Am J Physiol Endocrinol Metab 301: E307–E316, 2011.
First published May 3, 2011; doi:10.1152/ajpendo.00009.2011.
Differential effects of glucocorticoids on energy homeostasis
in Syrian hamsters
Matia B. Solomon, Randall R. Sakai, Stephen C. Woods, and Michelle T. Foster
1
Department of Psychiatry and Behavioral Neuroscience, Obesity Research Center, Metabolic Disease Institute, University
of Cincinnati, Cincinnati, Ohio
Submitted 6 January 2011; accepted in final form 29 April 2011
stress; body weight; Cushing’s syndrome; obesity; hypothalamicpituitary-adrenal axis
of the hypothalamic-pituitary-adrenal (HPA)
axis due to prolonged stress or endocrine disorders (e.g., Cushing’s syndrome) is linked to numerous pathological conditions,
including cardiovascular disease and obesity (2). Glucocorticoids (cortisol and corticosterone), the final products and
active components of the HPA axis, are secreted from the
adrenal cortex, and because they are elevated in rodent and
human models of obesity (2, 11, 27), they are often considered to be the culprits for the increased risk of developing
the metabolic syndrome. In response to mild psychological
stressors or glucocorticoid administration, humans often
increase food intake and/or body weight (8, 14, 36). Although humans predominately secrete cortisol as their stress
hormone, identification of mechanisms involved in stressinduced metabolic alterations is commonly investigated in
CHRONIC ACTIVATION
Address for reprint requests and other correspondence: M. T. Foster, 2170
E. Galbraith Rd., Dept. of Psychiatry and Behavioral Neuroscience. Univ. of
Cincinnati, Cincinnati, OH 45237 (e-mail: [email protected]).
http://www.ajpendo.org
rat and mouse models, in which corticosterone is the more
abundant glucocorticoid. In addition, the characteristic response of most rodents exposed to social, psychological, or
physical stressors is to decrease food intake and lose body/
adiposity mass (17, 19, 23, 25), an outcome similar to
humans following severe stress (13, 22). However, because
mild day-to-day stressors are associated with increased body
weight gain in some humans, an effect proposed to be
attributed to elevated glucocorticoids, there is a critical need
for more rodent models that better mimic this phenomenon.
We have reported previously that repeated social stress
increases food intake, body mass, and adiposity, primarily in
the form of increased visceral obesity (i.e., increased mesenteric and omental fat), in Syrian hamsters (15, 32), consistent
with previous findings in Swiss mice (5). We hypothesized that
increases in circulating glucocorticoids in response to social
defeat facilitates this positive energy balance. Because Syrian
hamsters tend to gain weight in response to stress, they may be
a particularly apt rodent model for investigating stress-induced
body mass gain that is commonly observed in a subset of
humans. Of note, Syrian hamsters are dual secretors of cortisol
and corticosterone, although cortisol is proposed to be the more
liable glucocorticoid (31, 39) and predominant hormone following stress exposure in Syrian hamsters (18, 28). Therefore,
we hypothesized that cortisol, but not corticosterone, mediates
stress-induced alterations in energy homeostasis in this species.
To test this hypothesis, Syrian hamsters were injected with
cortisol or corticosterone to mimic the transitory increases in
these hormones, as seen following a brief social defeat encounter. We next implanted Syrian hamsters with pellets to determine the effects of prolonged glucocorticoid exposure on
energy homeostasis in this species. This approach allowed us
to investigate the individual effects of corticosterone and cortisol secretion on food intake, body mass, adiposity, and lipid
profiles in this species.
METHODS
Animals and housing conditions. Adult male Syrian hamsters
(⬃130 g upon arrival) were individually housed in standard polycarbonate cages (20 ⫻ 40 ⫻ 20 cm) and acclimated to the housing
conditions for ⱖ1 wk before initiation of the experiment. Hamsters
were maintained in a temperature- and humidity-controlled vivarium with a 14:10-h light-dark cycle (lights off at 1300). Hamsters
were given free access to pelleted rodent chow (rodent diet,
LM485; Harlan Teklad, Madison, WI) and water. All procedures
and protocols were conducted in accordance with the National
Institutes of Health guidelines for the care and use of animals and
approved by the University of Cincinnati Institutional Animal Care
and Use Committee.
