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Departments of Neuroscience and Biostatistics, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We previously reported that rats exposed
to repeated restraint (3 h/day for 3 days) experience
temporary hypophagia and a sustained reduction in body weight compared
with nonrestrained controls. Studies described here determined the
involvement of central corticotropin-releasing factor (CRF) receptors
in the initiation of this chronic response to acute stress. In
experiment 1, Sprague-Dawley rats were
fitted with cannulas in the lateral ventricle and infused with 50 µg
of 
hCRF-(9
41) or saline immediately before restraint on each of
the 3 days of restraint. The receptor antagonist inhibited hypophagia
and weight loss on day 1 of restraint but not on days 2 and
3. In experiment
2, 10 µg of hCRF-(941) or saline were infused
into the third ventricle immediately before each restraint. The
receptor antagonist totally blocked stress-induced hypophagia and
weight loss. These results demonstrate that CRF receptors located in or
near the hypothalamus mediate the acute responses to stress that lead
to a permanent change in the hormonal or metabolic processes that
determine body weight and body composition.
hCRF-(941); restraint stress; food intake
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IT IS WELL ESTABLISHED that stressors such as restraint and immobilization acutely inhibit food intake and consumption of sweet solutions (12, 17). Less information is available concerning the sustained changes in energy balance that follow stress. A majority of studies have focused on energy balance during or immediately after repeated stress, which causes significant weight loss in rats (10, 12). However, it has been reported that 3 wk after a single social defeat, stressed rats weigh less than controls (13). We also reported that rats exposed to a single bout (20) or repeated bouts (8) of 3 h of restraint stress experience a sustained weight loss, such that restrained rats weigh significantly less than their controls even 40 days after the end of stress (8).
The mechanisms that initiate the process that reduces the level at which body weight is regulated have not been identified. Stress stimulates corticotropin-releasing factor (CRF) release, which activates the hypothalamic-pituitary-adrenal (HPA) axis, serotonergic and catecholaminergic systems, the sympathetic nervous system, and the immune system (27). As CRF and CRF receptors are widely distributed in the brain and peripheral tissues, this results in a complex neurological and physiological response to the disruption of homeostasis (4). Understanding the complexity of these responses has been made more difficult by the identification of multiple subtypes of CRF receptors (5), CRF binding protein (2), and urocortin (UCN), a peptide with structural similarity to CRF and to urotensin and with a high affinity for CRF receptors (28).
Although CRF, UCN, and CRF receptors are present in multiple central and peripheral sites, the paraventricular nucleus of the hypothalamus (PVN) is the brain area of primary interest when the effects of stress on food intake are considered. The hypothalamus, including the PVN, has a high density of CRF2 receptors (11, 29) and permits CRF/UCN modulation of hypothalamic hormones and of hypothalamic input to the anterior and posterior pituitary gland. Central infusions of CRF or UCN cause an immediate inhibition of food intake (24).
The requirement for activation of CRF receptors in acute,
stress-induced hypophagia was confirmed with intraventricular infusions of the CRF receptor antagonist hCRF-(941) before restraint. The
antagonist partially prevented hypophagia during the hour after
restraint (9, 21). The objective of the studies described here was to
determine whether antagonism of central CRF receptors immediately
before restraint stress would also prevent or modify the chronic change
in body weight. Rats received central infusions of hCRF-(941)
immediately before restraint on each of 3 days of repeated restraint.
In experiment 1, antagonist was
infused into the lateral ventricle, as this treatment had previously
been reported to partially reverse acute stress-induced hypophagia (9,
21); however, it was effective only on day
1 of restraint in our study. In
experiment 2 we found that third
ventricle infusions of the antagonist totally blocked stress-induced
weight loss.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1: lateral ventricle infusion of
hCRF-(941) in repeatedly restrained rats.
Twenty-four male Sprague-Dawley rats (~300 g body wt) were obtained
from Harlan Sprague Dawley (Indianapolis, IN). They were housed in
individual hanging wire mesh cages with free access to water and food
in a temperature (73-75°F)- and
humidity-controlled room with lights on for 12 h/day from 7 AM. After 7 days of quarantine the rats were implanted with cannulas in the lateral
cerebral ventricle, as described previously (23), and allowed to
recover from surgery for 5 days, during which time they were also
adapted to a liquid diet containing 10% of kilocalories from protein
and 21% of kilocalories from fat (Research Diets, New Brunswick, NJ). Baseline food intakes and body weights were recorded for 7 days. Before
the start of the experiment, cannulas were tested for patency by
infusing 20 ng of angiotensin II in 3 µl of sterile saline and
confirming that the animals drank within 5 min of the infusion.
hCRF-(941) in 3 µl of saline (AC and AR). Restrained rats were placed in Perspex
restraining tubes (Plas Labs, Lansing, MI) for 3 h from 8 to 11 AM.
