA-IR were also present (with r >0.5 and P < 0.05) with the exception of %fat (r = 0.52, P = 0.09) and glucose (r = 0.43, P = 0.18) in Caucasians. In general, similar but somewhat weaker relationships were observed with adipose 11-HSD1 mRNA (Table 2).
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Ethnicity was not significantly related to 11-HSD1 activity as a single predictor (P = 0.53) or in the above models. Overall Caucasians tended to have higher 11-HSD1 mRNA levels as a single predictor (Table 1
, P = 0.07), and this was significant in the above models (P = 0.0007 in model with sex, %fat, waist, and fasting insulin; P = 0.0005 in model with sex, %fat, waist, and HOMA-IR).
No difference in 11-HSD1 activity or mRNA was found in individuals with IGT vs. NGT (P = 0.71), even after adjustment for other covariates (sex, %fat, ethnicity; P for effect of glucose tolerance status = 0.68). In multivariate models fasting glucose was not related to 11-HSD1 mRNA or activity (data not shown)
Sex was not related to 11-HSD1 activity or mRNA either as a single predictor (P = 0.73, P = 0.11, respectively) or after inclusion of %fat, fasting insulin, or HOMA-IR as additional predictors.
Relation of intra-adipose cortisol and cortisone to obesity and metabolic variables
Correlations between intra-adipose cortisol and anthropometric or metabolic variables were generally positive but significant only in the case of fasting insulin (Table 2). Intra-adipose cortisol was not significantly related to fasting insulin or HOMA-IR in multivariate models (including %fat, sex, and waist). Neither intra-adipose cortisone nor cortisol:cortisone ratios correlated with anthropometric or metabolic variables (data not shown). There were no ethnic differences in intra-adipose cortisol or cortisone levels.
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Discussion |
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The concept of tissue-specific dysregulation of 11-HSD1 activity in human obesity is now supported by a series of studies. It arose from observations that conversion of oral cortisone to plasma cortisol is impaired in obese men (5, 17), consistent with impaired hepatic 11-HSD1, yet urinary ratios of cortisol/cortisone metabolites are highly variable (5, 6, 17, 18, 19) suggesting compensatory differences in extrahepatic 11-HSD1 activity. The concept was supported by increased 11-HSD1 activity in adipose of Zucker obese rats and ob/ob obese mice associated with reduced 11-HSD1 activity in livers in these animals (4, 10). Moreover, an earlier study using arteriovenous cannulation of abdominal sc fat suggested increased conversion of cortisone to cortisol in obesity (3). Three recently published studies have confirmed increased 11-HSD1 activity (5, 6) and mRNA (7) in sc adipose tissue of obese men and women.
The current data confirm the magnitude of this increase in 11-HSD1 activity; demonstrate a close relationship of 11-HSD1 activity and mRNA from the same biopsies, as has previously been seen in studies in rodents (20); and support higher 11-HSD1 activity and gene transcription in adipose tissue in obesity. By contrast, one study, examining biopsy material obtained during intra-abdominal surgery, has recently reported no relationship to BMI of 11-HSD1 mRNA levels in freshly homogenized adipose tissue (21). Furthermore, 11-HSD1 activity was measured in cultured preadipocytes and adipocytes and was either not correlated with, or in omental preadipocytes showed an inverse relationship with, BMI (21). To explain this discrepancy with published results, it has been suggested (21) that measurement of 11-HSD1 activity in the dehydrogenase direction, as we have done here and previously (5, 6), might produce spurious results. However, we think this is unlikely because the dehydrogenase direction is preferred when 11-HSD1 is liberated from its intracellular environment in homogenized tissue (15), is more stable than reductase activity in vitro (1), and in the conditions used here is proportionate to the amount of protein added to the assay. We think it more likely that confounding effects of obtaining biopsies during the stress of major surgery, and loss of phenotype during culture of cells in vitro, accounts for the apparent discrepancy. The current data show for the first time a close relationship between 11-HSD1 mRNA and (dehydrogenase) activity in human adipose tissue and support the conclusion that increased adipose 11-HSD1 activity in obesity is due to increased gene transcription.