Experiment 1: glucocorticoid injections. Adrenal-intact hamsters
were injected subcutaneously with cortisol (10 or 40 ␮g/100 g;
0193-1849/11 Copyright © 2011 the American Physiological Society
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Solomon MB, Sakai RR, Woods SC, Foster MT. Differential
effects of glucocorticoids on energy homeostasis in Syrian hamsters. Am J Physiol Endocrinol Metab 301: E307–E316, 2011. First
published May 3, 2011; doi:10.1152/ajpendo.00009.2011.—Syrian
hamsters, like many humans, increase food intake and body adiposity
in response to stress. We hypothesized that glucocorticoids (cortisol
and corticosterone) mediate these stress-induced effects on energy
homeostasis. Because Syrian hamsters are dual secretors of cortisol
and corticosterone, differential effects of each glucocorticoid on
energy homeostasis were investigated. First, adrenal intact hamsters
were injected with varying physiological concentrations of cortisol,
corticosterone, or vehicle to emulate our previously published defeat
regimens (i.e., 1 injection/day for 5 days). Neither food intake nor
body weight was altered following glucocorticoid injections. Therefore, we investigated the effect of sustained glucocorticoid exposure
on energy homeostasis. This was accomplished by implanting hamsters with supraphysiological steady-state pellets of cortisol, corticosterone, or cholesterol as a control. Cortisol, but not corticosterone,
significantly decreased food intake, body mass, and lean and fat tissue
compared with controls. Despite decreases in body mass and adiposity, cortisol significantly increased circulating free fatty acids, triglyceride, cholesterol, and hepatic triglyceride concentrations. Although
corticosterone did not induce alterations in any of the aforementioned
metabolic end points, Syrian hamsters were responsive to the effects
of corticosterone since glucocorticoids both induced thymic involution and decreased adrenal mass. These findings indicate that cortisol
is the more potent glucocorticoid in energy homeostasis in Syrian
hamsters. However, the data suggest that cortisol alone does not
mediate stress-induced increases in food intake or body mass in this
species.
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Fig. 1. Pellet verification. A: plasma cortisol concentration. Cortisol concentration
was significantly increased in animals with the 100% cortisol pellet. B: plasma
corticosterone concentration. Corticosterone concentration was significantly
increased in animals with the 100% corticosterone pellet. C: plasma ACTH
concentration. ACTH concentration was significantly decreased in animals
with 100% cortisol pellet. a,bUnlike letters indicate significance, P ⬍ 0.05.
Steraloids, Wilton, NH), corticosterone (250 ␮g/kg or 1.25 mg/kg;
Steraloids), cocktail (mixed) of the lowest doses of both glucocorticoids (10 ␮g/100 g cortisol and 250 ␮g/kg), or vehicle (propylene
glycol). Glucocorticoids were dissolved in propylene glycol (n ⫽
10/dose). Animals were injected once/day for 5 days, specifically on
days 7, 11, 12, 14, and 17, within the first 2 h of dark onset to mimic
the time frame of our previous defeat studies (15, 32).
Experiment 2: pellet implantation. Hamsters were anesthetized
with isoflurane and received control (cholesterol) or cortisol/corticosterone pellets (Steraloids) inserted subcutaneously in the dorsal neck
area. Note that all animals had intact adrenals for this study. Hamsters
were implanted with 100% (wt/wt) of cortisol, corticosterone, or
cholesterol in the pellets (n ⫽ 10/group). Hardened pellets were
trimmed to weigh 50 mg.
Experiment 3: pellet implantation. Following the same procedure
as experiment 2, a separate group of hamsters were implanted with
control (cholesterol) or a range of cortisol or corticosterone 12.5, 25,
and 50% (wt/wt) in the pellets (n ⫽ 10/group). Hardened pellets were
trimmed to weigh 50 mg.
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Fig. 2. A: thymus mass (g). Significant involution occurred in both pellet
groups. The cortisol group was also significantly decreased compared with the
corticosterone group. B: adrenal mass (mg). Mass was decreased in both
glucocorticoid groups. a– cUnlike letters indicate significance, P ⬍ 0.05.
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Food intake and body mass. Food intake and body mass were
measured daily at 1200 for all experiments.
Body composition analysis. Body composition was analyzed with a
quantitative nuclear magnetic resonance (Echo MRI Whole Body
Composition Analyzer; Echo Medical Systems, Houston, TX) at the
beginning and end of the experiments.