Small blood samples (~50 µl) were collected by tail bleeding from
each rat exactly 1 h after infusion for measurement of serum
corticosterone (corticosterone RIA kit, ICN Biomedicals, Costa Mesa,
CA). At the end of restraint, animals were returned to their home cages
in their home room and were given food and water. Food intake was
measured during the light phase at 2, 4, 7, 8, and 9 h after the end of
stress. Two more measurements were taken 1 and 2 h into the dark phase.
The same procedures were followed for days
2 and 3 of repeated
restraint. Body weights and food intakes were measured daily for 3 days
after the end of restraint, and the animals were killed by
decapitation. Feed efficiency ratio was calculated by dividing weight
change during the experimental period by total volume of food consumed
during the experimental period. Blood was collected for serum analysis of corticosterone, insulin (rat insulin RIA kit, Linco Research, St.
Louis, MO), leptin (rat leptin RIA kit, Linco Research), glucose (diagnostic kit 510, Sigma Chemical, St. Louis, MO), and free fatty
acids (NEFA C kit; WAKO Chemicals, Richmond, VA). Inguinal, epididymal,
and retroperitoneal fat pads, liver, adrenals, and thymus were weighed
and returned to the carcass. The carcass, less gut content, was frozen
for subsequent determination of body composition, as described
previously (7). Immediately before decapitation, 1 µl of 1%
methylene blue solution was infused into the cannula to allow
postmortem confirmation of cannula placement.
Experiment 2: third ventricle infusion of
hCRF-(941) in repeatedly restrained rats.
Forty-four 300-g male Sprague-Dawley rats were housed as described
above and implanted with cannulas in the third cerebral ventricle with
use of stereotaxic techniques. Guide cannulas (25 gauge, 15 mm long)
were placed using the following coordinates applied to a flat skull:
anteroposterior 
2.8, lateral 0.0, ventral 8.1 from
bregma. They were secured with machine screws and dental cement and
fitted with 30-gauge wire stylets. The injection cannulas (31 gauge)
were designed to project 1 mm beyond the guide cannula tip. The rats
were adapted to a dry 16% of kilocalories from protein-40% of
kilocalories from fat diet (8) for 5 days. Before the start of the
experiment, cannula patency was tested as described above using 5 ng of
angiotensin II in a 1.0-µl infusion. Baseline measures of daily body
weight and food intake corrected for spillage were made for 6 days,
then on the day before the onset of repeated restraint the rats were
divided into four weight-matched groups. The infusion and restraint
procedures were the same as for experiment 1, except on each day of restraint the rats received a
1-µl infusion of saline or 10 µg of hCRF-(941) in 1 µl of
saline 10 min before stress. Tail blood samples were collected 1 h
after infusion on each of the 3 days for measurement of corticosterone.
At the end of stress, rats were returned to their home cages in their
home room and given free access to food and water. Food intakes and body weights were recorded at 24-h intervals for 4 days after the end
of stress, and feed efficiency ratio was calculated for the
experimental period. On the next day the animals were decapitated immediately after a 1-µl infusion of methylene blue solution. Blood
was collected for determination of serum corticosterone, insulin,
leptin, glucose, and free fatty acids. The hypothalamus was dissected
and snap frozen. The PVN was collected by punch, as described
previously (20), using the method of Palkovits (16), and CRF
concentration was determined by RIA (CRF RIA kit, Peninsula
Laboratories, Belmont, CA). Inguinal, epididymal, and retroperitoneal
fat pads, liver, adrenals, and thymus were weighed and returned to the
carcass. Gut content was removed, and body composition was determined.
Statistical analysis. The repeated measures of body weight, food intake, and corticosterone were compared by repeated-measures two-way ANOVA and post hoc calculation of least significant difference (SAS for Windows, release 6.12, SAS Institute, Cary, NC). Other end-point measures were compared by two-way ANOVA and post hoc Duncan's multiple range test (Statistica, StatSoft, Tulsa, OK).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1: lateral ventricle infusion of
hCRF-(941) in repeatedly restrained rats.
