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Division of Medical Sciences, Queen Elizabeth Hospital, University of Birmingham (J.W.T., J.M., M.S.C., I.B., M.H., P.M.S.), Birmingham, United Kingdom B15 2TH; Department of Genitourinary Medicine, Selly Oak Hospital (M.S.), Birmingham, United Kingdom B29 6JD; Department of Hepatology, Queen Elizabeth Hospital, University of Birmingham (C.S., A.S.), United Kingdom B15 2TH
Address all correspondence and requests for reprints to: Prof. P. M. Stewart, M.D., F.R.C.P., F.Med.Sci. Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom B15 2TH. E-mail: p.m.stewart{at}bham.ac.uk
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Treatment with tumor necrosis factor-
(TNF) caused a
dose-dependent increase in 11ßHSD1 activity in primary cultures of
both sc [1743.1 ± 1015.4% (TNF, 10 ng/ml);
P < 0.05 vs. control (100%)] and
omental [375.8 ± 57.0% (TNF, 10 ng/ml);
P < 0.01 vs. control (100%)] ASC,
but had no effect on activity in human hepatocytes [90.2 ± 2.8%
(TNF, 10 ng/ml); P = NS vs.
control (100%)]. Insulin-like growth factor I (IGF-I) caused a
dose-dependent inhibition of 11ßHSD1 activity in sc [49.7 ±
15.0% (IGF-I, 100 ng/ml]; P < 0.05
vs. control (100%)] and omental [71.6 ± 7.5
(IGF-I, 100 ng/ml); P < 0.01 vs.
control (100%)] stromal cells, but not in human hepatocytes
[101.8 ± 15.7% (IGF-I, 100 ng/ml); P = NS
vs. control (100%)]. Leptin treatment did not alter
11ßHSD1 activity in human hepatocytes, but increased activity in
omental ASC [135.8 ± 14.1% (leptin, 100 ng/ml);
P = 0.08 vs. control (100%)].
Treatment with interleukin-1ß induced 11ßHSD1 activity and
expression in sc and omental ASC in a time- and dose-dependent manner.
15-Deoxy-
12,14-PGJ2, the putative endogenous ligand of the orphan
nuclear receptor peroxisome proliferator-
, significantly increased
11ßHSD1 activity in omental cells [179.7 ± 29.6% (1
µM); P < 0.05 vs.
control (100%)] and sc [185.3 ± 12.6% (1 µM);
P < 0.01 vs. control (100%)] ASC,
and it is possible that expression of this ligand may ensure continued
cortisol generation to permit adipocyte differentiation. Protease
inhibitors used in the treatment of human immunodeficiency virus
infection are known to cause a lipodystrophic syndrome and central
obesity, but saquinavir, indinavir, and neflinavir caused a
dose-dependent inhibition of 11ßHSD1 activity in primary cultures of
human omental ASC.
11ßHSD1 expression is increased in human adipose tissue by
TNF, interleukin-1ß, leptin, and orphan nuclear receptor
peroxisome proliferator- agonists, but is inhibited by IGF-I. This
autocrine and/or paracrine regulation is tissue specific and explains
recent clinical data and animal studies evaluating cortisol metabolism
in obesity. Tissue-specific 11ßHSD1 regulation offers the potential
for selective enzyme inhibition within adipose tissue as a novel
therapy for visceral obesity.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(TNF), and leptin] produced locally by mature adipocytes may
differentially regulate 11ßHSD1.
As adipocytes mature and differentiate, expression of the orphan
nuclear receptor peroxisome proliferator- (PPAR) increases
(8). Although still debated, it is likely that 15
deoxy-12,14-prostaglandin J2 (15D-PGJ2) represents the endogenous
ligand to this receptor (9, 10). To assess whether the
known effects of this agent on adipocyte development could be mediated
at least in part through cortisol metabolism, we treated cultures of
omental and sc ASC with 15D-PGJ2 and determined its effect on 11ßHSD1
activity.