Blood collection, radioimmunoassay, and ELISA. Animals were
euthanized via rapid decapitation between the hours of 0500 and 0900.
Trunk blood was collected and centrifuged at 3,000 g for 20 min at
4°C. Plasma samples were stored at ⫺80°C until they were assayed.
Kits for cortisol (DiaSorin, Stillwater, MN), corticosterone (MP Biomedicals, Orangeburg, NY), adrenocorticotrophin hormone (ACTH)
(DiaSorin, Stillwater, MN), leptin (Crystal Chem, Downers Grove,
IL), and insulin (Crystal Chem) were assayed for experiments 2 and 3
according to the manufacturers’ instructions. Intra-assay variability
was ⬍10% for all assays, and all samples for each hormone were run
in a single assay. For the cortisol kit the cross-reactivity with corticosterone is ⬍0.4%, and for corticosterone the cross-reactivity with
cortisol is ⬍0.05%. Cortisol, corticosterone, and ACTH were analyzed by radioimmunoassay, and leptin and insulin were analyzed
with an ELISA.
Tissue harvesting. For experiments 2 and 3, white adipose tissue
(WAT) depots, including inguinal (IWAT), epididymal (EWAT),
retroperitoneal (RWAT), and mesenteric (MWAT) fat pads, were
collected and weighed. Thymi and adrenals were collected and
cleaned. All tissues were weighed to the nearest 0.01 g. A portion of
the liver was also collected and immediately frozen to later determine
liver triglycerides.
Lipid profile. Commercially available kits were used to measure
triglycerides (Randox Laboratories, Crumlin, UK), cholesterol (Thermo
Fisher Scientific, Middletown, VA), and nonesterified free fatty
acids (NEFA; Wako, Richmond, VA) for experiments 2 and 3 as
per the manufacturers’ instructions. To determine liver triglyceride
CORTISOL AND CORTICOSTERONE METABOLIC OUTCOME IN HAMSTERS
E309
concentration, 50-mg samples were homogenized in 1 ml of 50
mM Tris·HCl buffer, pH 7.4, containing 150 mM NaCl, 1 mM
EDTA, and 1 ␮M phenylmethylsulfonyl. They were centrifuged at
8,000 g for 20 min, and the supernatant was collected and stored at
⫺80°C until it was assayed.
Statistics. Data were analyzed using SigmaStat. Body mass data were
analyzed using a repeated-measures ANOVA, with drug treatment as the
between-subjects factor and time (i.e., day) as the within- or repeatingsubjects factor. For the total food intake, NMR, individual fat pad and
tissue weights, and hormonal analyses, data were analyzed with one-way
ANOVA, with drug treatment as the fixed factor, followed by least
significant difference post hoc tests. Differences among groups were
considered statistically significant if P ⬍ 0.05. Exact probabilities and test
values were omitted for simplicity and clarity of presentation of the results.
Fig. 4. Incremental pellet verification. A: thymus mass
(g). The 25 and 50% CL group had significantly reduced
thymus mass compared with controls, whereas only the
50% CT caused a significant reduction. B: adrenal mass
(mg); 25% and 50% CL and CT groups had significantly smaller adrenals a– cUnlike letters indicate significance, P ⬍ 0.05.
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Fig. 3. Incremental pellet verification. A: plasma cortisol
concentration. Cortisol (CL) concentration was significantly increased in those with 25 and 50% cortisol
pellets compared with controls and both corticosterone
(CT) groups. B: plasma corticosterone concentration.
Circulating corticosterone was significantly increased in
all corticosterone pellet groups compared with control
and all cortisol pellet groups. a– dUnlike letters indicate
significance, P ⬍ 0.05.
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CORTISOL AND CORTICOSTERONE METABOLIC OUTCOME IN HAMSTERS
RESULTS
AJP-Endocrinol Metab • VOL
Fig. 5. A: body mass (g). Postsurgery days 5–10, animals with 100% cortisol
pellets had a significant decline in body mass (*P ⱕ 0.05 vs. control and 100%
corticosterone). B: total 10-day food intake. Cumulative food intake was
significantly decreased in the cortisol group compared with corticosterone
treatment. a,bUnlike letters indicates significance, P ⬍ 0.05.
study (P ⬍ 0.05; days 6 –10) compared with controls and
animals with 100% corticosterone pellets. Cumulative 10-day
food intake (Fig. 5B) was deceased in the 100% cortisol group
and was significantly lower than the intake of the 100%
corticosterone-treated group (P ⬍ 0.05).