Body weights and food intakes of rats that received lateral ventricle
infusions of saline or hCRF-(941) are shown in Fig. 1. Two-way ANOVA, with baseline weight on
day 0 as a covariant, indicated a
significant effect of stress (P < 0.0001) and day (P < 0.0001) and no
significant effect of infusion (saline vs. antagonist) but a
significant interaction between infusion and day
(P < 0.03). During the baseline
period the four groups of rats had similar body weights. All rats lost
a small amount of weight at the beginning of the experimental period,
presumably because of the stress of the manipulations required for
infusion and tail bleeding. After the first bout of restraint, SR rats lost ~22 g and weighed significantly less than SC rats. This
significant difference in weight was maintained to the end of the
study. In contrast, SC, AC, and AR rats lost ~9 g after the first
restraint. On subsequent days of restraint the AR rats continued to
lose weight and weighed significantly less than their controls from day 3 to day
6 of the experiment. Statistical analysis of food intakes from day 1 to the end of the
study indicated a significant effect of stress
(P < 0.0001) and day
(P < 0.0001) and a significant interaction between stress and day (P < 0.02) but no effect of antagonist infusion. In saline-infused
animals the restrained rats had a significantly lower food intake than
their controls on all but the last day of the experiment. In
antagonist-infused rats the intakes of restrained rats were
significantly lower than those of their controls only on the last 2 days of restraint. There were no significant differences in intake of
the two control groups or the two groups of restrained rats. Feed
efficiency ratio during the experimental period was negative for all
animals, as even the controls lost some weight in response to the
experimental manipulations (Table 1).
Efficiency was significantly decreased by stress
(P < 0.0003), but there was no
effect of treatment and no significant interaction.
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hCRF-(941). There were no differences in the weights
of inguinal or epididymal fat, liver, or adrenal gland. Stress caused a
significant decrease in thymus weight
[P < 0.007 for stress, not
significant (NS) for infusion, NS for interaction].
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Experiment 2: third ventricle infusion of
hCRF-(941) in repeatedly restrained rats.
Daily body weights and food intakes of rats in
experiment 2 are shown in Fig.
4. Before stress, there were no differences in body weight or weight gain of the four groups of rats. As in experiment 1, all rats lost some
weight at the start of the experimental period. There was a significant
effect of stress (P < 0.03) and day
(P < 0.001) on body weight and a
significant interaction between day and stress
(P < 0.001) when body
weight on day 0 was used as a
covariant. There was a tendency for the infusion (antagonist vs.
saline) to influence the response and for an interaction between infusion and stress, but neither of these reached statistical significance (P < 0.08). Post hoc
analysis showed no differences in the weights of AC and AR rats on any
day of the experiment, whereas SR rats weighed significantly less than
SC rats from day 1 of restraint to the
end of the experiment. Comparison of food intakes of the rats, with
intake on day 0 as a covariant, showed no significant effect of restraint but significant effects of infusion
(P < 0.005) and day
(P < 0.0001) and a significant
interaction between restraint and infusion
(P < 0.008). The interaction between infusion and day did not reach statistical significance
(P < 0.07). Post hoc analysis
indicated no difference in intakes of AR and AC rats on any day of the
experiment. Intakes of SR rats were significantly lower than those of
SC rats on each of the 3 days of restraint (days
1-3) and were significantly lower than those of AR
rats on days 1-7. Feed efficiency
ratios during the experimental period are shown in Table
2. Efficiency was negative for all rats in
the experiment but was significantly increased in rats treated with the
receptor antagonist compared with those infused with saline. There was
no effect of stress on efficiency, and there was no significant
interaction.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results from these studies demonstrate that antagonism of CRF receptors in areas adjacent to the third ventricle prevents stress-induced weight loss. The antagonist was acutely applied immediately before each restraint, which indicates that events that occur during or soon after stress initiate a cascade with an end point of temporary hypophagia but sustained downregulation of body weight. As there were no differences in PVN CRF concentrations or in serum corticosterone at the end of experiment 2, chronic activation of the adrenal glands or the hypothalamic CRF system is not needed for the sustained effects of stress on body weight. Although different doses of antagonist were infused into the lateral and the third ventricles, the lower dose in the third ventricle totally blocked stress-induced changes in body weight, whereas a larger dose in the lateral ventricle was only partially effective, suggesting that nuclei adjacent to the third ventricle are the areas of primary response in this model. One area that may mediate the initial responses to stress is the PVN, as neurochemical activity in this area is associated with feeding behavior (25), and lesioning of the PVN leads to the development of obesity (22). It is well established that CRF and UCN inhibit food intake when they are infused centrally (24), and these effects are probably mediated by CRF2 receptors, which are present at high concentrations in several nuclei of the hypothalamus (11, 29) and are also likely candidates as mediators of stress-induced changes in food intake and body weight. However, as stress activates multiple neurochemical pathways in many brain nuclei (4, 27), further studies are needed to clarify the sites at which stress-activated CRF receptors mediate their effect on food intake and body weight.
