Original Article

International Journal of Obesity (2007) 31, 1826–1831; doi:10.1038/sj.ijo.0803677; published online 26 June 2007

Type 2 diabetes and metabolic syndrome are associated with increased expression of 11bold italic beta-hydroxysteroid dehydrogenase 1 in obese subjects

L Alberti1, A Girola1, L Gilardini1, A Conti1, S Cattaldo2, G Micheletto3 and C Invitti1

  1. 1Unit for Metabolic Diseases and Diabetes, Istituto Auxologico Italiano, Milan, Italy
  2. 2Laboratory of Clinical Neurobiology, Istituto Auxologico Italiano, Piancavallo, Italy
  3. 3Department of Surgery, University of Milan, Milan, Italy

Correspondence: Dr C Invitti, Unit of Metabolic Diseases and Diabetes, Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milan, Italy. E-mail: invitti@auxologico.it

Received 7 March 2007; Revised 17 May 2007; Accepted 1 June 2007; Published online 26 June 2007.





The role of glucocorticoids production in adipose tissue in the development of metabolic disorders in humans has not been fully characterized. We investigated whether in obese subjects, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) expression in subcutaneous (SAT) and visceral (VAT) adipose tissue is associated with the occurrence of metabolic disorders and the expression of adiponectin and tumor necrosis factor alpha (TNFalpha) and two glucocorticoid-regulated adipokines able to influence the metabolic control.

Design and subjects:


Sixty-two obese patients were enrolled in the study. SAT and VAT samples were obtained from 13 patients undergoing bariatric surgery (body mass index (BMI) 39.1plusminus5.3 kg/m2). SAT samples were obtained from 49 patients who underwent periumbilical biopsy (BMI 36.9plusminus5.1 kg/m2).



Oral glucose tolerance tests in subjects without known diabetes. Circulating glucose, lipid, insulin, adiponectin, TNFalpha and urinary-free cortisol levels. Real-time PCR to quantify mRNA levels of 11beta-HSD1, hexose-6-phosphate dehydrogenase (H6PDH), adiponectin and TNFalpha. Western blot analysis to evaluate 11beta-HSD1 protein expression.



In the majority of the obese subjects, VAT expresses more 11beta-HSD1 than SAT. VAT 11beta-HSD1 expression was not associated with metabolic disorders. SAT 11beta-HSD1 mRNA levels were higher in subjects with than in those without metabolic syndrome (P<0.05) and in patients with type 2 diabetes compared to patients with impaired or normal glucose tolerance (P<0.0001). SAT 11beta-HSD1 expression was independently related to fasting glucose (P<0.0001) and urinary-free cortisol levels (P<0.01), and increased expression of 11beta-HSD1 was associated with increased adiponectin and TNFalpha expression and decreased serum adiponectin levels (all P's <0.05).



In obese subjects, increased 11beta-HSD1 expression in SAT, but not in VAT, is associated with the worsening of metabolic conditions. We hypothesize that higher glucocorticoid production in adipose tissue would favor the development of metabolic disorders through a decrease in adiponectin release.


11beta-HDS 1, type 2 diabetes, adipose tissue, adiponectin, urinary-free cortisol, TNFalpha



Excessive exposure to glucocorticoids induces several metabolic alterations.1 Glucocorticoid metabolism is controlled by a microsomal enzyme, the hydroxysteroid dehydrogenase type 1 (11beta-HSD1) which catalyzes the interconversion of inactive cortisone and active cortisol and regulates the interaction of cortisol with glucocorticoid receptors. In adipose tissue, the reductase activity of the enzyme predominates driving to cortisol production.2 A role for 11beta-HSD1 in the impairment of metabolic control has been widely demonstrated in mice. Indeed, transgenic mice that overexpress 11beta-HSD1 in adipose tissue develop visceral obesity, insulin resistance, hyperglycemia and hyperlipidemia,3 and 11beta-HSD1 knockout mice are protected against metabolic alterations.4, 5 This association is less clear in humans. Selective inhibitors of 11beta-HSD1 have been shown to have beneficial effects on insulin resistance and hyperglycemia in man as well as in mice.6, 7 In skeletal muscle, 11beta-HSD1 expression was reported to be positively associated with insulin resistance and blood pressure8 and to be increased in obese diabetic subjects compared to those without diabetes.9 In regard to adipose tissue, 11beta-HSD1 activity/expression was shown to be associated with fasting glucose levels and insulin resistance by some, but not all the previous studies.10, 11, 12, 13, 14