In parallel with changes in body mass, lean, fat, and water
mass as measured by NMR were significantly reduced in
hamsters with 100% cortisol pellets but unaltered in animals
with 100% corticosterone pellets compared with controls (P ⬍
0.05; Fig. 6, A–C). Dissected adipose tissue mass was also
significantly decreased in animals with 100% cortisol pellets,
with both visceral (MWAT) and subcutaneous (IWAT) adipose
depots being significantly decreased compared with the control
and 100% corticosterone groups (P ⬍ 0.05; Fig. 6D) and with
intra-abdominal (EWAT and RWAT) adipose tissue depots
being significantly decreased compared with controls only
(P ⬍ 0.05).
Although there were no differences in cumulative food
intake among groups with incremental glucocorticoid pellets
(data not shown), body mass was significantly reduced in
animals with the 25 or 50% cortisol pellets (P ⬍ 0.05; Fig. 7).
More specifically, beginning 3 days after surgery the 25 and
50% cortisol groups weighed significantly less than control
animals (P ⬍ 0.05), and 1 day later those groups also weighed
significantly less than all corticosterone pellet groups (P ⬍
0.05). These differences remained through the end of the study.
Decreases in body mass in the 25 and 50% cortisol groups
were a consequence of reduced lean, fat, and water mass as
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Subcutaneous injections. In experiment 1, there were no
differences in body weight (data not shown), food intake, or
body composition, i.e., lean, fat, or water mass, (data not
shown), among any of the groups.
Glucocorticoid pellet verification. Terminal plasma cortisol
concentration in the 100% cortisol pellet group was significantly higher, approximately eight times, than that of controls
with vehicle pellets (P ⬍ 0.05; Fig. 1A). In contrast, implantation of 100% corticosterone did not alter endogenous cortisol
levels. The opposite was true with corticosterone concentration
(Fig. 1B), where the 100% corticosterone pellets caused a
significant increase (P ⬍ 0.05), approximately four times,
compared with controls, whereas the 100% cortisol pellets did
not alter endogenous corticosterone levels, suggesting little to
no cross-reactivity between the kits. A second implication is
that neither glucocorticoid significantly suppressed the secretion of the other. ACTH concentration was only significantly
decreased in animals with 100% cortisol pellets compared with
controls (P ⬍ 0.05; Fig. 1C). Thymus mass was significantly
decreased in both glucocorticoid groups compared with controls (P ⬍ 0.05; Fig. 2A), and the 100% cortisol pellet group had
significantly lighter thymi than the 100% corticosterone group
(P ⬍ 0.05). Adrenal mass was also significantly decreased in both
the 100% cortisol and corticosterone groups relative to controls;
however, there were no differences between the cortisol and
corticosterone groups (P ⬍ 0.05; Fig. 2B).
Incremental concentrations of cortisol pellets resulted in a
gradual incremental increase in plasma cortisol (Fig. 3A).
Plasma cortisol did not increase in hamsters with 12.5%
cortisol pellets compared with controls but was significantly
increased in those with ⱖ25% cortisol pellets (P ⬍ 0.05). In
addition, the 50% cortisol pellet group was significantly higher
than the 12.5 and 25% cortisol pellet groups (P ⬍ 0.05), and
levels in both the 25 and 50% cortisol pellet groups were
significantly higher than those in any of the corticosterone
pellet groups (P ⬍ 0.05). The 25 and 50% corticosterone pellet
groups significantly decreased endogenous cortisol levels compared with control, whereas the 25% did not alter cortisol
release.
Circulating corticosterone was significantly increased in all
corticosterone pellet groups compared with controls and all
cortisol pellet groups (P ⬍ 0.05; Fig. 3B). Corticosterone
levels in animals with 50% corticosterone pellets were significantly higher than those with 12.5 or 25% pellets (P ⬍ 0.05).
There were no differences in ACTH levels among the
incremental glucocorticoid groups (data not shown). Thymus
mass was not decreased in either of the 12.5% pellet groups or in
the 25% corticosterone group compared with controls (Fig. 4A).
Conversely, both the 25 and 50% cortisol pellets significantly
reduced thymus mass (P ⬍ 0.05) compared with controls,
whereas only the 50% corticosterone caused a significant
reduction (P ⬍ 0.05). The 25 and 50% cortisol and corticosterone groups had significantly smaller adrenals compared with
control groups (P ⬍ 0.05; Fig. 4B).
