JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2011, 62, 4, 395-402

www.jpp.krakow.pl

E. BOJANOWSKA, E. RADZISZEWSKA

COMBINED STIMULATION OF GLUCAGON-LIKE PEPTIDE-1 RECEPTOR

AND INHIBITION OF CANNABINOID CB1 RECEPTOR ACT SYNERGISTICALLY
TO REDUCE FOOD INTAKE AND BODY WEIGHT IN THE RAT
Department of Behavioral Pathophysiology, Institute of General and Experimental Pathology, Medical University of Lodz, Lodz, Poland
Pharmacological activation of the glucagon-like peptide-1 (GLP-1) receptor and inhibition of the cannabinoid CB1
receptor were found to reduce food intake and body weight in humans and animals. Since earlier studies revealed that
endocannabinoids may interact with other neurotransmitters to affect feeding behavior, we have examined whether a
stable GLP-1 agonist, exendin-4 and a CB1 receptor antagonist, AM 251, may reciprocally enhance their inhibitory
effects on food consumption in the rat. Additionally, we have tested whether the blockade of the GLP-1 receptor by
exendin (9-39) modifies AM 251-dependent effects on energy balance. In a dose-response study, male Wistar rats were
injected intraperitoneally with either 1.5-6.0 g/kg exendin-4, 0.5-2 mg/kg AM 251, 80-320 g/kg exendin (9-39) or
their vehicle and the daily food and water intake as well as body weight changes were monitored two days before and
two days after the injection. Exendin-4 at a dose of 3.0 and 6.0 g/kg and AM 251 at a dose 2 mg/kg decreased
significantly 24-hour food intake and body weight. Therefore, in the next study, the effects of lower doses of exendin-4
(1.5 g/kg) and AM 251 (1.0 mg/kg) administered alone or together on food consumption were compared. As opposed
to being injected alone, the co-administration of the two resulted in a marked decrease in both daily food intake and body
weight. Exendin (9-39) did not modify the suppressory effect of the highest AM 251 dose on food consumption.
Apparently, the effect of AM 251 on the appetite is not mediated by GLP-1. The concomitant stimulation of GLP-1
receptor and blockade of CB1 receptor, however, may act synergistically to inhibit appetite in the rat.
K e y w o r d s : Cannabinoid, body weight, exendin-4, exendin (9-39), CB1 receptor antagonist, food intake, glucagon-like peptide-1

INTRODUCTION
Feeding behavior is controlled by both physiological factors,
such as metabolites and hormones released during food
ingestion and psychological (hedonic or aversive) factors related
to the brain reward system and motivation (1). The presence of
nutrients in the gastrointestinal tract triggers biochemical
changes in the blood and stimulates the secretion of gut
hormones (2). Along with biochemical messages, these
hormones provide the information on the current alterations in
body's energy homeostasis to the nucleus of the solitary tract and
hypothalamus via either vagal afferents in the digestive tract or
the blood (3). For instance, increased secretion of an orexigenic
hormone, ghrelin, precedes food intake and stimulates appetite
(3). Other intestinal hormones, secreted after food consumption,
e.g., cholecystokinin and GLP-1, inhibit appetite (3). On the
other hand, stimulation of a peripheral receptor for somatostatin,
a hormone involved in the intestinal hormone release, has been
recently found to have no significant effect on food consumption
in the rat (4). Interestingly, gastrointestinal hormones, including
GLP-1, are likely to be involved in appetite inhibition in obese
subjects after the gastric bypass surgery (5).
Both starvation and satiety are associated with changes in
brain (6) and intestinal (7) levels of endocannabinoids known to

increase food intake by the effect on motivational centers in the

limbic system and the hypothalamic feeding centers (8). At the
level of hypothalamus endocannabinoids were found to interplay
with neuropeptides involved in the food intake control including
corticotrophin-releasing hormone, melanin-concentrating
hormone, cocaine-amphetamine-regulating transcript, orexin (9,
10), ghrelin (11), and neuropeptide Y (12). However,
endocannabinoids are produced not only in the brain but also in
the gastrointestinal system (13). It is well established that the
peripheral administration of cannabinoid antagonists reduces
food consumption and body weight in both humans and rats (1416). To date, however, there has been little information on the
possible cross-talk between the peripheral gut-brain peptides and
endocannabinoids.
Among all intestinal peptides GLP-1 gains particular
attention. Its stable agonists/analogs are recommended for
adjunctive therapy for type 2 diabetes mellitus not only due to
their stimulatory action on insulin secretion but also due to their
weight-reducing properties (17). GLP-1and its agonists, when
administered peripherally, were shown to inhibit food
consumption in humans and animals (18-21). These beneficial
therapeutic effects of GLP-1 agonists, however, may be
associated with adverse reactions, such as nausea and vomiting
(22). Similarly, administration of CB1 receptor antagonists was