Within adipose tissue, modulation of 11ßHSD1 may well explain the observed side-effects of many pharmaceutical agents. Notably, patients with human immunodeficiency virus infection treated with protease inhibitors develop a lipodystrophic syndrome characterized by central adiposity and peripheral fat loss (11, 12). Although these drugs may have potent effects on adipocyte development and metabolism, it is interesting to hypothesize that some of their effects may be mediated through dysregulation of cortisol metabolism within adipose tissue. We therefore determined the effects of three protease inhibitors (saquinavir, indinavir, and neflinavir) on 11ßHSD1 activity in ASC.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cells were treated for 8–48 h with IGF-I (Sigma; 10–100
ng/ml), GH (Sigma; 10–100 ng/ml), TNF
(Sigma; 0.01–10 ng/ml), interleukin-1ß (IL-1ß;
PeproTech, London, UK; 0.01–10 ng/ml), IL-6 (PeproTech; 1–10
ng/ml), or 15D-PGJ2 (Calbiochem-Novabiochem, Darmstadt,
Germany; 1–10 µM) or for 24 h with indinavir
(Crixivan, Merck & Co., Inc., Whitehouse Station,
NJ; 1–10 µM), neflinavir (Viracept,
Agouron Pharmaceuticals, Inc., La Jolla, CA; 1–10
µM), or saquinavir (Invirase,
Roche, Mannheim, Germany; 1–10 µM).
Primary cultures of human hepatocytes
Primary cultures of human hepatocytes were established as
described previously (14). Briefly, cells were isolated
via a two-step collagenase perfusion, and viability was assessed by
trypan blue staining. In some preparations Percoll gradients were used
to improve viability. Cells were plated onto six-well, rat tail
collagen-coated dishes at a density of 2.5–3.0 x
105/ml in DMEM with 10% FBS for 2 h.
Subsequently, cells were washed with PBS, and medium was changed to
Williams E medium (Life Technologies, Inc.) supplemented
with insulin (20 ng/ml) and cortisol (100 nM). After
24 h cells were treated with leptin, TNF, IGF-I, and GH as
described above for a period of 48 h. Specific enzyme assays for
11ßHSD1 activity and RNA extraction were then performed.
Stable transfected fetal kidney cells
293 cells (devoid of endogenous 11ßHSD) were transfected with
either human 11ßHSD type 1 complementary DNA (cDNA; 293T1) or type 2
cDNA (293T2) as previously reported (15) and grown in MEM
with 10% FBS and Geneticin (Life Technologies, Inc.)
until confluence, at which point they were trypsinized using 0.125%
trypsin (Life Technologies, Inc.) in 1 mM EDTA
in PBS and plated on 12-well plates. The medium was then changed
24 h before treatment to serum- and phenol-free DMEM (Life Technologies, Inc.) containing 1% MEM nonessential amino acids
(Life Technologies, Inc.) and 2 mM glutamine
(Life Technologies, Inc.). Cells were then treated as
described above.
3T3-L1
The mouse fibroblast 3T3-L1 cell line represents an in
vitro adipocyte model and is known to express 11ßHSD1
(16). Under basal conditions before confluence these cells
resemble preadipocytes. Postconfluence in defined medium they
differentiate into mature adipocytes. Cells were cultured until
confluence in DMEM containing 10% FBS, 1% MEM nonessential amino
acids, and 2 mM glutamine. Once confluent they
were trypsinized (0.125%) and plated in 12-well plates until
confluence, then the medium was changed to serum- and phenol red-free
DMEM for 24 h before treatments.
11ßHSD assay
Assays for 11ßHSD activity were performed by incubating intact
cells with 250 nM cortisone (hepatocyte, omental, and sc
ASC and 293T1), 50 nM cortisol (293T2 cells), or 250
nM 11-dehydocorticosterone (3T3-L1) with appropriate
tritiated tracer for 1–5 h to ensure first order kinetics in each
case. After incubation, steroids were extracted using dichloromethane,
separated using a mobile phase consisting of ethanol and chloroform
(8:92) by TLC, and scanned using a Bioscan, Inc., 3000
image analyzer (Lablogic, Sheffield, UK). Protein levels were
assayed using a commercially available kit (Bio-Rad Laboratories, Inc., Hercules, CA), and activity was expressed as
picomoles of product per mg protein/h. Activity levels are presented as
the percent change from the control value ± SE. All
experiments were carried out on at least three separate occasions in
triplicate. Statistical analysis was performed using one-way ANOVA on
activity values corrected to the percentchange from control.
