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Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom B15 2TH
Address all correspondence and requests for reprints to: Prof. Paul M. Stewart, Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom B15 2TH. E-mail: p.m.stewart{at}bham.ac.uk
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Abstract |
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In primary cultures of paired omental (om) and sc human adipose stromal cells (ASC; n = 34), 11ßHSD1 oxo-reductase activity was significantly higher in om ASC (median, 40.2 pmol/mg protein·h; 95% confidence interval, 1.8–105) compared with sc ASC (median, 11.4; 95% confidence interval, 0–48.1; P < 0.001) despite similar endogenous NADPH/NADP concentrations. Both cortisol and insulin increased the differentiation of ASC to adipocytes (as assessed by glycerol-3-phosphate dehydrogenase expression), but only cortisol increased 11ßHSD1 activity and messenger RNA levels in a dose-dependent fashion. Cortisone (500 nM) was as effective as 500 nM cortisol in inducing ASC differentiation, but this stimulatory effect was inhibited by coincubation with the 11ßHSD1 inhibitor, glycyrrhetinic acid.
The higher local conversion of cortisone to active cortisol through expression of 11ßHSD1 in om compared with sc ASC may explain the specific action of glucocorticoids on different adipose tissue depots. 11ßHSD1 expression in om ASC is regulated at a transcriptional level and is increased by glucocorticoids, but is not entirely dependent upon ASC differentiation. Inhibition of 11ßHSD1 within om ASC inhibits cortisone-induced ASC differentiation. These findings indicate that local metabolism of glucocorticoid may control differentiation of adipose tissue in a site-specific fashion. Specific inhibitors of 11ßHSD1 may offer a novel approach for the treatment of patients with central obesity.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A key factor in the analysis of corticosteroid hormone action is the activity of the enzyme 11ß-hydroxysteroid dehydrogenase (11ßHSD). Two isozymes of 11ßHSD catalyze the interconversion of hormonally active cortisol (F) and inactive cortisone (E) (10, 11, 12). 11ßHSD type 1 (11ßHSD1) is a low affinity NADP(H)-dependent enzyme that is predominantly expressed in human liver, adrenal, gonad, and decidua. By contrast, 11ßHSD2 is a high affinity NAD-dependent enzyme that inactivates F to E in mineralocorticoid target tissues, such as kidney and colon (11, 12), thereby preventing illicit occupancy of the mineralocorticoid receptor (MR) by F (13, 14). 11ßHSD1 expression has been shown to facilitate glucocorticoid hormone action in liver, skin, gonad, and central nervous system tissues (15, 16). We have recently described 11ßHSD1 immunoreactivity in human adipose tissue (17) and have demonstrated that activity at this site is predominantly reductase (i.e. E to F >> F to E); reductase activity is higher in cultured omental (om) ASC compared with abdominal sc ASC (18). This suggests that om adipose tissue has a greater capacity to generate F from E compared with sc adipose tissue, and based on observations from patients with Cushing’s syndrome, this may be an underlying factor in the pathogenesis of central obesity. The aim of this study was to further investigate the role of 11ßHSD1 expression in human om and sc fat depots. Specifically, we have evaluated the functional consequences of altered 11ßHSD1 expression on adipose tissue differentiation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1–2 g/plate). Cells were allowed to adhere to plastic
overnight in DMEM-Ham’s F-12 medium (DMEM/F12) with 15% FBS
(Life Technologies, Paisley, UK). The next day, cells were
washed and cultured until confluence (7–12 days) in growth medium
(control) or growth medium supplemented with variable concentrations of
insulin (1–500 ng/ml) and/or F (10 nM-1 µM).
For differentiation experiments, cells were allowed to adhere overnight
in DMEM/F12 with 15% FBS, washed, and grown until confluence in
serum-free DMEM/F12 containing attachment supplement (insulin,
transferrin, and selenium; Life Technologies) (5). For 7
days postconfluence, cells were cultured in serum-free medium with the
addition of 500 nM F or E and with or without 5
µM glycyrrhetinic acid (GE), which was previously shown
to totally inhibit 11ßHSD1 activity (19).
