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Local and Systemic Impact of Transcriptional Up-Regulation of 11ß-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue in Human Obesity

Endocrinology Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital (D.J.W., D.E.W.L., B.R.W.), Edinburgh, Scotland EH4 2XU; and Department of Medicine, Umea University Hospital (E.R., S.S., T.O.), Umea, S-901 85 Sweden

Address all correspondence and requests for reprints to: Prof. Tommy Olsson, Department of Medicine, Umea University Hospital, Umea, Sweden. E-mail: tommy.olsson{at}medicin.umu.se.

	Abstract

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In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11ß-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized ß coefficient (SBC) = 0.58; P < 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P < 0.05 for activity, and SBC = 0.63; P < 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P < 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR- and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P < 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P < 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 ± 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
11ß-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (11HSD1) is a potential target for pharmacological inhibition in obesity and the metabolic syndrome. It catalyzes the conversion of inactive cortisone to active cortisol, thereby amplifying activation of intracellular glucocorticoid receptors (GR), e.g. in adipose and liver (1). The potential importance of 11HSD1 in the metabolic syndrome is illustrated by experiments in rodents. In obese Zucker rats (2), 11HSD1 activity is increased selectively in adipose tissue and decreased in the liver. Selective overexpression of 11HSD1 in white adipose tissue under the AP2 promoter/enhancer results in central obesity, dyslipidemia, and insulin resistance (3). Conversely, homozygous 11HSD1 knockout mice are protected from features of the metabolic syndrome (4).

Whether similar tissue-specific dysregulation of 11HSD1 occurs in human obesity has been controversial. Conversion of oral cortisone to cortisol on first-pass metabolism in the liver is consistently impaired in obese individuals (5, 6, 7), indicating impaired hepatic 11HSD1. We reported that sc adipose 11HSD1 activity in homogenized whole biopsies was positively correlated with parameters of obesity and insulin resistance in cohorts of men (6) and women (7). Paulmyer-Lacroix et al. (8) and Lindsay et al. (9) supported these findings, showing increased sc adipose 11HSD1 mRNA in obese subjects using semiquantitative in situ hybridization and real-time PCR respectively. However, Tomlinson et al. (10) recently showed no correlation of 11HSD1 mRNA (using real-time PCR) with obesity in either sc or omental adipose biopsies taken from women undergoing elective surgery and further showed that 11HSD1 activity in omental preadipocytes in primary culture was inversely correlated with body mass index (BMI). It has been suggested that measurement of in vitro 11HSD1 in adipose homogenates in the dehydrogenase (cortisol to cortisone) direction, rather than the reductase (cortisone to cortisol) direction, which is predominant in whole cells, may have yielded spurious associations with obesity (10). This appears unlikely because the dehydrogenase direction has consistently been shown to be both predominant and more stable when 11HSD1 is liberated from its intracellular environment in homogenized tissue (1) and, in the conditions used, is proportionate to the amount of protein in the incubation and hence is proportionate to total 11HSD1 protein. Nonetheless, it is important now to validate whether the increased activity we have measured in homogenized adipose tissue reflects increased 11HSD1 gene transcription. More conventional measurements of in vivo 11HSD activities, such as urinary ratios of cortisol/cortisone metabolites, have been unhelpful in resolving this controversy. This ratio is inconsistently altered in obesity, being reported as increased (7, 11, 12), decreased (5, 6), or unaltered (13, 14). This may reflect a different balance between down-regulation of 11HSD1 in liver and up-regulation of 11HSD1 in adipose in groups with different anthropometric characteristics.

There is further uncertainty concerning the impact of altered adipose 11HSD1 on the severity of obesity and its metabolic complications in humans. Complications of obesity include hypertension, dyslipidemia, and insulin resistance. A number of key genes controlling these metabolic processes in adipose are glucocorticoid regulated (e.g. angiotensinogen, lipoprotein lipase, glucose transporter 4, and leptin). In mice with adipose 11HSD1 overexpression, intraadipose corticosterone levels and angiotensinogen and leptin mRNA are elevated (3). Increased intraadipose cortisol (generated by 11HSD1) and GR activation may be important in the generation of downstream metabolic consequences of obesity and as such may be a useful target for pharmacological inhibition in humans. To date, however, the metabolic effects of inhibition of human 11HSD1 with carbenoxolone have been reported only in healthy lean men (15) and in lean men with type 2 diabetes (16), in whom it has been shown to enhance hepatic insulin sensitivity, but not peripheral glucose uptake.

