Histomorphometric changes in the perirenal adipocytes of adrenalectomized rats treated with dexamethasone.

Abstract

Prolonged steroid treatment administered to any patient can cause visceral obesity, which is associated with metabolic disease and Cushing's syndrome. Glucocorticoids have a profound negative effect on adipose tissue mass, giving rise to obesity, which in turn is regulated by the 11β-hydroxysteroid dehydrogenase type 1 enzyme. Adrenalectomized rats treated with dexamethasone exhibited an increase in visceral fat deposition but not in body weight.
The main aim of this study was to determine the effect of dexamethasone on the histomorphometric characteristics of perirenal adipocytes of adrenalectomized, dexamethasone-treated rats (ADR+Dexa) and the association of dexamethasone treatment with the expression and activity of 11 β-hydroxysteroid dehydrogenase type 1 (11 β-hydroxysteroid dehydrogenase type 1).
A total of 20 male Sprague Dawley rats were divided into 3 groups: a baseline control group (n = 6), a sham-operated group (n = 7) and an adrenalectomized group (n=7). The adrenalectomized group was given intramuscular dexamethasone (ADR+Dexa) 2 weeks post adrenalectomy, and the rats from the sham-operated group were administered intramuscular vehicle (olive oil).
Treatment with 120 μg/kg intramuscular dexamethasone for 8 weeks resulted in a significant decrease in the diameter of the perirenal adipocytes (p<0.05) and a significant increase in the number of perirenal adipocytes (p<0.05). There was minimal weight gain but pronounced fat deposition in the dexamethasone-treated rats. These changes in the perirenal adipocytes were associated with high expression and dehydrogenase activity of 11β-hydroxysteroid dehydrogenase type 1.
In conclusion, dexamethasone increased the deposition of perirenal fat by hyperplasia, which causes increases in the expression and dehydrogenase activity of 11 β-hydroxysteroid dehydrogenase type 1 in adrenalectomized rats.

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BASIC RESEARCH
Histomorphometric changes in the perirenal
adipocytes of adrenalectomized rats treated with
dexamethasone
Fairus Ahmad,IIma Nirwana Soelaiman,IIElvy Suhana Mohd Ramli,ITan Ming Hooi,IIIFarihah H. SuhaimiI
IAnatomy, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
IIIBiomedical Science, Universiti Tunku Abdul Rahman, Kampar Perak, Malaysia.
IIPharmacology, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
INTRODUCTION: Prolonged steroid treatment administered to any patient can cause visceral obesity, which is
associated with metabolic disease and Cushing’s syndrome. Glucocorticoids have a profound negative effect on
adipose tissue mass, giving rise to obesity, which in turn is regulated by the 11b-hydroxysteroid dehydrogenase type
1 enzyme. Adrenalectomized rats treated with dexamethasone exhibited an increase in visceral fat deposition but
not in body weight.
OBJECTIVES: The main aim of this study was to determine the effect of dexamethasone on the histomorphometric
characteristics of perirenal adipocytes of adrenalectomized, dexamethasone-treated rats (ADR+Dexa) and the
association of dexamethasone treatment with the expression and activity of 11b-hydroxysteroid dehydrogenase
type 1 (11b- hydroxysteroid dehydrogenase type 1).
METHODS: A total of 20 male Sprague Dawley rats were divided into 3 groups: a baseline control group (n=6), a
sham-operated group (n=7) and an adrenalectomized group (n=7). The adrenalectomized group was given
intramuscular dexamethasone (ADR+Dexa) 2 weeks post adrenalectomy, and the rats from the sham-operated
group were administered intramuscular vehicle (olive oil).
RESULTS: Treatment with 120 mg/kg intramuscular dexamethasone for 8 weeks resulted in a significant decrease in
the diameter of the perirenal adipocytes (p,0.05) and a significant increase in the number of perirenal adipocytes
(p,0.05). There was minimal weight gain but pronounced fat deposition in the dexamethasone-treated rats. These
changes in the perirenal adipocytes were associated with high expression and dehydrogenase activity of 11b-
hydroxysteroid dehydrogenase type 1.
CONCLUSIONS: In conclusion, dexamethasone increased the deposition of perirenal fat by hyperplasia, which causes
increases in the expression and dehydrogenase activity of 11b-hydroxysteroid dehydrogenase type 1 in
adrenalectomized rats.