11ßHSD1 assays
Monolayers of ASC were washed in 1 x HBSS, and 1 ml fresh
serum-free DMEM/F12 with 0.25 µM E and less than 1.5
nM [3H]E tracer [synthesized in-house as
previously reported (11, 19)] was added to each well. Cells were
incubated in air-5% CO2 at 37 C for 4 h, and the
medium was transferred to a 10-ml glass tube. Cells were lysed, and
protein concentrations were measured using a modification of the
Bradford method (Bio-Rad Laboratories, Inc.,
München, Germany). These conditions ensured first order
kinetics for all of the 11ßHSD1 activity studies (11, 19).
Steroids were extracted from the medium in 10 vol dichloromethane and separated by TLC using chloroform-absolute ethanol (92:8) as the mobile phase. The TLC plates were scanned using Bioscan, Inc. 200 image detector (Lablogic, Sheffield, UK), and the fractional conversion of E to F was calculated and expressed as picomoles of F per mg total protein/h. Enzyme activity studies were carried out in triplicate for each individual patient preparation.
Glucose-6-phosphate dehydrogenase assay (G6PDH)
To investigate whether changes in the activity of the pentose
phosphate pathway (dictating the intracellular NADPH/NADP ratio) could
account for any differences in the relative expression of 11ßHSD1 in
om vs. sc ASC, G6PDH activity assays were carried out in
parallel with 11ßHSD1 activity studies (n = 4, in triplicate).
G6PDH was measured using a commercially available kit (Biozyme
Laboratories Ltd., Blaenavon, UK). Briefly, cultured cells were
lysed, scraped in 100 µl triethanolamine buffer (TEA; 0.1
M; pH 8), and transferred to Eppendorf tubes.
After a protein assay, G6PDH activity was analyzed in a 1-ml total
volume of TEA buffer with 20 µg protein, glucose-6-phosphate (1.27
mM), NADP+ (0.44 mM), and
MgCl2 (6.6 mM). Optical density changes at 340
nm were measured for 30 min at 5-min intervals and expressed as G6PDH
units per mg protein/min; 1 U is the amount of enzyme that caused the
reduction of 1 µmol NADP+/min at 25 C and pH 8.
RNA extraction
After enzyme assays, total RNA was extracted from ASC using a
single step extraction method (RNAzol B, AMS Biotechnology,
Witney, UK). The glucocorticoid receptor (GR) and MR expression studies
were undertaken on freshly isolated ASC or adipocytes from om and sc
sites as described above. Positive controls employed stored RNA samples
from human liver and colon. Unless otherwise stated, all other reagents
for the RNA analyses were purchased from Promega Corp.
(Southampton, UK). RNA integrity was confirmed by electrophoresis on
1% agarose gels, and concentration was assessed by spectrophotometry
at OD260.
RT reaction
Total RNA (0.5 µg) was denatured by heating to 70 C for 10
min. Fifteen units of avian myeloblastosis virus, 100 ng random
hexamers, 10 U ribonuclease inhibitor, and 20 nmol deoxy-NTPs with
5 x reaction buffer were added to a total volume of 20 µl. The
reaction was performed at 37 C for 1 h, and complementary DNA
(cDNA) was heated at 95 C for 10 min to inactivate any remaining
enzymes. For synthesizing GR and MR cDNA template, the above RT
protocol was modified, and 0.5 µg oligo(deoxythymidine)15
primers were used at 42 C for 1 h.