Visceral adipose tissue (VAT) is believed to have a primary role in the development of metabolic disorders because it releases high amounts of free fatty acids to the liver through the portal system and expresses an higher number of glucocorticoid receptors compared to subcutaneous adipose tissue (SAT).15 However, a recent study indicated that VAT and SAT express similar levels of glucocorticoid receptors.16 Another issue that has not been completely clarified yet deals with the ability of the different fat compartments to produce glucocorticoids. Indeed, the few previous studies that have investigated this aspect in humans have led to contradictory results.16, 17, 18, 19

To investigate whether 11beta-HSD1 expression in adipose tissue is associated with metabolic syndrome and glucose intolerance in humans, this study was set up to measure 11beta-HSD1 mRNA levels in SAT and VAT derived from obese subjects with and without metabolic disorders. In addition, we studied the relationship between 11beta-HSD1 expression and adiponectin, and tumor necrosis factor alpha (TNFalpha) and two glucocorticoid-regulated adipokines that are involved in the metabolic control.



Experimental subjects

Sixty-two obese patients were enrolled in the study. Thirteen of them underwent bariatric surgery during which samples of SAT and omental VAT were obtained. Measures derived from SAT of the 13 patients were pooled with those derived from SAT of the remaining 49 subjects, all of whom underwent a periumbilical needle aspiration biopsy under local anesthesia. Of the 62 subjects, nine had type 2 diabetes and ten had impaired fasting glucose (IFG) characterized by fasting glucose levels greater than or equal to5.6 and <7.0 mM. Subjects without known diabetes underwent a 75 g oral glucose tolerance test which revealed that three patients were diabetic (2 h glucose greater than or equal to11.1 mM) and four patients had impaired glucose tolerance (IGT) (2 h glucose greater than or equal to7.8 mM and <11.1 mM). A fasting morning blood sample was obtained from all patients for measurement of insulin, glucose, high-density lipoprotein (HDL) cholesterol, triglycerides, adiponectin and TNFalpha.

Twenty-four hour urine samples were collected for 3 days to measure urinary-free cortisol. The mean of the three measurements was used for analysis. Metabolic syndrome was defined according to the criteria of the American Heart Association and National Heart, Lung, and Blood Institute.20 Subjects were classified as having the syndrome if they had at least three of the following: (1) waist circumference greater than or equal to102 cm (males) or greater than or equal to88 cm (females), (2) HDL cholesterol less than or equal to1.03 mM (males) or less than or equal to1.3 mM (females) or taking medication for reduced HDL cholesterol, (3) triglycerides greater than or equal to1.7 mM or taking medication for elevated triglycerides, (4) systolic blood pressure (BP) greater than or equal to130 mm Hg or diastolic BP greater than or equal to85 mm Hg or taking antihypertensive medication and (5) fasting glucose greater than or equal to5.6 mM or taking medication for elevated glucose.