Food intake and body mass, adiposity, and composition.
Groups were matched by average body mass on the day of
surgery (Fig. 5A). Four days postsurgery, animals with 100%
cortisol pellets had a significant decline in body mass (P ⬍
0.05; day 5) that continued throughout the remainder of the
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Fig. 6. Change in lean (A), fat (B), and water mass (C). Lean, fat, and water mass was significantly reduced in animals with cortisol pellets compared with controls.
D: total dissected adipose tissue mass (g). Visceral [mesenteric white adipose tissue (MWAT)] and subcutaneous [inguinal white adipose tissue (IWAT)] adipose
depots were significantly decreased in the cortisol group compared with control and corticosterone groups. Intra-abdominal [epididymal (EWAT) and
retroperitoneal white adipose tissue (RWAT)] depots were significantly decreased in corticol group compared with controls only. a,bUnlike letters indicate
significance, P ⬍ 0.05.
measured by NMR. Although the 50% cortisol group had
decreased lean mass relative to all other groups, this was not
significant. As such, lean mass did not differ significantly
among any of the groups. However, water mass was significantly decreased in the 50% cortisol group compared with all
other groups (Table 1). Of note, fat mass as determined by
AJP-Endocrinol Metab • VOL
NMR was significantly reduced only in the 25% cortisol group
(P ⬍ 0.05; Table 1). On the other hand, cortisol dose-dependently decreased total dissected adipose tissue mass, and the
highest dose (50%) was significantly different from all other
groups (total dissected adipose tissue mass ⫽ MWAT ⫹
IWAT ⫹ EWAT ⫹ RWAT; bilateral depots were averaged
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CORTISOL AND CORTICOSTERONE METABOLIC OUTCOME IN HAMSTERS
cortisol and corticosterone pellet groups (P ⬍ 0.05; Fig. 10A),
and the cholesterol in the 50% cortisol group was higher than
in the 50% corticosterone group. NEFA concentrations were
increased only in the 50% cortisol group (P ⬍ 0.05; Fig. 10B).
DISCUSSION
together before summation). The exact differences in individual adipose tissue mass are summarized in Table 1.
Lipid profile and insulin and leptin concentration. Liver and
plasma triglyceride, free fatty acid, and cholesterol levels were
all increased significantly in the 100% cortisol pellet group
compared with controls and 100% corticosterone (P ⬍ 0.05;
Fig. 8, A–D). Insulin (Fig. 9A-1) and leptin (Fig. 9B) concentrations were nonsignificantly increased in both groups with
glucocorticoid pellets. However, insulin concentrations of the
100% cortisol group (n ⫽ 10) contained two subpopulations,
those with high insulin values (n ⫽ 4) and those with extremely
low insulin values (n ⫽ 6), hence the large variability in the
group. Therefore, with subpopulations considered (Fig. 9A-2),
insulin is increased significantly in the cortisol high-insulin and
corticosterone groups, whereas the cortisol animals with the
low insulin are significantly lower than all groups (P ⬍ 0.05).
The high-insulin cortisol group is also significantly higher than
the corticosterone group.
Liver and plasma triglyceride concentrations did not differ
among incremental glucocorticoid groups (data not shown).