Relative RT-PCR of 11ßHSD type 1, MR, and GR messenger
RNA (mRNA)
QuantumRNA (Quantitative RT-PCR Module, Ambion, Inc., Austin, TX), was used to analyze 11ßHSD1 mRNA levels in
ASC between individual treatments (n = 4). Aliquots (0.5 µg) of
total RNA were reverse transcribed using random hexamers as described
above. 18S ribosomal rRNA (18S rRNA) and 11ßHSD type 1 DNA fragments
of 488 and 571 bp, respectively, were amplified in a one-tube
multiprimer PCR reaction (denaturation at 94 C, annealing at 50 C, and
extension at 72 C, 1 min each for 35 cycles), using human 11ßHSD1
primers as previously described (20). Similarly, using previously
reported methods (20), RT-PCR analysis of GR mRNA expression was
carried out using the following primers: sense,
5'-TCGACCAGTGTTCCAGAGAAC-3'; and antisense,
5'-TTTCGGAACCAACGGGAATTG-3'. Amplification of a 693-bp fragment was
performed using an initial denaturation cycle of 95 C (5 min) followed
by 30 cycles of 94 C (1 min), 55 C (1 min), and 72 C (1 min). Analysis
of MR mRNA expression was carried out using the following primers:
sense, 5'-AACTTGCCTCTTGAGGACCAA-3'; and antisense,
5'-AGAATTCCAGCAGGTCGCTC-3'. Amplification of a 471-bp fragment was
performed using an initial denaturation cycle of 95 C (5 min), followed
by 30 cycles of 94 C (1 min), 54 C (1 min), and 72 C (2 min). A final
elongation step of 72 C for 5 min was included for both GR and MR PCR
amplifications. To test the efficiency of the RT reaction, a 468-bp
fragment of ß-actin, a housekeeping gene, was amplified using 10 pmol
of each sense primer (5'-GTCACCAACTGGGACGACA-3') and antisense primer
(5'-TGGCCATCTCTTGCTCGAA-3') in 10 x reaction buffer with 0.25
mM MgCl2. Amplification was carried out for 30
cycles with a denaturing temperature of 94 C for 1 min, an annealing
temperature of 60 C for 1 min, and an extension step at 72 C for 2
min.
18S rRNA primers were used at a 3:7 ratio to 18S PCR competimers, which ensured linear amplification of this cDNA. Multiprimer amplification of target and endogenous internal control cDNAs, both of similar size, enabled a direct comparison between multiple samples by measuring the relative abundance of target transcript when separated on a 2% MetaPhor agarose gel (FMC Bioproducts, Rockland, ME). The image of the UV-illuminated gels was stored in digital form and analyzed using UVGel software (UV GelBase, UVP Ltd., Cambridge, UK).
G3PDH quantitative (competitive) RT-PCR
Levels of G3PDH mRNA were used as a marker of adipocyte
differentiation as previously reported (21). A quantitative
(competitive) RT-PCR approach employed an exogenous mutant G3PDH
complementary RNA as an internal control (n = 4). This mutant
G3PDH complementary RNA differed from wild-type G3PDH by having a
deleted EcoRI restriction site, permitting the resolution of
wild-type (198-bp) and mutant (220-bp) PCR products when digested with
1 U EcoRI/µl PCR product on 3% (FMC, Rockland, ME)
agarose gel. After a series of studies to define the linearity of this
reaction, 5 pg mutant G3PDH/0.5 µg total RNA were transcribed using
random hexamers as described above. Two microliters of this 50-µl
reaction were used for amplification (denaturation at 94 C, annealing
at 60 C, and extension at 72 C for 1 min each, 35 cycles). The relative
changes in wild-type/mutant mRNA levels were assessed by measuring the
area ratios in amplified DNA fragments using an image analyzer and
UVGel software.
G3PDH enzyme assay
The G3PDH enzyme assay was carried out using a previously
reported methodology (22). Monolayers of cultured human ASC were
disrupted by storage at -80 C. Enzyme assays were performed in a 1-ml
total volume of 0.1 M TEA buffer (pH 7.6) with 0.1% BSA,
0.8 mM dihydroxyacetone phosphate (substrate), 0.2
mM NADH, and 10 µg cellular protein. The rate of decrease
in absorbance at 340 nm was followed spectrophotometrically for 30 min
at 5-min intervals. In each assay, dilutions of a G3PDH standard
(0.0125 U/ml; Sigma Chemical Co.) were analyzed, and G3PDH
activity was expressed as units per mg protein; 1 U is the amount of
enzyme that catalyzed the conversion of 1 nmol dihydroxyacteone
phosphate to 
-glycerophosphate/min at 25 C (pH 7.6).