RNA extraction and RT
Total RNA was extracted using a single step extraction method
(RNAzol B, AMS Biotechnology, Whitney, UK). RNA integrity was assessed
by electrophoresis on 1% agarose gels, and quantity was determined
spectrophotometrically at OD260. One microgram of
total RNA was initially denatured by heating to 70 C for 5 min 30 U
avian myeloblastososis virus, 200 ng random primers, 20 U ribonuclease
inhibitor, and 40 nmol deoxy-NTPs with 5 x reaction buffer added
to the RNA and the reverse transcriptase reaction carried out at 37 C
for 1 h. The reaction was terminated by heating the cDNA to 95 C
for 5 min.
Analysis of 11ßHSD1 and TNF receptor (p60) messenger RNA
(mRNA) expression
The RT reaction was carried out as described above. PCR
amplification of cDNA was performed in a one-tube multiprimer reaction
using 18S ribosomal RNA (rRNA; 18S rRNA) as an internal control. Linear
amplification of 18S rRNA was ensured by using 18S PCR
competimers at a ratio of 2:8 (primer:competimer). Amplification
for 11ßHSD1 used primers and conditions described previously
(13). Amplification of TNF receptor (p60) used the
following conditions and primer sequences for 36 cycles: denaturation
at 94 C, annealing at 60 C, and extension at 72 C, sense primer
sequence TGA GGC ATG TCA CCA CAA GT, and antisense primer sequence GAG
AAG GTG GCG CAG ATT AG, yielding a specific product length of 319
bp.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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resulted in a
dose-dependent increase in 11ßHSD1 activity. In omental ASC, activity
increased to 170 ± 23% (TNF, 1 ng/ml) and 376 ± 57%
[TNF, 10 ng/ml; P < 0.01 vs. control
(100%)]. Similar changes were observed in sc ASC [590 ± 271%
(TNF, 1 ng/ml), P < 0.05; 1743 ± 1015%
(TNF, 10 ng/ml), P < 0.05; Fig. 1A
]. However, in primary cultures of
human hepatocytes TNF had no effect on 11ßHSD1 oxo-reductase
activity [97 ± 10% (TNF, 1 ng/ml) and 90 ± 3%
(TNF, 10 ng/ml); Fig. 1A]. Similarly, treatment with IL-1ß caused
a significant induction of 11ßHSD1 activity in both omental and sc
ASC [omental, 397 ± 47% (IL-1, 1 ng/ml; P <
0.01) and 415 ± 71% (IL-1, 10 ng/ml; P < 0.01);
sc, 416 ± 71% (IL-1, 1 ng/ml; P < 0.01) and
388 ± 62% (IL-1, 10 ng/ml; P < 0.01)]. Changes
in enzyme activity were paralleled by changes in enzyme expression, as
demonstrated by semiquantitative RT-PCR using 18S as an internal
control (Fig. 1B). TNF receptor type 1 (p60) was expressed in both
primary cultures of human hepatocytes and ASC, but did not appear to be
regulated at the mRNA level by treatment with TNF (Fig. 1B)
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and IL-1 treatment in sc ASC was dependent not
only upon the dose but also upon the duration of incubation (Fig. 2, A and B). At the highest doses of
TNF and IL-1ß used, induction of 11ßHSD1 activity continued to
rise with increasing duration of treatment [TNF (10 ng/ml),
105 ± 11 pmol/mg·h (24 h), 181 ± 74 (48 h), and 353
± 7 (72 h; P < 0.01 vs. 24 h);
IL-1ß (10 ng/ml), 96 ± 20 (24 h), 153 ± 46 (48 h), and
353 ± 6 (72 h; P < 0.01 vs. 24
h)].
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Treatment with IGF-I in omental and sc ASC significantly reduced
11ßHSD1 activity [omental, 89 ± 5% (IGF-I, 10 ng/ml) and
72 ± 8 (IGF-I, 100 ng/ml; P < 0.01); sc, 62
± 17% (IGF-I, 10 ng/ml) and 50 ± 15% (IGF-I, 100 ng/ml;
P < 0.05)]. In cultures of human hepatocytes, IGF-I
was without effect [104 ± 18% (IGF-I, 10 ng/ml) and 102 ±
16% (IGF-I, 100 ng/ml); Fig. 3A].