In this study we report additional investigations using aliquots from the sc adipose biopsies from our previous two studies (6, 7). We investigated whether adipose 11HSD1 is transcriptionally up-regulated in obesity, explains variations in cortisol/cortisone metabolite ratio in vivo, and is associated with measurable changes in intraadipose cortisol levels and glucocorticoid-dependent gene transcription. We also examined the balance between 11HSD1 and GR expression in determining obesity and insulin sensitivity.

	Subjects and Methods

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Subjects

Subjects were recruited from a population-based study in northern Sweden, the WHO-conducted MONICA Project. From an original random sample of 2815 women and men, 41 Caucasian women and 40 men were selected to represent high and low fasting insulin concentrations and a wide range of BMIs. Investigations in these groups have been reported previously (6, 7) A subgroup of these subjects, selected at random (16 females and 16 males), attended in the morning after an overnight fast. After local anesthetic injection of prilocaine (10 mg/ml; Citanest, Astra, Sodertalje, Sweden) in the skin area to the right of the umbilicus, approximately 1.5 cm² sc fat were excised through a 2- to 3-cm incision and frozen immediately in two aliquots at -70 C.

Diabetes mellitus and liver, renal, and thyroid disease were excluded by routine laboratory tests. In the pre- and perimenopausal women, investigations were performed in the follicular phase of the menstrual cycle (5–10 d after starting menstruation). These studies were approved by the ethics committee of Umea University Hospital, and written informed consent was obtained.

Previous clinical and biochemical measurements

Measurements, as described previously (6, 7), included baseline anthropometry, blood pressure, and body composition. Insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp technique. Cortisol metabolites were measured in 24-h urine samples by gas chromatography and electron impact mass spectrometry. The conversion of cortisone to cortisol by 11HSD1 on first pass through the liver was measured in vivo after subjects took oral dexamethasone (3.5 µg/kg body weight) at 2300 h, fasted overnight, and presented at 0830 h for iv cannulation and oral cortisone acetate (25 mg).

Adipose 11HSD1 activity was measured in one aliquot of the biopsies as previously described (6, 7) by homogenizing in Krebs buffer, pH 7.4, and incubating 750 µg/ml protein at 37 C with NADP (2 mM) and [1,2,6,7-³H₄]cortisol (100 nM) for 30 h. Samples were withdrawn at 3, 6, 20, and 30 h for separation of cortisol and cortisone by HPLC with on-line liquid scintillation detection. In 5 of the 32 biopsies, either biopsy material was not available at the time of analysis or insufficient protein concentrations were obtained in the homogenate to allow measurement of 11HSD1 enzyme activity under these conditions.

Adipose mRNAs for 11HSD1, GR, GRß, angiotensinogen, and leptin

A second aliquot of the biopsy was analyzed for mRNA (in samples where sufficient biopsy material remained (n = 27)). Approximately 500 mg fat were homogenized in 1.5 ml TRIzol (registered trademark of Life Technologies, Inc., Gaithersburg, MD), and RNA was purified using RNAid RNA binding matrix (Anachem, Luton, UK), washed three times, and dissociated by addition of diethylpyrocarbonate H₂O/dithiothreitol/RNAsin. RNA was quantified using spectrophotometric analysis at OD₂₆₀. RNA integrity was checked by agarose gel electrophoresis. Oligo(deoxythymidine)-primed cDNA was synthesized from 0.5 µg RNA samples using the Promega Reverse Transcription System (Madison, WI). PCR amplification using GR and angiotensinogen primers confirmed successful cDNA synthesis. Transcript level quantification for 11HSD1, GR, GRß, angiotensinogen, and leptin was performed with real-time PCR primer-probe sets using the ABI PRISM 7700 Sequence Detection System (PE Applied Biosystems, Cheshire, UK) with the following primers and probes: 11HSD1, 5'-GGAATATTCAGTGTCCAGGGTCAA-3' (forward), 5'-TGATCTCCAGGGCACATTCCT-3' (reverse), and 5'-6-FAM-CTTGGCCTCATAGACACAGAAACAGCCA-TAMRA-3' (probe); GR, 5'-CATTGTCAAGAGGGAAGGAAACTC-3' (forward), 5'-GATTTTCAACCACTTCATGCATAGAA-3' (reverse), and 5'-6-FAM-TTTGTCAGTTGATAAAACCGCTGCCAGTTCT-TAMRA-3'(probe); GRß, 5'-CATTGTCAAGAGGGAAGGAAACTC-3' (forward), 5'-TAACCACATAACATTTTCATGCATAGAAT-3' (reverse), and 5'-6-FAM-TTTGTCAGTTGATAAAACCGCTGCCAGTTCT-TAMRA-3' (probe); angiotensinogen, 5'-TCTCCCCGGACCATCCA-3' (forward), 5'-TGCTCAATTTTTGCAGGTTCAG-3' (reverse), 5'-6-FAM-CCATGCCCCAACTGGTGCTGCTAMRA3' (probe); and leptin, 5'-CATTTCACACACGCAGTCAGTCT-3' (forward), 5'-TGTCTGGTCCATCTTGGATAAGGT-3' (reverse), and 5'-6-FAM-AACAGAAAGTCACCGGTTTGGACTTCATTCC-TAMRA-3' (probe).