Data were expressed as the median and 5th-95th percentile (for nonparametric data) or as the mean ± SE (for normally distributed data), and statistical analysis between groups was performed as appropriate, using either the Mann-Whitney U test or Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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]. Dose-response studies carried out on
om ASC cells indicated that this induction of 11-oxo-reductase activity
was maximal at F concentrations of 500-1000 nM (Table 1).
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, a
and b).
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). After
35 cycles of PCR, very weak expression of MR mRNA was observed in sc
and om ASC. The relative expression of GR mRNA was much higher (Fig. 3).
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) and 11ßHSD1 mRNA (control,
22.2 ± 3.2; F, 45.1 ± 9.2 11ßHSD/18S, arbitrary units;
Fig. 4, b and c) was not entirely dependent upon the process of
adipocyte differentiation. Using G3PDH as a marker of ASC
differentiation, cotreatment with insulin and F resulted in an
independent and synergistic increase in ASC differentiation (control,
1.0 ± 0.9; insulin, 11.2 ± 0.7; F, 43.4 ± 3.1; F plus
insulin, 79.3 ± 11.3, wild-type/mutant G3PDH mRNA; Fig. 5), which was also reflected in G3PDH
enzyme activity (control, 3.9 ± 0.7; insulin, 5.5 ± 1.0; F,
6.1 ± 0.6; F plus insulin, 7.0 ± 0.02 U/mg protein·min).
Only F increased 11ßHSD1 activity (Fig. 4a) and mRNA levels (Fig. 4b); insulin had no effect (e.g. 11ßHSD1 activity with F
was 110 ± 25.5 and with F plus insulin was 97.3 ± 20.4
pmol/mg·h; Fig. 4a).
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. F and E in doses of 500
nM caused a similar induction of G3PDH activity (control,
3.5 ± 0.5; F, 7.8 ± 0.9; E, 6.1 ± 0.5 U/mg
protein·min). GE (5 µM) itself had no effect on ASC
differentiation (control plus GE, 4.1 ± 0.6 U/mg protein·min),
but by blocking the conversion of E to F resulted in an inhibition of
E-induced ASC differentiation (3.9 ± 0.7 U/mg protein·min; Fig. 6, a and b). GE did not inhibit F-induced ASC differentiation (data not
shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There are many precedents for the autocrine or paracrine control of
hormone action through the local metabolism of steroid hormones, for
example 5-reductase and the actions of testosterone (29) and
aromatase and the peripheral activity of estrogens (30). Perhaps the
best example, however, relates to 11ßHSD and corticosteroid hormone
action. 11ßHSD2 is a high affinity dehydrogenase expressed in kidney,
colon, and salivary gland. This enzyme inactivates F to E, enabling
aldosterone to bind to the MR in vivo (13, 14). Deficiency
of 11ßHSD2, either inherited in the syndrome of apparent
mineralocorticoid excess (31, 32) or acquired after licorice ingestion
(33), results in F gaining access to the MR to act as a potent
mineralocorticoid. By contrast, 11ßHSD1 acts as a reductase in
vivo, generating F from E, and has been shown to facilitate
glucocorticoid hormone action at keys sites, including the liver and
central nervous system (15, 16). Circulating E is principally derived
from the activity of renal 11ßHSD2, with circulating concentrations
approximately 1/10th those of F (34). However, E has a much lower
affinity for F-binding globulin than F, and free levels are probably
more similar. The characterization of 11ßHSD within adipose tissue
has shown the presence of 11ßHSD1, but not 11ßHSD2 (17, 18), in
keeping with a functional role for 11ßHSD1 in modulating tissue
glucocorticoid hormone action. Specifically, our data suggest a crucial
role for 11ßHSD1 in regulating the process of glucocorticoid-induced
ASC differentiation. E, through its conversion to F by 11ßHSD1, was
shown to stimulate ASC differentiation as effectively as F itself.