KEYWORDS: Dexamethasone; Adrenalectomized rat; Perirenal fat; Hyperplasia; 11b-hydroxysteroid dehydrogenase
type 1.
Ahmad F, Soelaiman IN, Ramli ESM, Hoo TM, Suhaimi F. Histomorphometric changes in the perirenal adipocytes of adrenalectomized rats treated
with dexamethasone. Clinics. 2011;66(5):849-853.
Received for publication on January 14, 2011; First review completed on January 30, 2011; Accepted for publication on January 30, 2011
E-mail: farihah@medic.ukm.my
Tel.: 603-9289 7263
INTRODUCTION
Prolonged steroid treatment causes visceral obesity.
Visceral obesity is associated with metabolic diseases, which
increase the risk of cardiovascular disease and diabetes
mellitus.1The deposition of visceral adipocytes is the result
of an increase in the intake of dietary fat and a decrease in
the demand for energy.2This positive energy balance is
stored as adipose tissue, causing the adipose mass to
expand. The expansion of adipose mass can occur because
of an increase in adipocyte size (hypertrophy) or number
(hyperplasia) or both. Different adipose tissues have
different tendencies to undergo hypertrophy and hyperpla-
sia. Mesenteric and epididymal adipose tissue depots have a
tendency to undergo hypertrophy, whereas retroperitoneal
and inguinal adipocytes have a tendency to undergo
hyperplasiaduringthe
Additionally, fat cells with different mean adipocyte
diameters have been obtained from biopsies from different
locations and donors.4
Glucocorticoids are essential for the differentiation of
adipocytes, and they play an important role in the
developmentofobesity.3
Copyright ? 2011 CLINICS – This is an Open Access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-
commercial use, distribution, and reproduction in any medium, provided the
original work is properly cited.
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pathogenesis of visceral obesity.5The enzyme 11b-hydro-
xysteroid dehydrogenase type 1 (11b-HSD1) catalyzes the
interconversion of the active glucocorticoid, cortisol in
humans and corticosterone in rodents, to the inactive
glucocorticoid, cortisoneand
respectively. In rat adipose tissue, 11b-HSD1 acts predomi-
nantly as a reductase enzyme; it catalyzes the conversion of
11-dehydrocorticosterone to corticosterone, which results in
hypertrophy of adipocytes.6The dehydrogenase activity of
11b-HSD1 converts corticosterone to 11-dehydrocorticoster-
one, which results in hyperplasia of adipocytes.7
Body weight was noted to be reduced in several animal
models of obesity after removal of glucocorticoids by
adrenalectomy.8There was pronounced fat deposition in
adrenalectomized rats after treatment with glucocorticoids,
but no significant increase in weight was observed.9,10
However, the activity of 11b-HSD1 in omental fat was noted
to decrease in adrenalectomized obese rats.11Therefore, in
this study, we aimed to investigate the histomorphometric
effects on perirenal adipocytes and the associated increase
in fat deposition following glucocorticoid treatment. We
also aimed to investigate the relationship of fat deposition
with the activity and expression of 11b-HSD1.
11-dehydrocorticosterone,
MATERIALS AND METHODS
Animals and surgery
MaleSpragueDawleyratsweighingbetween200and250g
were housed in a temperature-controlled (20—22˚C) envir-
onment witha 12-hourlight-darknesscycle.Allanimals were
housed in groups of 2 for 2 weeks before adrenalectomy. The
rats were given a normal rat chow diet (Gold Coin, Malaysia)
and normal saline ad libitum. Prior ethical approval was
obtained from the Animal Ethics Committee of Universiti
Kebangsaan Malaysia (UKMAEC No: PP/ANAT/2008/
FARIHAH/21-AUGUST/240-0CT-2008-JUNE-2009).
Bilateral adrenalectomy was performed through a mid-
line dorsal incision followed by a small incision through the
muscle layer under 1:1 Xylazil (Ilium, Australia) and
Ketapex (Troy, Australia) anesthesia at 0.1 ml/100 g of
body weight. After removal of the adrenal glands, the
incision was sutured, and a topical antiseptic, Poviderm
(Hoe, Malaysia), was applied over the wound. For the
sham-operated rats, the adrenals were left in place.