Similarly, GH failed to regulate 11ßHSD1 activity in hepatocytes
[102 ± 26% (GH, 10 ng/ml) and 108 ± 29% (GH, 100
ng/ml)], but in ASC, GH caused a small, but significant, inhibition in
activity at both sc and omental sites [omental, 77 ± 9% (GH, 10
ng/ml; P < 0.05 vs. control) and 80 ±
5% (GH, 100 ng/ml; P < 0.05 vs. control);
sc, 71 ± 8% (GH, 10 ng/ml; P < 0.05) and
78 ± 8% (GH, 100 ng/ml; P = 0.05)]. Treatment
with leptin had no effect on 11ßHSD1 activity in hepatocytes [103
±19% (leptin, 10 ng/ml) and 92 ± 11% (leptin, 100 ng/ml)].
However, in omental, but not sc, ASC, treatment with leptin caused a
borderline significant increase in 11ßHSD1 activity [omental,
111 ± 13% (leptin, 10 ng/ml) and 136 ± 14% (leptin, 100
ng/ml; P = 0.08); sc, 80 ± 20% (leptin, 10
ng/ml) and 91 ± 17% (leptin, 100 ng/ml); Fig. 3B].
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The protease inhibitor saquinavir caused a dose-dependent inhibition of
11ßHSD1 activity in omental and sc ASC, 293T1, and 3T3-L1 cells
[omental, 85 ± 18% (1 µM) and 75 ± 9% (10
µM; P < 0.05); 293T1, 74 ± 9% (1
µM) and 39 ± 11% (10
µM; P < 0.01); 3T3-L1, 84
± 4% (1 µM; P < 0.05) and
10 ± 9% (10 µM; P <
0.001); Fig. 4A]. Similar results were
obtained using alternative protease inhibitors indinavir and neflinavir
[indinavir: omental, 67 ± 10% (1 µM;
P < 0.05) and 77 ± 7% (10
µM; P < 0.05); 293T1, 80
± 4% (1 µM; P < 0.01) and
61 ± 5% (10 µM; P <
0.01); 3T3-L1, 103 ± 23% (1 µM) and
74 ± 5% (10 µM; P <
0.01); neflinavir: omental, 72 ± 2% (1
µM; P < 0.05) and 71 ±
4% (10 µM; P < 0.05); 293T1,
69 ± 1% (1 µM; P <
0.01) and 64 ± 3% (10 µM;
P < 0.01); 3T3-L1, 85 ± 3% (1
µM) and 27 ± 3% (10
µM; P < 0.01); Fig. 4, B and
C]. Saquinavir, indinavir, and neflinavir had no effect on 11ßHSD2
activity in 293T2 cells [saquinavir, 111 ± 8% (1
µM) and 125 ± 10% (10
µM); indinavir, 110 ± 11% (1
µM) and 119 ± 9% (10
µM); neflinavir, 101 ± 5% (1
µM) and 93 ± 9% (10
µM)].
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Despite these in vitro data, clinical studies have suggested inhibition of 11ßHSD1 activity, as measured by urine steroid profiles and the appearance of circulating cortisol after oral cortisone acetate (6). These measures undoubtedly reflect hepatic 11ßHSD1 activity, but it is still plausible that 11ßHSD1 expression may be increased in adipose tissue. Indeed, such a tissue-specific regulation of 11ßHSD1 expression has been shown in an animal model of obesity, the Zucker rat (7).
Mature adipocytes produce a variety of growth factors and cytokines,
including IGF-I, leptin, and TNF, that may have powerful effects on
11ßHSD1 expression in a paracrine/autocrine fashion. Levels of TNF
are elevated 2- to 3-fold in obesity and seem particularly associated
with insulin resistance (18). Previous studies have shown
induction of 11ßHSD1 activity by TNF in rat glomerular mesangial
cells (19) and human breast preadipocytes
(20). In this study we demonstrated a dramatic enhancement
of activity and expression of 11ßHSD1 in sc and omental ASC after
treatment with TNF. Based on our earlier observations
(13), this local cortisol generation will promote
adipocyte differentiation. The fold induction of 11ßHSD1 activity is
far greater in sc than omental ASC. However, basal activity is
significantly lower in sc ASC, and even after treatment with either
TNF or IL-1ß the absolute activity of the enzyme remains higher in
omental cells. This basal and stimulated differential cortisol
generation between omental and sc depots may well be crucial to the
development of central obesity. However, TNF also has potent direct
effects on developing adipocytes to inhibit differentiation and
proliferation and to promote apoptosis and dedifferentiation
(21, 22, 23). It is possible that enhanced expression of
11ßHSD1 and the resulting increased local production of cortisol may
serve as a regulatory feedback loop to balance these direct effects of
TNF. This may also provide an explanation for the phenotype observed
in both TNF and TNF receptor knockout mice. These mice appear to
have a normal fat distribution (24), although TNF
knockout mice eventually become leaner than controls (25).