Determination of gene expression

Total RNA from adipose tissue was extracted using RNeasy Lipid Tissue Mini Kit (QIAGEN, Germantown, MD, USA) according to the manufacturer's protocols. From 1 mug of total RNA, cDNAs were reverse transcribed with SuperScript III (Invitrogen, Carlsbad, CA, USA). Real-time PCR was used to quantify mRNA. For each sample, 10 ng of template was amplified in triplicate in PCRs on an ABI PRISM 7700 machine using Assay-on-Demand Gene Expression Products (Applied Biosystems, Foster City, CA, USA). TaqMan probes (Applied Biosystems) for 11beta-HSD1, adiponectin, TNFalpha, hexose-6-phosphate dehydrogenase (H6PDH) and the housekeeping gene beta-glucuronidase (GUSB) mRNA were labeled with carboxyfluorescein. Analyses were performed with SDS 2.1 software (Applied Biosystems). The relative amount of the mRNA of interest was normalized to the amount of GUSB transcript in the samples, and data were expressed as 2-DeltaCT.

Protein extraction and western blot analysis

Adipose tissue proteins were extracted in Cell Lysis buffer (Cell Signaling Technology Inc., Danvers, MA, USA) supplemented with 1 mM phenylmethanesulfonylfluoride according to the manufacture's instructions. Whole tissue extracts were stored at -80°C and protein concentration was determined with BCA protein assay kit (Pierce, Rockford, IL, USA). Thirty micrograms of proteins were separated by 15% sodium dodecyl sulfate–polyacrylamide gel electrophoresis under denaturating conditions and blotted onto nitrocellulose filter. Membranes were blocked in tris buffer saline (10 mM Tris-Hcl, 166 mM NaCl, pH 7.4) and 5% milk for 2 h, incubated overnight in the same buffer supplemented with 1 : 1000 11beta-HSD1 (alpha Diagnostic International San Antonio, TX, USA) and washed with TBS 0.1% Tween-20. Secondary antibodies were horseradish peroxidase-conjugated anti-rabbit antibodies (Amersham Biosciences, Little Chalfont, Buckinghamshire, UK). Enhanced Chemiluminescence Plus western blot detection system (Amersham Biosciences) for detection was used.

Biochemical measurements

Circulating levels of glucose, cholesterol and triglycerides were measured using an automated analyzer (Roche Diagnostic, Manheim, Germany). Serum insulin was measured by an electrochemiluminescent assay (Roche Diagnostic) with a sensitivity of 1.4 pmol/l and intra - and interassay coefficient of variations (CVs) of 2.0 and 3.7%.

Serum adiponectin levels were determined by an enzyme-linked immunosorbent assay (B-Bridge International Inc., San Jose, CA, USA). Sensitivity was 0.37 ng/ml and the intra- and interassay CVs were 3.3 and 7.4%. Serum TNFalpha levels were determined by a solid-phase Enzyme Amplified Sensitivity Immunoassay kit (TNFalpha EASIA, BioSource Europe, SA, Nivelles, Belgium). Sensitivity was 3 pg/ml and the intra- and interassay CVs were 5.2 and 9.9%. Urinary-free cortisol was measured by radioimmunoassay after urine extraction with dichloromethane (DPC, Los Angeles, CA, USA). Sensitivity, intra- and interassay CVs were 0.5 mug/dl, 3.5 and 6.2%.

Statistical analysis

Variables that were not normally distributed were log transformed. Paired t-test was used to compare the expression levels of 11beta-HSD1 mRNA in SAT and VAT and two sample t-tests to examine the differences between obese subjects with and without metabolic syndrome. Pearson's correlation analyses were used to evaluate bivariate relationships. Multiple regression analysis was performed using variables that were statistically significant at the 0.05 level in the univariate analysis. Analysis of variance was used to compare differences in categories of glucose tolerance and in tertiles of 11beta-HSD1 mRNA. The odds ratio (OR) for having metabolic syndrome and diabetes and the corresponding 95% CI were calculated for tertiles of 11beta-HSD1 mRNA using logistic regression analysis. Data are expressed as meanplusminuss.d. A P-value<0.05 was considered statistically significant. All analyses were performed using SPSS version 14.01 (SPSS Inc., Chicago, IL, USA).