However, hamsters receiving 50% cortisol or corticosterone
pellets had a significant increase in plasma cholesterol compared with controls as well as compared with the 12.5 and 25%
Table 1. Change in lean and fat mass as measured by NMR and dissected individual and total adipose tissue mass in Syrian
hamsters with incremental glucocorticoid concentrations
NMR Change in Body Composition
Lean mass
Vehicle
Cortisol, %
12.5
25
50
Corticosterone,%
12.5
25
50
⫺2.96 ⫾ 6.83
Fat mass
Dissected Adipose Tissue Mass, g
Water mass
⫺12.80 ⫾ 7.21
a,c
MWAT
5.645 ⫾ 3.861
a
IWAT
EWAT
RWAT
Total
3.24 ⫾ 0.24
1.95 ⫾ 0.26
1.52 ⫾ 0.10
1.26 ⫾ 0.16
7.97 ⫾ 0.65a,b
a,b
a,b
1.14 ⫾ 7.35
⫺11.84 ⫾ 3.56
⫺30.06 ⫾ 12.05
⫺9.02 ⫾ 11.42a,c
⫺42.70 ⫾ 6.01b
⫺33.01 ⫾ 7.68b,c
0.043 ⫾ 4.33a
⫺5.588 ⫾ 1.85a
⫺21.28 ⫾ 6.25b
3.57 ⫾ 0.27a
2.79 ⫾ 0.21b
2.62 ⫾ 0.17b
2.29 ⫾ 0.20a
1.63 ⫾ 0.09b
1.5 ⫾ 0.11b
1.87 ⫾ 0.16
1.51 ⫾ 0.09
1.57 ⫾ 0.09
1.30 ⫾ 0.14
0.10 ⫾ 0.05
1.11 ⫾ 0.17
9.09 ⫾ 0.73a
6.93 ⫾ 0.50b,c
5.95 ⫾ 0.92c
⫺1.53 ⫾ 5.24
⫺4.87 ⫾ 5.68
⫺7.26 ⫾ 7.55
⫺12.97 ⫾ 13.76a,c
8.36 ⫾ 8.74a
⫺2.75 ⫾ 8.79a
1.337 ⫾ 3.03a
⫺2.218 ⫾ 3.08a
⫺5.382 ⫾ 3.92a
3.19 ⫾ 0.28a,b
3.74 ⫾ 0.30a
3.56 ⫾ 0.30a
2.05 ⫾ 0.14a
2.16 ⫾ 0.17a
2.21 ⫾ 0.24a
1.62 ⫾ 0.12
1.75 ⫾ 0.10
1.77 ⫾ 0.17
1.12 ⫾ 0.10
1.48 ⫾ 0.18
1.35 ⫾ 0.16
7.96 ⫾ 0.58a
9.11 ⫾ 0.60a
8.90 ⫾ 0.84a
Values are means ⫾ SE. MWAT, mesenteric white adipose tissue; IWAT, inguinal white adipose tissue; EWAT, epididymal white adipose tissue; RWAT,
retroperitoneal white adipose tissue. Change in lean body mass: no significant differences among groups. Change in body fat mass: 12.5% cortisol group fat mass
was significantly reduced compared with control animals as well as all other experimental groups, except for the 50% cortisol group. Change in water mass: 50%
cortisol group; water mass was reduced compared with all other groups. Total dissected fat mass: total dissected adipose tissue mass was significantly decreased
in the 25 and 50% cortisol groups compared with 12.5% cortisol and all corticosterone pellet groups; the 50% cortisol group was also significantly decreased
compared with controls. Individual dissected adipose tissue mass: MWAT and IWAT were significantly reduced in the 25 and 50% cortisol groups compared
with 25% cortisol and corticosterone groups as well as the 50% corticosterone group. a– cUnlike letters indicate significance, P ⬍ 0.05.
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Fig. 7. Incremental dosage: body mass (g). Three days after surgery the 25 and
50% cortisol groups weighed significantly less than control animals (*P ⬍
0.05). By day 4, the groups also weighed significantly less than all corticosterone pellet groups (**P ⬍ 0.05), followed by significant difference from
12.5% cortisol group on days 5–7 (***P ⬍ 0.05).
The goal of the present study was to determine whether
increases in glucocorticoids (as occurs following social defeat)
facilitate stress-induced body weight and adiposity gain. To
accomplish this, we injected Syrian hamsters with varying
concentrations of cortisol and corticosterone to emulate our
previously published defeat regimens (15, 32). The selected
doses were based upon data that indicated significant changes
in stress-related behavior and/or energy homeostasis (7, 41).
Food intake, body weight, and composition were not altered
following glucocorticoid injections. As such, we moved toward
examining the effect of sustained glucocorticoid exposure on
energy homeostasis with pellets. The primary finding is that
cortisol, but not corticosterone, dose-dependently decreases
food intake, body mass, lean tissue, and adiposity, whereas
plasma free fatty acids, cholesterol and triglyceride, and hepatic triglyceride content simultaneously increase. Although
corticosterone did not impact any of the metabolic end points
in the study, both glucocorticoids induced thymic involution
and decreased adrenal mass, thus confirming that both exogenous glucocorticoids were active. To our knowledge, these data
are the first to demonstrate differential metabolic effects of
cortisol and corticosterone in Syrian hamsters. However, it
appears as though neither glucocorticoid exclusively mediates
stress-induced increases in food intake/body mass.