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reported to produce undesirable and potentially dangerous
psychiatric side effects when used at doses sufficient to inhibit
appetite (23). This prompted scientists to look for safer methods
for obesity treatment using cannabinoid antagonists (24). One of
these methods might involve a polydrug therapy employing low
doses of drugs that act synergistically to decrease food
consumption. The aim of this study was, therefore, to investigate
the effects of a cannabinoid CB1 receptor antagonist, AM 251,
and a stable GLP-1 agonist, exendin-4, administered together at
low doses on food intake and body weight in the rat.
Additionally, we have tested the effect of GLP-1 receptor
blockade by exendin (9-39) on AM 251-induced changes in the
energy balance.
MATERIAL AND METHODS
Animals
Experiments were carried out on male Wistar rats weighing
between 290 and 370 g. During the experiment, the animals
were housed in individual, plastic cages and maintained on a
12:12 hour light-dark cycle, at 20-22C with free access to
standard, pelleted rat chow (Motycz, Poland) and water. Each
rat received a preweighed amount (100 g) of food and water in
a calibrated bottle every day throughout the experiment. The
rats were handled every day for 4 days before the injection to
accustom them to experimental conditions and to attenuate the
possible effect of stress on their feeding behavior. Each group
consisted of 6-9 animals. All the experimental procedures were
approved by the Local Ethical Committee at the Medical
University of Lodz.
Experimental procedure
1. Dose-response study
The aim of this study was to investigate the dose-response
effect of increasing doses of exendin-4 (BACHEM,
Switzerland), exendin (9-39) (BACHEM, Switzerland), and AM
251 (1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-4-methyl-N(1-piperidinyl)-1H-pyrazole-3-carboxamide; SIGMA, USA) on
feeding behavior as well as to identify the lowest dose of each
drug that affects significantly food intake. In experiment 1, each
rat received a single intraperitoneal (i.p.) injection of 1.5, 3.0 or
6.0 g/kg body weight (bw.) exendin-4 or its vehicle (0.9%
sterile saline). In experiment 2, rats were injected i.p. with 0.5,
1.0 or 2.0 mg/kg bw. AM 251. AM 251 was initially dissolved in
dimethylsulphoxide (DMSO, SIGMA, USA) and then diluted
with saline to obtain the required concentrations. The maximum
DMSO concentration was 2% v/v and this vehicle solution was
injected to control rats. In experiment 3, the animals were given
an i.p. injection of 80, 160 or 320 g/kg bw. exendin (9-39) or
0.9% sterile saline. All solutions were administered in a volume
of 0.1 ml/100 g bw. All injections were made 1-1.5 hour before
lights off. Daily food and water intake as well as body weight
were recorded two days before and two days after the injection.
2. Combined-treatment study
In the first experiment, rats were injected i.p. with either 1.5
g/kg exendin-4, 1 mg/kg AM 251, 1 mg/kg AM 251 followed
15 min later by 1.5 g/kg exendin-4, or saline. The doses of the
drugs were selected based on results obtained in series 1. For
both drugs, doses lower than those found to be sufficient for the
significant food intake inhibition were administered. Daily
food/water consumption and body weight were measured as
described previously.

In the second experiment, rats were injected ip. with either

160 g/kg exendin (9-39), 2 mg/kg AM 251, 160 g/kg exendin
(9-39) followed 15 min later by 2 mg/kg AM 251, or saline.
Body weight as well as food and water intake were measured as
indicated above.
Statistical analysis
The data from both studies were analyzed by one-way
repeated measures ANOVA followed by the Fisher's post-hoc
test using STATISTICA 8 (Statsoft, Poland). The differences
were considered to be significant when p 0.05.
RESULTS
There were no significant differences between rats in all
groups in both studies with respect to the initial body weight as
well as food and water intake.
Dose-response study
Exendin-4 significantly (p<0.001) reduced food
consumption 24 h after the injection (Fig. 1A) when
administered at a dose of 3.0 or 6.0 g/kg bw. Therefore, we
employed the lowest dose of 1.5 g/kg bw. for further
experiments aimed at the examination of possible interactions
between exendin-4 and a CB1 receptor antagonist. Exendin-4
had no effect on the daily water intake (Fig. 1B) in either group.
Only the highest dose of exendin-4 (6.0 g/kg) diminished
significantly body weight both 24 (p<0.001) and 48 hours
(p<0.05) after the injection as shown in Fig. 1C.
A significant (p<0.01) decrease in the daily food intake was
shown only when AM 251 was used at a dose of 2 mg/kg bw.
(Fig. 2A) and, therefore, we employed a lower dose of 1 mg/kg
bw. in the combined-treatment study. AM 251 diminished
remarkably (p<0.05) daily water intake at a dose of 2 mg/kg only
(Fig. 2B). Although body weight tended to decrease in rats
treated with 2 mg/kg AM 251 (Fig. 2C), these changes were not
significant (p=0.060).
Exendin (9-39) at any dose did not change significantly the
daily food and water intake as well as body weight.
Combined-treatment study
Exendin-4 and AM 251 administered alone at low doses, as
indicated above, had no significant effects on daily food and
water intake as well as body weight changes (Fig. 3). When,
however, these drugs were administered together, a clear
(p<0.05) suppressory effect on the 24-hour food consumption
occurred (Fig. 3A). This effect was associated with a significant
(p<0.05) reduction in body weight (Fig. 3C).
Both AM 251 2 mg alone and in combination with exendin
(9-39) significantly (both p<0.05) diminished food intake when
compared to controls (Fig. 4A). There was, however, no
difference in the reduction in food intake between rats treated
with AM 251 only and those given AM 251 together with exendin
(9-39). AM 251 administered alone reduced markedly (p=0.050)
body weight. However, previous exendin (9-39) injection
abolished AM 251-induced body weight changes (Fig. 4C).
DISCUSSION
The main finding of this study is that simultaneous
administration of two anorexigenic drugs, exendin-4 and AM
251, at subanorectic doses results in a decrease in 24-hour food