The propensity for adipocyte differentiation that can occur due to lack
of TNF may be counteracted by the relative reduction in local
cortisol caused by the absence of induction of 11ßHSD1.
Similarly, levels of IL-6 are elevated in obesity and fall with weight loss (26). Induction of 11ßHSD1 activity in sc ASC by IL-6 will enhance cortisol generation and is likely to further contribute to the obese phenotype.
Leptin is a cytokine produced and secreted by mature adipocytes that is
known to have potent central effects on feeding behavior and appetite.
Its peripheral actions have been less extensively investigated.
Circulating leptin levels are elevated in obesity, which has widely
been regarded as a state of leptin resistance (27).
Incubation with leptin appeared to increase 11ßHSD1 activity in
omental ASC, although this did not reach statistical significance
(P = 0.08). In sc ASC, leptin was without effect. It is
possible that leptin may promote further adipogenesis at an autocrine
level through increased generation of cortisol, again in a
depot-specific fashion. However, compared with the effects of TNF
and IL-1ß, the effects were small.
Patients with obesity have relative GH deficiency (28); conversely, hypopituitary patients with GH deficiency are frequently obese (29, 30). Our previous clinical studies have demonstrated inhibition of 11ßHSD1 in patients with acromegaly and increased expression in hypopituitary patients (31, 32). In vitro studies have shown that this inhibition is most likely mediated by IGF-I (31). In this study using human primary ASC, we demonstrated a dose-dependent inhibition of 11ßHSD1 activity by IGF-I in both sc and omental ASC. IGF-I had no effect on 11ßHSD1 activity in primary cultures of human hepatocytes. The lack of response to GH/IGF-I in this hepatocyte model is intriguing. Clinical studies demonstrating regulation of 11ßHSD1 activity by GH suggest that the observed alterations in urinary steroid metabolites are mediated via hepatic 11ßHSD1 activity (31). Furthermore, animal studies have clearly demonstrated decreased hepatic 11ßHSD1 expression in response to continuous GH infusion (33). However, there is conflicting in vitro data suggesting that GH may either have no effect or cause an inhibition of 11ßHSD1 activity in primary cultures of rat hepatocytes (34, 35). Our study showed no effect of GH on 11ßHSD1 activity in primary cultures of human hepatocytes.
The PG derivative 15D-PGJ2 is believed to be the endogenous
ligand for PPAR (9, 10). 15D-PGJ2 has been demonstrated
to have potent effects to promote adipocyte development
(9), but intriguingly also to inhibit leptin production
(36). Treatment with PGJ2 increased 11ßHSD1 activity in
ASC, and it is exciting to speculate that some of the effects of
PPAR agonists on adipocyte differentiation are mediated indirectly
via glucocorticoids through this action on 11ßHSD1.
Local regulation of 11ßHSD1 may also offer an explanation for
side-effects of some pharmaceutical agents and potentially may be a
site for future novel therapeutic targets. Protease inhibitors used in
the treatment of human immunodeficiency virus infection are known to
cause a lipodystrophic syndrome characterized by proximal fat loss and
central fat accumulation (11, 12, 37). Our data indicate
that these drugs potently inhibit 11ßHSD1 activity, but have no
effect on 11ßHSD2. On the basis of these results, it would appear
that local enhanced activity and expression of 11ßHSD1 do not explain
the central obesity observed in patients taking protease inhibitors.
The lipodystrophic syndrome is likely to result from many complex
interactions during adipocyte metabolism and development. Recent
studies have shown that these agents are capable of inhibiting the
generation of metabolites of retinoic acid through inhibition of
cytoplasmic retinoic acid-binding protein type 1 (38).