A total of 20 male Sprague Dawley rats were divided into
3 groups: a baseline control group (n=6), a sham-operated
group (n=7) and an adrenalectomized group (n=7). The
adrenalectomized group was given intramuscular dexa-
methasone (Sigma, USA) (ADR+Dexa) at a dose of 120 mg/
kg 2 weeks post adrenalectomy.12The dexamethasone was
started 2 weeks after adrenalectomy to reduce the risk of
infection and to allow full recovery of the rats. The rats from
the sham-operated group were given intramuscular vehicle
(olive oil). The intramuscular treatment and vehicle were
given to the rats for 8 weeks before sacrifice. All of the rats
in the baseline group were sacrificed after 2 weeks of
acclimatization in the Animal Unit. The animals were
weighed regularly to allow accurate dosing and to monitor
the weight gain.
The rats were given diethyl ether (BDH, England) before
being sacrificed by cervical dislocation. Pictures of visceral
adipose tissue were taken, and perirenal adipose tissues
were dissected bilaterally. Some of the adipose tissues were
kept at -70˚C, and others were fixed in 10 % formalin.
Histological analysis
Samples of perirenal adipose tissue were immediately
fixed in 10 % formalin, and after 24 hours, the samples were
processed using an automatic tissue-processing machine
(Microm, Germany). The samples were then embedded in
paraffin, and 5 mm sections were obtained. Approximately
25 sections were obtained, and every fifth section was taken
for staining. Sections were stained with hematoxylin (Sigma
Chemical, USA) and eosin (BDH, England) (H&E) using an
automatic staining machine (Leica, Germany). Finally,
sections were mounted on dibutyl phthalate in xylene
(DPX). Photomicrographs of adipocytes were taken using a
camera (CTRMIC from Leica, Germany) and were analyzed
with Video T-Test Morphology 5.1 software from Russia.
The diameter and the total number of adipocytes were
determined.
Immunohistochemistry
After samples were fixed in 10 % formalin and processed,
5 mm sections were cut and placed on polysine slides
(Thermo Scientific, Germany) for immunohistochemistry.
Slides were dewaxed in xylene and dehydrated in a series of
alcohol to water. For antigen retrieval, the slides were
treated with citrate-buffered solution (200 ml; 0.01 M; pH 6)
and rinsed with phosphate-buffered solution (PBS). The
slides were then treated with hydrogen peroxide before
being incubated with normal goat serum at a dilution of
1:50. Next, the slides were rinsed with PBS and incubated
with primary antibody (Cayman Chemical, USA) at a
dilution of 1:1000 for 1 hour. Negative-control sections were
incubated in PBS without primary antibody. After rinsing
with PBS, the tissue-bound primary antibody was detected
using biotinylated secondary antibody and the avidin-
biotin-peroxidase complex method (Vectastain Elite ABC
kit, USA) with diaminobenzidine tetrahydrochloride (DAB)
(Vector Laboratories, USA) as the chromogen. Finally, the
slides were counterstained with Meyer’s Hematoxylin
(Richard-Allan Scientific, USA) for 45 seconds and mounted
with DPX. Two blinded observers analyzed the slides, and
the slides were graded according to the intensity of the
immunoreactive stained area. The intensity grading was as
follows: no staining was ‘0’; weak staining was ‘1’; mild
staining was ‘2’; and strong staining was ‘3’.
Assay for 11b-HSD1 enzyme activity
The level of 11b-HSD1 dehydrogenase activity in adipose
tissue homogenates was determined by measuring the rate of
conversion of corticosterone to 11-dehydrocorticosterone, as
described by Moison et al., with some modifications.13
Perirenal adipose tissue was homogenized in Krebs-Ringer
bicarbonate buffer, and the total protein content was
estimated calorimetrically using aliquots of each homoge-
nate. Tissue homogenates containing 0.5 mg of protein were
added to a solution of 200 mM NADP (Sigma, Germany),
12 nM [1,2,6,7-3H] corticosterone (American Radioactive
Chemicals, USA) and Krebs-Ringer bicarbonate buffer (con-
taining 0.2 % glucose and 0.2 % BSA); the total reaction
volume was 250 ml. After incubation in a shaking water bath
at 37˚C for1 hour, thereactionwasarrested bytheadditionof
1 ml of ethyl acetate, and the steroids were extracted by
centrifugation at 4˚C and 3000 rpm for 10 minute. The top
layer was then transferred and evaporated to dryness at 55˚C
before being dissolved in ethanol containing corticosterone
and 11-dehydrocorticosterone. The steroid residue was
Effect of dexamethasone on perirenal adipocytes
Ahmad F et al.