Statement of ethics

We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers were followed during this research. The Ethics Committee of the Istituto Auxologico Italiano approved the study, and written informed consent was obtained from all patients.



Clinical and biochemical characteristics of the 13 obese subjects who underwent bariatric surgery and the 49 obese subjects who underwent periumbilical biopsy are shown in Table 1. Degree of obesity, proportion of males and prevalence of metabolic disorders were similar in the two groups.

11beta-HSD1 mRNA expression in SAT and VAT derived from 13 obese subjects who underwent bariatric surgery

11beta-HSD1 expression was higher in VAT than in SAT in 77% of subjects: mean mRNA levels were 2.06plusminus0.92 (range 0.96–3.65) and 1.39plusminus0.82 (range 0.46–3.44) arbitrary units, in VAT and SAT, respectively (P=0.05). To demonstrate that mRNA expression of 11beta-HSD1 parallels protein levels, we performed western blot analysis on SAT and VAT from three representative obese subjects. Since we used an antibody raised against mouse 11beta-HSD1 and able to detect the human enzyme,20 mouse adipose tissue was used as control. The antibody recognized a specific strong band at 34 kDa in mouse tissue (line control) and a weaker band in human adipose tissue which migrated at the expected molecular weight. Protein amounts reflected mRNA levels in two of the three subjects, with undetectable levels in the third (Figure 1).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Western blot analysis of 11beta-HSD1 in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from three representative obese subjects and in mouse adipose tissue (control). The arrow indicates the 34 kDa band of 11beta-HSD1. The densitometric values of 11beta-HSD1 protein normalized for the amounts of protein loaded for lane and the individual 11beta-HSD1 mRNA values obtained with real-time PCR are reported below the western blot panel. ND, not detectable.

Full figure and legend (42K)

SAT levels of 11beta-HSD1 mRNA were higher in subjects with than in those without metabolic syndrome and in subjects with IFG, IGT or diabetes when compared to those with normal glucose tolerance (NGT) (Figure 2). Univariate analysis showed that 11beta-HSD1 mRNA levels in SAT correlated with fasting glucose (r=0.558, P<0.05) and triglycerides (r=0.727, P<0.05) but not with body mass index (BMI), waist circumference, BP and fasting insulin. VAT levels of 11beta-HSD1 did not correlate with any of the metabolic variables.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

11beta-HSD1 mRNA levels in subjects with and without metabolic syndrome (MS) and with differing degrees of glucose tolerance in omental (visceral adipose tissue (VAT), striped columns) and in subcutaneous adipose tissue (SAT, solid columns) from 13 obese bariatric surgery patients. The third panel on the right shows mRNA levels in SAT from 62 obese subjects. 11beta-HSD1 mRNA values are relative to beta-glucuronidase (GUSB) expression. IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NGT, normal glucose tolerance.

Full figure and legend (32K)

Relationships between 11beta-HSD1 expression and metabolic alterations in SAT from 62 obese subjects

To confirm that in SAT, higher 11beta-HSD1 expression is associated with the presence of metabolic disorders, we extended the analysis to SAT samples derived from the 49 subjects who underwent periumbilical biopsy. When the data of those 62 obese subjects were pooled, a significant higher expression of 11beta-HSD1 was still present in subjects with the metabolic syndrome compared to those without it (1.8plusminus1.5 vs 1.0plusminus0.4 arbitrary units P<0.01). Diabetic subjects (n=12) had significantly higher levels of 11beta-HSD1 mRNA levels compared to subjects with IGT/IFG (n=10) and NGT (n=40) (P<0.001, Figure 2). 11beta-HSD1 expression in SAT positively correlated with fasting glucose (r=0.487, P<0.0001), triglycerides (r=0.318, P<0.05) and urinary-free cortisol (r=0.396, P<0.01) and negatively correlated with HDL cholesterol (r=-0.392, P<0.01), but not with waist circumference, BMI, fasting insulin or BP. A multivariate regression analysis with 11beta-HSD1 mRNA as a dependent variable revealed that fasting glucose and urinary-free cortisol were independently related to SAT 11beta-HSD1 expression (beta=0.460, P<0.0001; beta=0.423, P<0.001).