The metabolic impact of these observations has been uncertain. In mice with transgenic overexpression of 11-HSD1 in adipose tissue, a similar magnitude of increased 11-HSD1 activity to the range seen in this study (
3-fold) resulted in obesity that was much more obvious in omental fat than in sc fat (10). This effect on fat distribution probably reflects higher expression of glucocorticoid receptors in omental fat. In humans, studies in cultured cells from omental adipose tissue suggest that the same relatively high glucocorticoid receptor expression occurs (22) and is accompanied by higher 11-HSD1 expression (2). Although sc adipose 11-HSD1 predicts indices of both generalized and central obesity (3, 5, 6, 7), we cannot yet confirm whether increased 11-HSD1 in sc adipose tissue can be extrapolated to omental adipose tissue. Furthermore, if increased adipose 11-HSD1 activity does result in metabolic consequences, as is suggested by transgenic mouse models (10), it is not known whether increases in omental as well as sc 11-HSD1 would be a prerequisite for this.
Our data do suggest, however, that increased adipose 11-HSD1 could have a significant effect on the metabolic complications of obesity in humans. We report significant relationships of adipose 11-HSD1 and measures of insulin sensitivity. Previous studies in humans either did not report relationships of adipose 11-HSD1 to metabolic variables (7, 21) or found that relationships between increased adipose 11-HSD1 activity and insulin resistance (measured by euglycemic hyperinsulinemic clamp) could be entirely accounted for by coexisting obesity (5, 6). In the present larger study, there are strong relationships between 11-HSD1 in adipose and insulin resistance (as assessed by HOMA-IR and fasting plasma insulin). In multivariate analyses it appears that the principal relationship we are observing may be with insulin resistance. There are two caveats to this. First, given the relatively small number of subjects in our study, multivariate models should be interpreted with caution. Second, the measures we have used (fasting insulin and HOMA-IR), although correlated with measures of insulin resistance derived from euglycemic hyperinsulinemic clamp (23), are not gold standard measures of insulin resistance. Nevertheless, our study suggests that there is a relationship between the extent of increased adipose 11-HSD1 in obesity and the severity of associated hyperinsulinemia.
Given the cross-sectional nature of our study, it is not possible to infer whether higher 11-HSD1 is the cause or consequence of obesity and insulin resistance. It remains possible that 11-HSD1 is raised as a consequence of hyperinsulinemia or insulin resistance. A number of studies suggest that, at least in cell culture, insulin regulates 11-HSD1 expression in adipocytes. However, the effects are inconsistent. Up-regulation of 11-HSD1 by coincubation of cells with insulin and glucocorticoids may reflect increased 11-HSD1 expression during adipocyte differentiation (2). In mature cells insulin may down-regulate 11-HSD1 expression in adipocytes (2, 24) as it does in other tissues (25, 26). In animal models insulin sensitizing agents have inconsistent effects on 11-HSD1 activity and expression (20, 27). Finally, in a recent case-control study of patients with hyperglycemia and insulin resistance who were not more obese than controls, adipose 11-HSD1 activity was not altered (28). In light of these results, it is possible that insulin resistance at the level of adipocytes acts to increase 11-HSD1 activity, but we think it more likely that some other feature of obesity is responsible for changes in 11-HSD1, which, in turn, may contribute to the metabolic complications of the obesity. For example, adipose 11-HSD1 is potently stimulated by cytokines including TNF
(29, 30, 31). Notably, TNF is increased in obesity and has been proposed as a potential mediator of insulin resistance secondary to obesity (32).
In mice with transgenic overexpression of 11-HSD1 in adipose, plasma corticosterone levels are unaltered but intra-adipose corticosterone levels are elevated about 2-fold (10). To test whether the adverse metabolic consequences of increased adipose 11-HSD1 could similarly be attributed to increased intra-adipose generation of cortisol, we extracted glucocorticoids from adipose biopsies. We found that the concentrations of intra-adipose cortisone approximate those found in plasma (16), but concentrations of cortisol were approximately 10-fold lower than would be expected in plasma, given that the biopsies were obtained between 0830 h and 1000 h. This is likely to reflect the absence of corticosteroid-binding globulin in adipose tissue, and hence intra-adipose cortisol concentrations approximate free cortisol concentrations in plasma. Notably, there was no significant relationship of adipose 11-HSD1 to concentrations of intra-adipose cortisol or cortisone. There may be a number of explanations of this. First, although the technique of extraction of steroids from tissues has recently been applied in animal studies (10) the small size of human adipose biopsies is technically demanding and application to small samples is novel. Second, we have not assessed influences of variations in plasma concentrations of cortisol, including those relating to the stress of the biopsy. Unfortunately concomitant plasma samples were not available to allow assessment of this. In the transgenic mice with adipose 11-HSD1 overexpression, samples were obtained during the diurnal nadir of glucocorticoid secretion (10), when 11-HSD1 is putatively more important in maintaining intra-cellular glucocorticoid levels (1).