Human cyclophyllin (PE Applied Biosystems) primers/probes were included in a multiplex reaction with the probes/primers for the gene of interest to normalize the transcript levels. Each sample was run in duplicate, and the mean values of the duplicates were used to calculate transcript level. Values were calculated as a relative fold change in mRNA from an internal control sample. RT negative controls and intron spanning primers were used to examine for genomic DNA and prevent amplification

Intraadipose cortisol and cortisone levels

After 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 Pharmacia Biotech, Little Chalfont, UK) were added to the homogenate to correct for steroid extraction efficiency. Samples was centrifuged to remove the lipid layer and extracted on a Sep-Pak (C₁₈ cartridges, Waters, Watford, UK), further purified with hexane, and reextracted with ethyl acetate. Sample extracts were assayed using a RIA for cortisone (17) and a cortisol ELISA (Salimetrics LLC, State College, PA). These methods produced similar results to RIAs after HPLC separation of cortisone and cortisol (not shown). Extraction efficiency for each sample was assessed by recovery of the ³H-labeled steroid. Steroid concentrations are expressed per gram of wet weight of adipose tissue after adjustment for extraction efficiency. Steroid extraction efficiency was 28.4 ± 1.2% (mean ± SEM).

Statistics

Data are the mean ± SEM unless otherwise stated. Where indicated, data were naturally log-transformed to obtain a normal distribution for parametric testing. Areas under the curve for 11HSD1 activity in vitro and conversion of cortisone to cortisol in vivo were calculated using the trapezoidal rule. Results in men and women were compared by t tests. Multiple regression analyses were employed to adjust for the influence of gender, and standardized ß coefficients (SBC) are presented. P < 0.05 was considered to indicate statistical significance.

	Results

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Subject characteristics

The characteristics of the participants are shown in Table 1. Men had lower percentage body fat; lower urinary cortisol/cortisone metabolite ratios; lower high density lipoprotein cholesterol, angiotensinogen, and leptin mRNA levels; and higher waist/hip ratios than women. Other variables did not differ significantly.

Adipose 11HSD1 activity and mRNA levels were associated with each other (Fig. 1) and with parameters of obesity and insulin resistance (Fig. 2). To minimize potential confounding by effects of gender, relationships with obesity and other metabolic variables were adjusted for gender in multiple regression analyses. Further, BMI was chosen as the measurement of obesity in multiple regression because it was distributed similarly between men and women (unlike waist circumference, waist/hip ratio, or percentage fat). Results are shown in Table 2. Higher 11HSD1 activity was associated with both obesity and fasting hyperinsulinemia, whereas higher 11HSD1 mRNA was significantly associated with obesity alone. In multiple regression analyses, the influence of BMI on adipose 11HSD1 activity was adjusted for insulin sensitivity and vice versa; associations of BMI and insulin sensitivity with 11HSD1 activity or mRNA could not be shown to be independent of each other in these models (data not shown). Neither 11HSD1 activity nor mRNA was associated with in vivo urinary cortisol/cortisone metabolites ratios.

View larger version (16K): [in this window] [in a new window]   FIG. 1. 11HSD1 mRNA levels and in vitro activity correlate in sc adipose biopsies in men (open circles; n = 13) and women (filled squares; n = 14). 11HSD1 mRNA levels were analyzed by real time PCR and expressed as a ratio against cyclophyllin mRNA. 11HSD1 activity is calculated as area under the curve of percentage conversion of cortisol to cortisone after incubation for 3, 6, 20, and 30 h.