Infusion of the CRF receptor antagonist into the lateral ventricle only
partially prevented the loss of weight in restrained rats. In these
animals, weight loss followed food intake, as the antagonist prevented
hypophagia on day 1 of restraint but
not on day 2 or
3. Body weight was not significantly
lower than that of antagonist-treated controls until the last day of
stress. This delayed response to stress meant that the weight of
antagonist-treated rats was not as low as that of the saline-treated
restrained rats. This partial reversal of stress-induced behaviors may
be attributable to inadequate amounts of antagonist reaching the
hypothalamic area, which appears to be responsible for initiating
energy balance response to stress. The effect of hCRF-(941) on
rats exposed to repeated restraint are very similar to those reported
for rats exposed to 1 h of restraint, in which infusion of the
antagonist into the lateral ventricle immediately before restraint only
partially prevented the stress-induced hypophagia during the 1 h
immediately after stress (9, 21).
Although the food intake of restrained rats was at control levels or
was returning to control levels by the end of the experiment, there was
no indication that weight loss was being reversed. These observations
are consistent with our previous report that restrained rats do not
achieve the same weight as controls even 40 days after the end of
repeated restraint (8). This suggests that acute activation of the
hypothalamic CRF system initiates a series of events that leads to the
resetting of metabolic equilibria that determine body weight and
composition. The changes in feed efficiency in
experiment 1 suggest that increased
energy expenditure may contribute to the weight loss in stressed rats,
and further studies are needed to determine whether the decreased
efficiency is maintained over time and contributes to the sustained
reduction in body weight of restrained rats. We previously found that
weight loss during stress is due entirely to lean tissue (water + protein) but that 5 days after the end of repeated restraint body
composition has adjusted so that fat and lean tissue contribute to the
weight difference (8). This appeared to be true in these experiments, although the differences were generally too small to be statistically significant. In experiment 2, rats
that were infused with hCRF-(941) had an increased carcass ash
content. Cushing's disease, inappropriate activation of the HPA axis,
leads to osteoporosis due to stimulation of bone resorption by
glucocorticoids (26). Therefore, it is possible that the increased bone
mineralization in this study resulted from decreased glucocorticoid
function associated with antagonism of HPA axis activity. Measures made
in this study did not clarify whether repeated acute application of
hCRF-(941) caused a chronic change in HPA activity or whether the
short period of interference with normal regulation of adrenal function
on days of restraint caused a significant change in bone mineralization detectable 4 days later.
Infusion of the CRF receptor antagonist into the lateral or the third ventricle did not have any significant effect on stress-induced corticosterone release. Although we assume that the receptor antagonist inhibited hypothalamic CRF/UCN activity, this is not the exclusive mechanism for stress-associated responses of the HPA axis. It is well established that stress activates the sympathetic nervous system, which in turn can promote release of glucocorticoids (6). In addition, other stress-activated neurotransmitters, such as serotonin and catecholamines, can directly stimulate hypothalamic CRF neurons and activate the HPA system. ACTH release in response to stress would have provided a better measure of HPA activity in the antagonist-treated rats; however, larger blood samples would have been required, and the extended period of sampling may have caused acute stress responses in control rats, minimizing differences between control and restrained animals.
One surprising finding was that serum corticosterone was elevated 4 days after stress in control and restrained rats that had received
lateral infusions of the receptor antagonist. This change in
corticosterone was not present in rats that received third ventricle
infusions. The sustained change in corticosterone could reflect one of
two potential changes in the rats. The first possibility is that
repeated infusions of the receptor antagonist cause a permanent,
compensatory increase in CRF receptor number or receptor affinity, so
that basal levels of CRF lead to abnormally high levels of adrenal
hormone release. Alternatively, interruption of the normal diurnal
rhythm of the HPA axis by the receptor antagonist causes a shift in the
circadian pattern of release of adrenal hormones. Thus, as the rats
were killed in the morning, corticosterone would be expected to be low,
but if the circadian rhythm was shifted, there could be an early peak
in corticosterone concentrations. Further studies with repeated
measures of HPA activity and adrenal hormone concentrations are needed
to determine which of these responses were present in rats that
received lateral ventricle infusions of hCRF-(941). Corticosterone
was not elevated at the end of experiment
2, in which rats received third ventricle infusions.