In the logistic regression analysis, obese subjects in the third tertile of SAT 11beta-HSD1 expression had a significantly higher risk of type 2 diabetes (OR 9.6; 95% CI, 1.0–88.6; P<0.05) and metabolic syndrome when compared to those in the first tertile (OR, 8.0; 95% CI, 1.7–36.7; P<0.01).

H6PDH expression in adipose tissue

In order to demonstrate that 11beta-HSD1 expression reflects the reductase activity of the enzyme driving cortisol production, we evaluated whether its expression was paralleled by that of the colocalizing enzyme H6PDH which has been shown to be critical for its reductase activity.21

The results obtained indicated that H6PDH mRNA levels were correlated with urinary-free cortisol concentrations (r=0.307, P<0.05) and with the expression of 11beta-HSD1 (r=0.326, P<0.01) in SAT, but not in VAT.

Relationships between 11beta-HSD1 expression in adipose tissue, adiponectin and TNFalpha

After adjustment for sex and BMI, expression levels of adiponectin in SAT were positively correlated with urinary-free cortisol (r=0.308, P<0.05) and increased with the increase in 11beta-HSD1 expression (17.2 3.5 vs 24.8plusminus4.1 arbitrary units, P<0.05 in the I vs III tertile of 11beta-HSD1 mRNA levels). Conversely, serum adiponectin levels decreased with increased 11beta-HSD1 expression in SAT (5.1plusminus0.2 vs 4.4plusminus0.6 mug/ml, P<0.05). TNFalpha mRNA increased, with no changes in serum levels, with increased 11beta-HSD1 expression (0.02plusminus0.01 vs 0.06plusminus0.01 arbitrary units, P<0.05). In VAT, 11beta-HSD1 mRNA levels were not related to expression or serum levels of adiponectin and TNFalpha (data not shown).

Adiponectin expression in SAT and serum adiponectin levels were lower in subjects with metabolic disorders (15.5plusminus5.1 vs 21.3plusminus13.1 arbitrary units, P<0.05 and 4.3plusminus2.5 vs 5.4plusminus2.4 mug/ml, P<0.05 in subjects with vs those without metabolic syndrome; 15.7plusminus5.7 vs 21.1plusminus12.9 arbitrary units, P=0.05 and 3.5plusminus2.2 vs 5.4plusminus2.4 mug/ml, P<0.05 in diabetic vs NGT subjects). Obese diabetic subjects compared to those with NGT had higher serum TNFalpha levels (13.7plusminus7.8 vs 8.7plusminus5.2 pg/ml, P<0.01), but similar TNFalpha expression in SAT.



We have shown that VAT express higher amounts of 11beta-HSD1 than SAT in the majority of obese subjects and that mRNA levels of 11beta-HSD1 are associated with metabolic disorders in SAT, but not in VAT. The few previous studies evaluating the expression of the enzyme in different fat compartments are not univocal reporting both similar mRNA levels of the enzyme in whole adipose tissue and adipocytes from VAT and SAT17, 18, 19 and higher 11beta-HSD1 expression in preadipocytes from VAT.16 These discrepancies might be explained by a high interindividual variability as also demonstrated by the finding that not all obese subjects in our cohort displayed higher expressions of the enzyme in VAT than in SAT.