View larger version (24K): [in this window] [in a new window]   FIG. 2. Associations of 11HSD1 mRNA (a and c) or 11HSD1 activity (b and d) with body mass index (BMI; a and b) or fasting plasma insulin (c and d) in sc adipose biopsies in men (open circles; n = 13) and women (filled squares; n = 14). 11HSD1 mRNA levels were analyzed by real time PCR and expressed as a ratio against cyclophyllin mRNA. 11HSD1 activity was calculated as area under the curve of percentage conversion of cortisol to cortisone after incubation for 3, 6, 20, and 30 h.

Tissue cortisol and cortisone concentrations are shown in Table 1. Values were log-transformed for analysis. Neither correlated with adipose 11HSD1 enzyme activity or mRNA. Higher intraadipose cortisol was associated with higher plasma cortisol levels after oral cortisone administration (Table 2) and nonsignificantly with cortisol levels at 0900 (SBC = 0.41; P = 0.06) and after overnight dexamethasone (SBC = 0.34; P = 0.18).

GR mRNA

GR was the predominant isoform in human adipose (mean of 26.7 cycles in real-time PCR vs. 37.5 cycles for GRß). GR mRNA showed no significant correlations with parameters of obesity or hyperinsulinemia (although trends were toward inverse correlations; Table 2). To test a possible interaction between 11HSD1 and GR expression in predicting obesity and insulin resistance, multiple regression analyses were performed. These did not suggest any interaction and did not attenuate the relationships shown in Table 2 (data not shown).

Glucocorticoid-regulated target gene expression

Angiotensinogen mRNA levels were higher in women (Table 1). There were no significant relationships with clinical parameters of obesity, insulin resistance, or hypertension or with adipose cortisol levels, 11HSD1 activity, or 11HSD1 mRNA (data not shown). Adipose leptin mRNA levels were higher in women (Table 1) and were positively associated with parameters of obesity, fasting insulin levels (Table 2), 11HSD1 activity (SBC = 0.59; P < 0.05), and mRNA levels (SBC = 0.40; P = 0.15) and negatively associated with plasma cortisol after oral cortisone (Table 2). In multiple regression, 11HSD1 activity was an independent predictor of leptin mRNA over and above the effects of obesity (percentage fat or BMI) and gender.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
These data confirm that increased ex vivo 11HSD1 activity in sc adipose biopsies in obesity is associated with increased 11HSD1 mRNA levels. The strong association between activity and mRNA for 11HSD1 validates the use of the activity assay, measuring dehydrogenase conversion of cortisol to cortisone, as an index of total 11HSD1 protein. A previous study in which 11HSD1 mRNA in homogenized adipose tissue and activity in cultured cells were not correlated with BMI (10) may be different because of the influence of stress during major surgery when the biopsies were collected and because the known plasticity of 11HSD1 in primary culture (18) may cause the cells to lose their in vivo phenotype. The current results are consistent with a series of reports that in vitro adipose 11HSD1 activity and/or mRNA correlated with obesity (7, 8, 9).

What none of these studies have addressed, however, is whether adipose regeneration of cortisol from cortisone is increased in vivo in obesity. These are difficult measurements to make; a previous attempt using arteriovenous sampling in large numbers of patients showed a strong trend that was not quite statistically significant (19). Here we sought to assess the impact of transcriptional up-regulation of 11HSD1 in obesity by further investigation of the biopsied material. Intraadipose cortisol concentrations were not measurably increased in subjects with higher adipose 11HSD1; rather, these correlated with plasma cortisol levels taken at other times and may be determined primarily by stress at the time of biopsy; unfortunately, simultaneous blood samples were not obtained at the time of biopsy to confirm this. Other studies suggest that subjects with insulin resistance and the metabolic syndrome may be more susceptible to elevated plasma cortisol during invasive procedures (20). However, the circumstances in which 11HSD1 is proposed to be most important in maintaining GR activation in key metabolic target tissues such as adipose and liver are not during the diurnal peak of cortisol in the morning (when these biopsies were taken), but during the diurnal nadir, when plasma cortisol is low, but cortisone is maintained as a pool for potential reactivation to cortisol (1). It may be that investigation of adipose cortisol generation in vivo will be more fruitful if performed in resting subjects during the diurnal nadir of cortisol at night.