There are several potential reasons for the difference between
experiments. The first is the site of antagonist infusion. It is
possible that the response in laterally infused rats was secondary to
disruption of the CRF system in areas distant from the third ventricle.
A second difference was the amount of antagonist infused, as the
lateral ventricle infusion contained five times more antagonist than
the third ventricle infusions. This high dose of antagonist may have
caused irreversible changes in CRF receptors or HPA activity that were
not caused with smaller amounts of antagonist.
Another difference between experiments
1 and 2 was that third
ventricle infusions of antagonist caused significant increases in body
fat content, whereas there was no difference in fat content of rats
that received lateral infusions. The increase in body fat appeared to
be depot specific, with increases in the weights of retroperitoneal and
inguinal, but not epididymal, fat. Rosmond et al. (18, 19) recently
reported that chronic, perceived stress increases abdominal fat content
in men. They hypothesize that abdominal obesity is caused by
hyperactivity of the HPA axis and increased levels of cortisol and
insulin with low concentrations of growth hormone and sex hormones (3).
We did not measure mesenteric fat in the rats in these experiments, but
it appeared that interference with HPA activity by repeated infusion of
hCRF-(941) into the third ventricle caused an increase in
subcutaneous (inguinal) and certain intraperitoneal (retroperitoneal)
fat depots. In the saline-treated rats that lost weight in response to
stress, inguinal and retroperitoneal fat depots decreased in size.
There are a number of differences between this model of stress and that
reported by Rosmond et al. (18). Other than the obvious species
difference, the men were reporting perceived stress, which would be
chronic low-level stress, whereas the rats were exposed to intense
bouts of a mixed physical and psychological stress. It is well
established that low-level stressors, such as tail pinch, induce
feeding in rats by activating the opioid system (15). Therefore, it is possible that there is a biphasic change in adiposity according to the
intensity of stress, as we and others have repeatedly demonstrated that
food intake is inhibited in restrained or immobilized rats (1, 8, 10,
12, 14, 20). The neurochemical pathway responsible for this hypophagia
has not been elucidated. We have demonstrated here that it involves the
CRF system in areas adjacent to the third ventricle. Activation of CRF
receptors may then influence other systems that control feeding behavior.
In conclusion, the experiments described here demonstrate that hypophagia and weight loss of rats exposed to repeated restraint are initiated by acute activation of CRF receptors located in or near the hypothalamus. This acute activation must result in a permanent change in regulatory systems that determine body weight and composition. These mechanisms have yet to be identified, but they do not involve chronic activation of the hypothalamic CRF system, as shown in this experiment, or of serotonergic or noradrenergic systems, as we have shown previously (20). It is possible that acute, stress-associated activity of the CRF system disrupts the relationship between anabolic and catabolic hormones that determine nutrient partitioning.
Perspective
A single exposure to restraint or immobilization stress causes acute hypophagia and weight loss (12), and repeated exposure to restraint stress produces a temporary hypophagia but a permanent downregulation of body weight in rats (8). Studies described here demonstrate that the stress-induced hypophagia and weight loss can be totally blocked by acute antagonism of CRF receptors in brain areas adjacent to the third ventricle. These results indicate that acute activation of the CRF system in these areas initiates a series of events that causes the downregulation of body weight. As we have not found chronic elevations of serum corticosterone in stressed vs. control rats and because PVN CRF was not different between stressed and control rats 4 days after the end of restraint, when body weights of the two groups were different, chronic activation of the CRF system does not appear to be essential to the response. A previous study indicated that stress-induced activation of serotonergic and adrenergic systems was also short-lived and undetectable 1 h after the end of restraint stress (20). Therefore, mechanisms responsible for the chronic change in body weight have not been defined, but it is possible that stress establishes a new temporal relationship between the catabolic and anabolic hormones and processes that determine body weight.| |
ACKNOWLEDGEMENTS |
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This study was supported by US Army Medical Research and Development Command Grant DAMD 17-97-2-7013.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: R. B. S. Harris, PBRC, 6400 Perkins Rd., Baton Rouge, LA 70808 (E-mail: harrisrb{at}mhs.pbrc.edu).
Received 30 October 1998; accepted in final form 25 January 1999.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Significant difference
between AR and SR rats.