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Fig. 1. Effects of various doses of exendin-4 on daily food

intake (panel A), water intake (panel B) and body weight
changes (panel C) in the rat. The initial value in panels A and
B is mean food/water consumption during two consecutive
days before the injection of the drug. The subsequent
measurements were made 24 and 48 hours after the injection.
Body weight was measured on the day of injection and
compared to results obtained 24 and 48 hours after the
injection. Data are mean S.E.M. * p<0.05, ** p<0.001.

ingestion and body weight in the rat. Exendin-4 is a potent and

selective agonist of the GLP-1 receptor whilst AM 251 is an
antagonist of the CB1 receptor. Since both activation of the
GLP-1 receptor and blockade of the CB1 receptor are known to
reduce appetite in animals and humans (25, 26), we have
compared the effects of exendin-4 and AM251 administered
alone or in combination on daily food intake in the rat.
In the first study, we evaluated the effects of various doses of
each drug on 24-hour food intake and body weight changes.
Based on the results of previous studies from our laboratory (21)
and those reported by other authors (14, 27, 28) we selected drug
dosages that could be supposed to affect the daily food intake in
the rat under the conditions of our experiments. As expected,
both exendin-4 and AM 251 at a dose of, respectively, 3.0 g/kg
and 2 mg/kg bw. reduced significantly daily food intake when
injected separately. Therefore, in the next series, where possible
synergistic effects of both pharmaceuticals were investigated, we
used a half-size dose of each drug that did not affect significantly
the daily food ingestion and body weight.

In the combined-treatment study, we have demonstrated that

the concurrent subthreshold stimulation of the GLP-1 receptor
with exendin-4 and blockade of the CB1 receptor with a low
dose of AM 251 caused a clear decrease in food consumption
and a resultant body weight reduction, the events that could not
be seen when each drug was administered alone in the same
dose. This finding indicates that these drugs may reciprocally
enhance their effects on energy balance of the body. On the other
hand, water intake in rats treated with both exendin-4 and AM
251 was comparable to that in the control group. This indicates
that the synergistic interaction of both drugs does not involve
their effects on water balance. It is of interest that exendin-4 was
found previously to exert similar, synergistic effects with
another anorectic gut hormone PYY (29) and an amylin analog,
calcitonin (30).
To date, there have been no reports on possible crosstalk
between the endocannabinoid system and GLP-1 with regard to
their effects on energy balance. However, blockade of the
cannabinoid CB1 receptor and concomitant inactivation of an

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Fig. 2. Effects of various doses of AM 251 on daily food

intake (panel A), water intake (panel B) and body weight
changes (panel C) in the rat. The initial value in panels A
and B is mean food/water consumption during two
consecutive days before the injection of the drug. The
subsequent measurements were made 24 and 48 hours after
the injection. Body weight was measured on the day of
injection and compared to results obtained 24 and 48 hours
after the injection. Data are mean S.E.M. * p<0.05, **
p<0.01.

opioid receptor were shown to have synergistic effects on food

intake and body weight changes (31). An opioid antagonist,
naloxone, and AM 251, when given collectively, inhibited food
intake to a greater extent than each drug injected alone (31).
Similarly, a CB1 receptor antagonist, SR 141716 (rimonabant)
and fenfluramine (32) as well as SR 141716 and cholecystokinin
(33) were shown to have additive, suppressory effects on food
intake in rats. On the other hand, such additive effects on food
consumption did not occur when rimonabant was injected along
with another anorectic drug, sibutramine (34). Although, in view
of the known adverse effects of CB1 receptor antagonists, the
conclusions from our study should be drawn carefully, the
finding that AM 251 and exendin-4 may reciprocally augment
their anorectic effects indicates potential utility of both drugs in
polydrug therapy for obesity. Moreover, the fact that the
significant reduction in body weight could be achieved at low
doses of the drugs as well as the lack of their effects on water
intake may prove the safety of such a combination therapy.