In humans, excess cortisol secretion is associated with obesity and many obesity-related diseases (i.e., diabetes) (6, 37).
However, in rats, depending upon the dosage, glucocorticoids
(corticosterone) can have both lipolytic as well as adipogenic
effects (9). In the present study, high doses of cortisol in Syrian
hamsters cause a significant loss of body mass via lean, fat, and
water mass. These decreases are specific to cortisol because
they do not occur with corticosterone. Analogous to these
cortisol-mediated effects on energy homeostasis in Syrian
hamsters, high doses of corticosterone blunt increases in body
CORTISOL AND CORTICOSTERONE METABOLIC OUTCOME IN HAMSTERS
E313
mass and significantly decrease lean tissue in rats (1), although
unlike hamsters, rats do not have an overall loss of body or
adipose tissue mass. In rats, corticosterone dose-dependently
breaks down muscle protein and at chronic high doses causes
significant decreases of lean tissue mass (35), which is consistent with what occurred with the high doses of cortisol (50 and
100%) in Syrian hamsters. Although glucocorticoids decrease
adipose mass in part by increasing lipolysis, studies in rats
demonstrate that high (100%) chronic levels of corticosterone
do not sufficiently induce loss of adiposity (9, 20, 38), and this
is in contrast to our findings. These inconsistencies between the
current and previous studies may be explained by the fact that
many previous studies were conducted in rats with the adrenals
removed, which in and of itself can drastically alter metabolism. In addition, different metabolic outcomes of the two
glucocorticoids in our model may reflect differential affinities
of glucocorticoids for specific receptors or for cortisol/corticosterone-binding globulin capacity.
Decreases in body, lean, and adipose tissue mass could to
some extent be attributed to decreases in food intake, but it is
likely that other metabolic effects of glucocorticoids played a
role. For example, the only cortisol pellet concentration to
elicit significant decreases in food intake was 100%, although
25, 50, and 100% cortisol pellets significantly decreased body
mass. This implies that decreased food intake in the cortisolAJP-Endocrinol Metab • VOL
treated groups is accompanied by a change in metabolism
favoring weight loss. Indeed, chronic glucocorticoid release is
reported to increase core body temperature (12) and overall
energy expenditure (42) and to decrease sleep/increase hours of
arousal (16), all of which will promote decreases in body mass
with normal food consumption. However, these parameters
were not assessed in the present experiment.
Humans with chronically elevated glucocorticoids are characterized by increased insulin and leptin concentrations. More
specifically, excessive glucocorticoid release increases gluconeogenesis in the liver, which subsequently inhibits insulin
sensitivity in the liver and skeletal muscle and ultimately
elevates circulating insulin (29). Initial evaluation revealed that
neither 100% cortisol nor corticosterone significantly increased
circulating insulin, but subsequent evaluation revealed two
divergent subpopulations in the 100% cortisol group, those
with extremely high or low circulating insulin. The deviation
within this group may represent a dynamic time point where
hamsters are transitioning from the consequences of acute
(soaring insulin levels) to chronic (severe decline in insulin
levels) excessive glucocorticoid release. Indeed, research demonstrates that high concentrations of glucocorticoids first elevate insulin (29), but if unrelenting, pancreatic ␤-cells undergo
apoptosis and dysfunction, which reduces insulin synthesis and
secretion (30). In humans, excessive glucocorticoid-induced
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Fig. 8. Liver triglyceride concentration (A), triglyceride (B), free fatty acid (C), and cholesterol (D). Liver and plasma triglyceride, free fatty acid, and cholesterol
were all significantly increased in the 100% cortisol pellet group compared with control and 100% corticosterone. a,bUnlike letters indicate significance, P ⬍ 0.05.
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increases in leptin result following enhanced leptin synthesis
and secretion (24); however, this was not significantly increased in the 100% cortisol or corticosterone groups.
It is established that insulin and leptin are adiposity signals
that are secreted in proportion to the quantity of stored fat.