Here biopsies were obtained during the diurnal peak of cortisol secretion when the influence of circulating cortisol may be more important. In that light we consider our examination of intra-adipose cortisol exploratory and clearly far from definitive. Nevertheless, we did find positive relationships between intra-adipose cortisol and most anthropometric and metabolic indices of obesity and insulin resistance, which reached statistical significance for fasting plasma insulin. These relationships deserve further exploration to establish whether they can be attributed to variations in adipose 11-HSD1 and/or increased plasma cortisol, which has been observed in subjects with the metabolic syndrome (33, 34, 35).
As part of this study, we investigated ethnic differences in 11-HSD1 in Pima and Caucasian subjects. The Pima Indians have a greatly increased propensity to obesity (36). Furthermore, for any degree of obesity, they have a similar degree of central adiposity (37) but a greatly increased prevalence of type 2 diabetes (38). We hypothesized that differences in 11-HSD1, and, by inference, glucocorticoid action in adipocytes might underpin this increased risk of progression to type 2 diabetes. Previous studies comparing Pima with Caucasian subject population have not detected any difference in 24-h urinary-free cortisol or fasting cortisol between Pima and Caucasian males (39). We detected no major differences in adipose 11-HSD1 activity between Pimas and Caucasians. The lack of ethnic differences in adipose 11-HSD1, together with the recent demonstration that up-regulation of adipose 11-HSD1 accompanies obesity with a demonstrable underlying cause of hypothalamic disease (40), supports the concept that 11-HSD1 dysregulation is downstream rather than a primary event in the pathophysiology of obesity. Levels of mRNA were higher in Caucasians in some models, leaving the possibility that differences exist in the relation of insulin sensitivity and adipose 11-HSD1 between ethnic groups; however, given the sample size, we were not able to explore this further.
In conclusion we find that, in this cross-sectional study, sc adipose 11-HSD1 activity and mRNA levels are closely related. Furthermore, increased 11-HSD1 activity and expression are closely associated with not only measures of adiposity but also insulin resistance and hyperglycemia. Our data support the hypothesis that 11-HSD1 may act in modulation of metabolic disease in humans.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMI, Body mass index; %fat, percentage body fat; HOMA-IR, homeostasis model of assessment insulin resistance index; 11-HSD1, 11ß-hydroxysteroid dehydrogenase type 1; IGT, impaired glucose tolerance; NGT, normal glucose tolerant.
Received December 30, 2002.
Accepted March 5, 2003.
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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]
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G. Apostolova, R. A. S. Schweizer, Z. Balazs, R. M. Kostadinova, and A. Odermatt Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E957 - E964. [Abstract] [Full Text] [PDF]
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P. A. Tataranni and E. Ortega A Burning Question: Does an Adipokine-Induced Activation of the Immune System Mediate the Effect of Overnutrition on Type 2 Diabetes? Diabetes, April 1, 2005; 54(4): 917 - 927. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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S. Boullu-Ciocca, A. Dutour, V. Guillaume, V. Achard, C. Oliver, and M. Grino Postnatal Diet-Induced Obesity in Rats Upregulates Systemic and Adipose Tissue Glucocorticoid Metabolism During Development and in Adulthood: Its Relationship With the Metabolic Syndrome Diabetes, January 1, 2005; 54(1): 197 - 203. [Abstract] [Full Text] [PDF]
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 P. W. Franks, W. C. Knowler, S. Nair, J. Koska, Y.-H. Lee, R. S. Lindsay, B. R. Walker, H. C. Looker, P. A. Permana, P. A. Tataranni, et al. Interaction Between an 11{beta}HSD1 Gene Variant and Birth Era Modifies the Risk of Hypertension in Pima Indians Hypertension, November 1, 2004; 44(5): 681 - 688. [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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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]
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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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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]
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C. Asensio, P. Cettour-Rose, C. Theander-Carrillo, F. Rohner-Jeanrenaud, and P. Muzzin Changes in Glycemia by Leptin Administration or High- Fat Feeding in Rodent Models of Obesity/Type 2 Diabetes Suggest a Link between Resistin Expression and Control of Glucose Homeostasis Endocrinology, May 1, 2004; 145(5): 2206 - 2213. [Abstract] [Full Text] [PDF]
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R. A. S. Schweizer, M. Zurcher, Z. Balazs, B. Dick, and A. Odermatt Rapid Hepatic Metabolism of 7-Ketocholesterol by 11{beta}-Hydroxysteroid Dehydrogenase Type 1: SPECIES-SPECIFIC DIFFERENCES BETWEEN THE RAT, HUMAN, AND HAMSTER ENZYME J. Biol. Chem., April 30, 2004; 279(18): 18415 - 18424. [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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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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