This inhibition may well influence activation and heterodimerization of
the retinoid X and PPAR receptors, resulting in dysregulation of
adipocyte development. Effects on lipoprotein-related protein have also
been described that have been implicated in the circulating
dyslipidemia associated with this condition. The etiology of the
lipodystrophic syndrome associated with protease inhibitors is
undoubtedly complex and the role of 11ßHSD1 inhibition in this
mechanism remains to be determined.
We have demonstrated the differential regulation of 11ßHSD1 in ASC
and hepatocytes by IGF-I, TNF, and leptin, data that may help to
explain existing clinical data. The local up-regulation of 11ßHSD1
within adipose tissue in the setting of inhibition in the liver
documented in obesity (6) and in an animal model, the
Zucker rat (7), has been described. Obesity is
characterized by low GH secretion, lower IGF-I levels, and elevated
levels of TNF and leptin, factors that would specifically increase
11ßHSD1 within adipose tissue, but not liver. Furthermore, expression
of the endogenous ligand to PPAR and IL-6 may further enhance local
cortisol generation. The relative contributions of all of these factors
to the enhanced activity and expression of 11ßHSD1 is perhaps
difficult to assess. TNF and IL-1ß have profound effects, whereas
15D-PGJ2, IL-6, and leptin enhance activity to a lesser degree. The
mechanism by which TNF, leptin, and IGF-I mediate differential
regulation needs further investigation. TNF, acting through the p60
receptor, signals either via mitogen-activated protein kinase and
nuclear factor-
ß or through activator protein-1 (39).
Activator protein-1 transcription factor-binding sites have been
identified in the 5'-promoter region of 11ßHSD1 gene
(40), and this may be the mechanism of signaling in ASC.
IGF-I acts via either inositol trisphospate or mitogen-activated
protein kinase. The specific intracellular pathway that is activated
can have profound effects on adipocyte development to promote either
proliferation or differentiation (41). However, the
precise mechanism of action of IGF-I to modulate 11ßHSD1 activity in
ASC requires further investigation.
In summary, we have documented inhibition of 11ßHSD1 expression by
protease inhibitors within adipose tissue, but, crucially, defined
differential tissue specific regulation of 11ßHSD1 by IGF-I and
TNF. The cytokine induction and IGF-I inhibition of 11ßHSD1 within
adipose tissue provide a mechanism to explain current clinical data and
have important ramifications for the pathogenesis of visceral
obesity.
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Footnotes |
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2 Medical Research Council Training Fellow.
3 Medical Research Council Senior Fellow.
Received November 10, 2000.
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References |
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C. Bruley, V. Lyons, A. G. F. Worsley, M. D. Wilde, G. D. Darlington, N. M. Morton, J. R. Seckl, and K. E. Chapman A Novel Promoter for the 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Gene Is Active in Lung and Is C/EBP{alpha} Independent Endocrinology, June 1, 2006; 147(6): 2879 - 2885. [Abstract] [Full Text] [PDF]
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S. K. Paulsen, S. B. Pedersen, J. O. L. Jorgensen, S. Fisker, J. S. Christiansen, A. Flyvbjerg, and B. Richelsen Growth Hormone (GH) Substitution in GH-Deficient Patients Inhibits 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression in Adipose Tissue J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1093 - 1098. [Abstract] [Full Text] [PDF]
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 J A P Da Silva, J W G Jacobs, J R Kirwan, M Boers, K G Saag, L B S Ines, E J P de Koning, F Buttgereit, M Cutolo, H Capell, et al. Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data Ann Rheum Dis, March 1, 2006; 65(3): 285 - 293. [Abstract] [Full Text] [PDF]
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 M. G. Gnanalingham, A. Mostyn, R. Webb, D. H. Keisler, N. Raver, M. C. Alves-Guerra, C. Pecqueur, B. Miroux, M. E. Symonds, and T. Stephenson Differential effects of leptin administration on the abundance of UCP2 and glucocorticoid action during neonatal development Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E1093 - E1100. [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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 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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J. W. Tomlinson, J. S. Moore, P. M. S. Clark, G. Holder, L. Shakespeare, and P. M. Stewart Weight Loss Increases 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression in Human Adipose Tissue J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2711 - 2716. [Abstract] [Full Text] [PDF]
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