Consistent with our results, Goedecke et al.18 have recently reported an association between the expression/activity of 11beta-HSD1 and metabolic variables in SAT, but not in VAT from South African women. These findings suggest that all fat depots may contribute to the development of metabolic disorders. In this context, it has been shown that SAT contributes to free fatty acid production to a higher extent than VAT22 and overall abdominal obesity equally predict the development of type 2 diabetes.23

We demonstrated that 11beta-HSD1 expression in SAT is associated with glucose intolerance, since (1) it was independently related to fasting glucose, (2) it increased in IGT/IFG and type 2 diabetes compared to NGT and (3) it increased the risk of diabetes. Previous studies in SAT from small cohorts did not find differences in in vitro 11beta-HSD1 activity in diabetic and nondiabetic subjects24 and reported a slightly higher 11beta-HSD1 expression in diabetic than in nondiabetic subjects.13 The higher 11beta-HSD1 expression that we observed in diabetic patients compared to NGT subjects is in line with the results obtained in myotubes from obese diabetic subjects9 and agree with the demonstration, in diabetic mice, that rosiglitazone reduces adipose tissue expression of 11beta-HSD1.25 We did not find associations between 11beta-HSD1 mRNA levels and measures of obesity. This is in contrast with what reported in some but not all previous studies.10, 19, 26, 27 Indeed, several reports were not able to confirm the relationship between obesity, weight changes and 11beta-HSD1 expression in whole adipose tissue and adipocytes.17, 18, 26, 28, 29 Furthermore, it was also reported that the 11beta-HSD1 activity in SAT is not correlated with BMI in presence of metabolic alterations,30 a condition that accounts for 45% of the patients enrolled in this study. An additional reason for the lack of association between 11beta-HSD1 expression and obesity might be the narrow BMI range in our patients who were all obese. Another interesting finding of this study is the positive relation found between urinary-free cortisol levels and both 11beta-HSD1 and H6PDH expression in SAT. Consistent with these data, H6PDH knockout mice were reported to have reduced plasma corticosterone levels.31 This evidence, together with the demonstration that tissues draining into the portal vein, including VAT, substantially contribute to systemic cortisol production in healthy men,24 suggests that cortisol produced in adipose tissue might contribute to total cortisol production. The alternative hypothesis that cortisol coming from plasma to adipose tissue by diffusion, might modulate 11beta-HSD1 gene transcription16, 26 seems unlikely because hypercortisolemic and normocortisolemic subjects have similar 11beta-HSD1 mRNA levels in SAT.32

We hypothesized that one of the mechanism by which higher adipose cortisol reactivation in SAT may compromise glucose tolerance might be through the modulation of adiponectin and TNFalpha production and/or release. Supporting this hypothesis and in accord with the negative association reported in diabetic subjects between 11beta-HSD1 activity and serum adiponectin,30 we observed a decrease in serum adiponectin levels with increased 11beta-HSD1 expression.

Surprisingly, adiponectin expression in SAT followed an opposite trend since it increased with increased 11beta-HSD1 expression and urinary-free cortisol levels. This is in contrast with what is reported in mice33 and is not easy to explain. It may be hypothesized that in humans, local glucocorticoids exert an inhibitory effect on adiponectin release, creating a compensatory increase in adiponectin gene transcription. This hypothesis is supported by the demonstration that dexamethasone inhibits adiponectin release from human adipocytes34 and decreases serum adiponectin levels.35 Subjects with metabolic abnormalities would not show increased adiponectin mRNA levels because of their high TNFalpha and insulin levels that would downregulate adiponectin synthesis.36

Finally, we reported that in SAT, TNFalpha expression increased in parallel with 11beta-HSD1 expression and this is in keeping with the evidence that TNFalpha increases 11beta-HSD1 transcription in human adipose tissue.37, 38 The hypothesized decrease in adiponectin release would contribute to increase TNFalpha mRNA levels due to the hampering effect of this protein on TNFalpha transcription.39

In conclusion, our study showed that in obese subjects, increased 11beta-HSD1 expression in SAT, but not in VAT, is associated with the worsening of metabolic conditions. Based on these observations, it is tempting to speculate that higher glucocorticoid regeneration in adipose tissue would favor the development of metabolic disorders through a decrease in adiponectin release.



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This work was supported by the Grant 195-2003 from the Italian Ministry of Health.

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