However, neither of the glucocorticoid groups gained body/
adiposity mass; in fact, the 100% cortisol group lost significant
fat mass despite moderate increases in insulin and leptin
compared with controls. Therefore, unlike Cushing’s in humans (3), excessive glucocorticoid release did not increase
visceral adipose tissue mass in Syrian hamsters. This may be
due to the fact that the cortisol concentrations used in the
present study are exponentially higher than those typically
observed to increase adiposity by pituitary/adrenal Cushing’s
or multiple glucocorticoid injections. However, excessive high
cortisol release in hamsters increases circulating triglycerides,
cholesterol, and free fatty acids, as demonstrated in humans
(4). Furthermore, like humans (10), but unlike rats (38), high
doses of cortisol in hamsters significantly increase liver triglyceride storage, which is likely a result of cortisol-enhanced
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Fig. 9. Insulin (A-1), insulin subpopulation (A-2), and leptin concentration (B).
With subpopulations considered, insulin concentration was significantly increased in one-half of the cortisol group, whereas it was significantly decreased
in the other compared with control and 100% corticosterone groups. The 100%
corticosterone was also significantly different from the control animals. No
significant differences in leptin concentration. a– dUnlike letters indicate significance, P ⬍ 0.05.
release of free fatty acids (4) and liver activity of lipidsynthetic enzymes (21).
Standard indices of increased HPA axis drive, due to either
chronic stress or excessive exogenous glucocorticoid administration, are thymus (33) and adrenal (40) mass reduction. Both
cortisol and corticosterone caused adrenal hypotrophy and
dose-dependently induced thymic involution in Syrian hamsters, although reductions in thymus mass were evident at
lower concentrations of cortisol. This finding indicates that
Syrian hamsters are responsive to corticosterone, although
cortisol appears to be generally more potent. Conversely, high
doses of cortisol, but not corticosterone, reduced ACTH levels,
a finding that is consistent with corticosterone in rats and mice
(26). This implies that the pituitary also has preferential affinity
for cortisol in the hamster model. To our knowledge, there are
no data regarding differential effects of the two glucocorticoids
on ACTH secretion in Syrian hamsters.
The data presented here indicate tissue-specific effects of
glucocorticoids in a dual secreting model, with cortisol having
marked effects on thymus and adrenal gland growth as well
metabolic end points. In contrast, corticosterone modulated
only thymus and adrenal mass growth. One may argue that the
differential effects of the glucocorticoids may be due to differential increases in blood concentrations of each hormone.
For example, the highest dose of cortisol (100%) increased
circulating cortisol concentrations approximately eightfold relative to vehicle-treated hamsters, whereas the same dosage of
corticosterone increased corticosterone concentrations only
fourfold. We do not believe that this is the reason for the more
potent effects of cortisol vs. corticosterone on metabolic end
points. As a case in point, the 50% cortisol dose that elicited a
fourfold increase in blood cortisol also modulated many of the
metabolic end points in the study. Although cortisol is the more
biologically active hormone in Syrian hamsters, previous studies indicate that cortisol and corticosterone bind the type II
glucorticoid receptor with similar affinity in the brain (34). At
present, we do not know the underlying mechanisms that may
account for the differential effects of these hormones on certain
target tissues. The most parsimonious explanation is differing
binding affinities of the glucocorticoids depending upon the
target tissue. For example, perhaps in this species, adipose
depots are more responsive to cortisol vs. corticosterone,
whereas the thymus and adrenal glands are equally responsive
to both glucocorticoids.
The goal of the study was to determine the underlying
hormonal mechanisms that may account for the social stressinduced increases in body mass and adiposity in Syrian hamsters. We hypothesized that the social stress-induced body
mass and adiposity gain (15, 32) might be due to increases in
circulating glucocorticoids. However, in the present study,
neither glucocorticoid regimen (i.e., acute injections or chronic
pellets) elicited an increase in body mass or adiposity, suggesting that glucocorticoids (at least the doses in this study) alone
are not sufficient to favor increased body mass and adipose
growth. Certainly, stress is not characterized solely by excess
glucocorticoids, since there are other factors that are released
in response to stress. Perhaps it is not increased glucocorticoids
that are responsible for stress-induced increases in body mass
but rather metabolic alterations that occur during the recovery
from stress that promote adiposity, as seen in our social stress
model.
CORTISOL AND CORTICOSTERONE METABOLIC OUTCOME IN HAMSTERS
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ACKNOWLEDGMENTS
We thank Dr. James P. Herman for thoughtful comments concerning this
project.
GRANTS
This research was supported by the National Institute of Diabetes and
Digestive and Kidney Diseases: DK-087816 (M. T. Foster), DK-017844 (S. C.
Woods), DK-078201 (S. C. Woods), and DK-066596 (R. R. Sakai).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
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