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separated using thin-layer chromatography (Whatman,
Germany) in chloroform and 95 % ethanol at a ratio of 92:8.
The bands containing the labeled corticosterone and 11-
dehydrocorticosterone were identified by UV light at 240 nm,
scraped and transferred into scintillation vials containing
scintillation fluid before being counted with a b-counter
(Wallac 1409, Finland). The percentage conversion of
corticosterone to 11-dehydrocorticosterone was calculated.
Data analysis
The results are expressed as mean ¡ standard error mean
(SEM). The means were compared using one-way analysis-
of-variance (ANOVA) followed by Tukey’s post hoc test and
a t-test. All of the statistical analyses were performed using
the Statistical Package for Social Sciences (SPSS) software.
RESULTS
Body weight
Adrenalectomized
(ADR+Dexa) showed less weight gain compared with rats
from the sham-operated group following 8 weeks of
treatment (Fig. 2(a)).
rats treatedwith dexamethasone
Observation of visceral adipose tissue
Adrenalectomized
(ADR+Dexa) and rats from sham-operated groups showed
more visceral fat deposition compared with the baseline
control group (Fig. 1(a)).
rats treated withdexamethasone
Adipocyte histomorphometry
Individual adipocytes in adrenalectomized rats treated
with dexamethasone (ADR+Dexa) had significantly smaller
diameters than the sham-operated and baseline control
groups (Figs. 1(b) and 2(b)). The average number of
adipocytes on one slide for adrenalectomized rats treated
with dexamethasone was significantly greater than that of
sham-operated and baseline control rats (Figs. 1(b) and 2(c)).
Expression of 11b-HSD1
Expression of 11b-HSD1 was greater in adrenalectomized
rats treated with dexamethasone (ADR+Dexa) than in sham-
operated and baseline control groups (Figs. 1(c) and 2(d)).
Activity of enzyme 11b-HSD1 dehydrogenase
The dehydrogenase activity of 11b-HSD1 in adrenalecto-
mized rats treated with dexamethasone (ADR+Dexa) was
Figure 1 - (a) An adrenalectomized rat treated with dexamethasone (ADR+Dexa) and a rat from the sham-operated group had more
visceral fat deposition (perirenal fat—red arrows; mesenteric fat—blue arrows) compared with the rat from the baseline control group.
(b) The number of adipocytes per slide (H&E staining) was greater in the adrenalectomized rats treated with dexamethasone
(ADR+Dexa), but the diameters of these cells were smaller than those seen in rats from the sham-operated and baseline control groups.
The circles show hyperplasia of adipocytes, and the arrows show blood vessels. Magnification X 20. (c) Immunoreactive staining of 11b-
HSD1 in adrenalectomized rats treated with dexamethasone (ADR+Dexa) showed stronger immunoreactive staining compared with
that of the baseline control and sham-operated rats. Magnification X 20.
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significantly higher than that in the sham-operated and
baseline control rats (Fig. 2(e)).