Inhibition of 11ßHSD1 by GE, the active component of licorice,
resulted in a significant inhibition of E-induced ASC differentiation.
GE is known to inhibit 11ßHSD2 as well as 11ßHSD1 (11, 12, 35) and
was used in these experiments in the absence of a specific 11ßHSD1
inhibitor. Although aldosterone has been shown to induce
differentiation of the mouse 3T3-L1 cell line via the MR (36), we were
unable to demonstrate appreciable levels of MR mRNA in either ASC or
adipocytes. By contrast, abundant GR mRNA was expressed in keeping with
earlier observations (23, 25), and it seems likely, therefore, that
11ßHSD1 is indeed modulating active glucocorticoid exposure to the
GR.
11ßHSD1 is a NADP(H)-dependent enzyme, and it is of some interest
that the principal sites of expression of this enzyme in human tissues
are those with the highest redox potential (10, 17), manifested as the
NADPH/NADP ratio. To investigate whether the availability of cofactor
could be a rate-limiting factor in explaining the higher om compared
with sc expression, assays of G6PDH, the first enzyme involved in the
pentose phosphate pathway, were undertaken. This pathway is responsible
for the production of pentose phosphates for DNA and RNA biosynthesis
and for the intracellular generation of reducing agent (NADPH) for
pathways that require NADPH as an essential cofactor, such as 11ßHSD1
and fatty acid synthesis. No differences were observed in G6PDH
activity between om and sc sites, suggesting that endogenous cofactor
concentrations are not rate limiting in determining 11ßHSD1
expression. The control of 11ßHSD1 mRNA and activity within ASC,
however, was subject to "fast forward" feedback in a dose-dependent
fashion by the substrate (F) itself, and this was more pronounced in om
compared with sc ASC. Glucocorticoids have been shown to regulate
11ßHSD1 expression at other sites (37, 38), and there are several
putative glucocorticoid response elements within the promoter region of
the human 11ßHSD1 gene. Other factors known to regulate ASC function,
such as CAAT enhancer-binding protein- (C/EBP), are also known to
stimulate 11ßHSD1 gene expression (39), and further studies
addressing the transcriptional control of 11ßHSD1 expression within
human ASC are required. Insulin, however, failed to stimulate 11ßHSD1
expression; on the contrary, it attenuated the glucocorticoid induction
of 11ßHSD1 mRNA and activity in keeping with earlier activity studies
carried out on skin fibroblasts (40) and cultured hepatocytes (37, 38).
This occurred despite stimulation of ASC differentiation in the
presence of insulin and glucocorticoids, suggesting that the induction
of 11ßHSD1 expression in ASC upon exposure to F is not entirely
dependent upon the differentiation process. It remains to be seen
whether this inhibitory effect of insulin is of relevance in subjects
with common insulin-resistant states such as type 2 diabetes
mellitus.
In summary, the enhanced expression of 11ßHSD1 and hence the generation of active F from E in om compared with sc ASC offers a novel explanation for the differential effects of glucocorticoids on regional depots of adipose tissue. The increased expression of 11ßHSD1 in om ASC cannot be explained on the basis of an alteration in redox potential at this site. Its expression is increased by glucocorticoids and attenuated by insulin through a process that appears to be transcriptionally regulated and not entirely dependent upon differentiation of ASC to mature adipocytes. Inhibition of 11ßHSD1 activity inhibits the differentiation of ASC by E; the future development of specific 11ßHSD inhibitors may represent a novel approach in the treatment of metabolic disorders linked to central obesity. To date, there are no specific inhibitors of 11ßHSD1 to test this hypothesis in clinical studies, but as the human 11ßHSD1 and 11ßHSD2 enzymes share only 14% identity (10, 12), it seems likely that selective inhibitors of 11ßHSD1 will emerge.
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Acknowledgments |
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Footnotes |
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2 Medical Research Council Senior Clinical Fellow.
Received November 25, 1998.
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References |
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-reductase:
two genes/two enzymes. Annu Rev Biochem 63:25–61[Medline]
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