We also examined mRNA from potential glucocorticoid-regulated genes. Angiotensinogen is produced in liver and adipose tissue. Animal studies suggest that its production is glucocorticoid regulated and contributes to obesity-induced hypertension (21, 22, 23), but human studies show inconsistent relationships of adipose angiotensinogen expression with obesity (24, 25, 26). We found that sc adipose angiotensinogen levels are higher in females (consistent with estrogen induction), but show no relationship with adipose 11HSD1 or parameters of obesity or blood pressure. Visceral adipose tissue was not assessed in this study, and we cannot infer that changes in 11HSD1, GR, intraadipose glucocorticoids, or downstream genes seen here in sc adipose would necessarily be reflected in visceral adipose tissue. Certainly, visceral fat is known to be the more abundant adipose source of angiotensinogen.

Adipose leptin synthesis and secretion are increased by exogenously administered glucocorticoids in vitro and in vivo (27). Adipose-specific transgenic overexpression of 11HSD1 in mice leads to substantial increases in adipose leptin mRNA and serum leptin (3). We demonstrated higher adipose leptin mRNA levels in women. This gender difference is well recognized and is thought to be androgen dependant (28). In contrast with the absence of a relationship with angiotensinogen mRNA, leptin mRNA was positively associated with BMI, fasting insulin levels, 11HSD1 activity, and mRNA levels. Indeed, in multiple regression, 11HSD1 activity was an independent predictor of leptin mRNA over and above the effects of obesity (percentage fat or BMI) and gender. Cortisol generation through 11HSD1 may therefore activate GR and play a major role in promoting leptin transcription. However, this would be anticipated to ameliorate, rather than account for, the metabolic consequences of obesity.

In the current study women tended to have higher adipose 11HSD1 activity and had higher percent body fat than men, but no difference in hepatic 11HSD1 activity. This is consistent with previous studies in nonobese men and women (29). In women, changes in 11HSD1 in adipose may therefore have a more potent effect on whole body cortisol/cortisone equilibrium than in men. This could explain the higher urinary cortisol/cortisone metabolite ratios and their positive association with obesity in women (7). However, in this study no direct association of adipose 11HSD1 and urinary ratios was demonstrated, and we confirmed that urinary ratios provide an inadequate assessment of adipose 11HSD1.

Finally, the current data do not support the hypothesis that differences in GR contribute to the impact of variations in 11HSD1, at least in sc adipose tissue. Hypertension (30), obesity (31, 32), and hyperinsulinemia (33) have been associated with polymorphisms in the GR gene. GR mRNA is increased in the muscle of insulin-resistant individuals (34, 35) and in adipose in some animal models of insulin resistance (36), but has not previously been assessed in human obesity. We found that GR is the dominant isoform in human sc adipose, but its levels did not correlate with any clinical or biochemical parameters. GR expression is markedly higher in visceral than in sc adipose depots (37), so studies of visceral fat may be required to establish its importance in obesity. We can infer from the current data, however, that there is no compensatory decrease in GR in sc fat that would ameliorate the effects of up-regulation of 11HSD1.

In summary, we have demonstrated that 11HSD1 activity and mRNA levels are closely correlated, increased in obesity, and associated with insulin resistance in both men and women. These data support the hypothesis that up-regulation of 11HSD1 in adipose tissue is an important determinant of metabolic complications in obesity. However, it remains to be shown to what extent this impacts on glucocorticoid-dependent processes in vivo, and whether pharmacological inhibition of 11HSD1 (38) will be useful in limiting obesity-induced insulin resistance, hypertension, and dyslipidemia.

	Acknowledgments

 
We thank Ruth Andrew, Inger Arnesjö, Maria Backlund, Jill Campbell, Karen Adamson, Mats Eliasson, Margareta Hedbäck, Owe Johnson, Else-Britt Lundström, Cecilia Nordenson, Cecilia Mattsson, Paska Permana, and Saraswathy Nair for their excellent advice and assistance.

	Footnotes

 
This work was supported by the British Heart Foundation, the Swedish Heart and Lung Foundation, the Swedish Medical Research Council, the Medical Faculty of Umea University, the Northern Councils Cooperation Committee (Visare Norr), and the Heart and Lung Association in Kramfors-Solleftea.

Abbreviations: GR, Glucocorticoid receptor 11HSD1, 11ß-hydroxysteroid dehydrogenase type 1; SBC, standardized ß coefficient.

Received February 20, 2003.

Accepted April 14, 2003.

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