DISCUSSION
The present study produced results similar to those of other
studies, whereby adrenalectomized rats treated with dexa-
methasone had increased fat deposition with minimal weight
gain.10Another study showed that after 2 weeks of adrena-
lectomy without supplementation of glucocorticoids, the
amount of perirenal fat was found to be decreased compared
with that of rats with intact adrenal glands.9However, in this
study, we found that the weight gain of the adrenalectomized
rats had increased after 2 weeks of adrenalectomy. Therefore,
the removal of endogenous glucocorticoids by adrenalectomy
may lead to a decrease in appetite and food intake, causing a
minimal increase in body weight.8
The increase in fat deposition in adrenalectomized rats
treated with dexamethasone appeared to be similar to that
of rats in the control group; however, there was a significant
difference in total body weight.14Indeed, studies have
shown that excessive doses and prolonged administration of
dexamethasone in adrenalectomized rats does not increase
the body weight, a result that might be due to the
generalizedwasting of
Therefore, prolonged administration of dexamethasone in
the adrenalectomized rats increased their visceral obesity
without increasing their total body weight.17
The administration of dexamethasone may lead to the
onset of the development of adipocytes. The perirenal
adipocytes have a tendency to undergo hyperplasia fol-
lowed by hypertrophy, as seen in the control rats.18The
photomicrograph in Fig. 1(b) shows clusters of smaller
adipocytes (circles) that formed with the presence of blood
all bodycomponents.15,16
Figure 2 - (a) Average body weight of the adrenalectomized rats treated with dexamethasone (ADR+Dexa) revealed that these rats
gained less weight than the sham-operated rats after 8 weeks.ap,0.05 indicates a significant difference between the ADR+Dexa
group and the sham-operated group.#p,0.05 indicates a significant difference between week 1 and week 8 for the sham-operated
rats. (b) The diameter of adipocytes of the adrenalectomized rats treated with dexamethasone (ADR+Dexa) was smaller than that of
adipocytes from baseline control and sham-operated rats. (c) The number of adipocytes per slide was greater for adrenalectomized rats
treated with dexamethasone (ADR+Dexa) than for baseline control and sham-operated rats. (d) The expression level of 11b-HSD1 in
adrenalectomized rats treated with dexamethasone (ADR+Dexa) was significant higher than that in baseline control and sham-
operated rats. (e) The dehydrogenase activity of 11b-HSD1 of the adrenalectomized rats treated with dexamethasone (ADR+Dexa) was
significantly greater than that of the baseline control and sham-operated rats.ap,0.05 indicates a significant difference between the
ADR+Dexa group and the baseline control and sham-operated groups.
Effect of dexamethasone on perirenal adipocytes
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vessels (arrows) close to the adipocytes that underwent
hyperplasia. The increases in the numbers of adipocytes
(hyperplasia) and blood vessels are characteristics of a
metabolically active state, which is seen in the development
of adipocytes.19
These findings were supported by an increase in the
expression and dehydrogenase activity of 11b-HSD1 in
adrenalectomized ratstreated
Balanchandran and colleagues showed that dexamethasone
stimulates the dehydrogenase activity of 11b-HSD1, and this
increased activity caused an increase in perirenal fat
deposition as a result of hyperplasia in the adrenalecto-
mized rats.20However, the inhibition of the activity of the
reductase activity of 11b-HSD1 by dexamethasone may be
due to a negative feedback effect of glucocorticoid.20
Therefore, we suggest that the perirenal adipocytes did
not undergo hypertrophy, and as a result, the body weight
of the adrenalectomized rats treated with dexamethasone
did not increase significantly.
Recently, a study showed that the reductase activity was
at its maximum if the dehydrogenase activity of the enzyme
was at its minimum as the result of the bidirectional
capacity of 11b-HSD1.21We therefore suggest that an
increase in the reductase activity of 11b-HSD1 caused the
increase in the diameter of the adipocytes as a result of
hypertrophy. This is because the expression and dehydro-
genase activity of 11b-HSD1 was decreased in the control
rats compared with adrenalectomized rats treated with
dexamethasone, as shown in our study. This result suggests
that the reductase activity of 11b-HSD1 may have caused
the adipocytes to undergo hypertrophy and, therefore,
played an important role in the weight gain of the rats.
withdexamethasone.
CONCLUSION
In conclusion,long-termglucocorticoid treatment
increased the expression and dehydrogenase activity of
the 11b-HSD1 enzyme. This increased expression and
activity was associated with hyperplasia of the perirenal
adipocytes but not with weight gain. Therefore, the
dehydrogenase activity of 11b-HSD1 plays an important
role in the onset of the development of obesity. However,
elucidating the underlying mechanism requires further
study.
ACKNOWLEDGMENTS
This work was supported by Universiti Kebangsaan Malaysia research
grant FF-239-2008. The authors gratefully acknowledge the staff of the
Department of Anatomy and Pharmacology, Faculty of Medicine,
Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia. The authors
declare that there are no conflicts of interest.
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