The possible mechanism underlying the synergistic

interaction between the GLP-1 agonist and CB1 receptor
antagonist remains unclear. The CB1 receptor has been
identified in vagal afferents in the digestive tract (35) and the
GLP-1 receptor gene has been detected in the nodose ganglion
cells (36) indicating that both drugs might directly modify the
activity of vagal afferents relaying information from the
alimentary tract to feeding centers in the brain. Interestingly,
GLP-1 and endocannabinoids use the same intracellular
signaling pathway, related to AMP-activated protein kinase
(AMPK), to affect the activity of feeding centers in the
hypothalamus (37). Since GLP-1 reduces the activity of the
enzyme and endocannabinoids produce the opposite effect, it
may be supposed that simultaneous activation of the GLP-1
receptor by exendin-4 and blockade of the CB1 receptor by AM
251, as employed in our study, diminish the AMPK activity more
than each drug administered alone. Possibly, this could account
for the synergism of both drugs.

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Fig. 3. Effects of a combination of subanorectic doses (see

Results) of exendin-4 (Ex-4) and AM 251 on daily food
intake (panel A), water intake (panel B) and body weight
changes (panel C) in the rat. The initial value in panels A
and B is mean food/water consumption during two
consecutive days before the injection of the drug. The
subsequent measurements were made 24 and 48 hours after
the injection. Body weight was measured on the day of
injection and compared to results obtained 24 and 48 hours
after the injection. Data are mean S.E.M. * p<0.05.

The CB1 receptor blockade was also found to attenuate the

intracellular signal transduction produced by stimulation of the
orexin receptor (38) as well as to reduce the orexigenic effect of
ghrelin (11). On the other hand, GLP-1 and its agonist were found
to attenuate the secretion of ghrelin (39). Hence, AM 251 and
exendin-4 might act additively to inactivate orexigenic pathways
and decrease appetite. It is also of interest that cholecystokinin,
an appetite-reducing gut-brain hormone, diminishes expression
of the CB1 receptor in vagal afferent terminals (35).
Hypothetically, the similar mechanism might be responsible, at
least in part, for the appetite-reducing effect produced by
subanorectic doses of exendin-4 and AM 251 seen in our study.
We have also found that the GLP-1 receptor antagonist,
exendin (9-39), did not change either food consumption or body
weight even when administered peripherally at a high dose of 320
g/kg bw. In the combined-treatment study, we used a lower dose
of exendin (9-39), similar to that reported previously to prevent
the action of another anorectic hormone, leptin (21). We found that

exendin (9-39) did not modify the AM 251-dependent suppression

of food intake indicating that the anorectic action of CB1 receptor
antagonist is not mediated by GLP-1. In contrast to rats treated
with AM 251 alone, however, there was no significant reduction
in body weight in animals injected with both exendin (9-39) and
AM 251. Apparently, the blockade of the GLP-1 receptor could
prevent the AM 251-treated rats from weight loss through a
mechanism other than that related to the control of feeding
centers. This mechanism might involve the concomitant reduction
in the metabolic rate. Data concerning possible effects of the GLP1 receptor inhibition on the metabolic rate are very scarce. The
lack of the effect of acute (this study) as well as chronic (40)
exendin (9-39) treatment on body weight indirectly indicates that
the blockade of the peripheral GLP-1 receptor has no effect on
metabolism in rats with normal energy balance. Possibly, the
hypothetical suppressory effect of GLP-1 receptor blockade on the
metabolic rate occurs only under conditions of negative energy
balance seen in rats treated with the CB1 receptor inhibitor. This

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Fig. 4. Effects of a combination of 160 g/kg bw. exendin

(9-39) and 2 mg/kg bw. AM 251 on daily food intake (panel
A), water intake (panel B) and body weight changes (panel
C) in the rat. The initial value in panels A and B is mean
food/water consumption during two consecutive days before
the injection of the drug. The subsequent measurements
were made 24 and 48 hours after the injection. Body weight
was measured on the day of injection and compared to
results obtained 24 and 48 hours after the injection. Data are
mean S.E.M. * p 0.05.
hypothesis, however, needs to be supported by the experimental
data that are beyond the scope of the present study.
In summary, we have found that concurrent inhibition of the
CB1 receptor and activation of the GLP-1 receptor by, AM 251 and
exendin-4, respectively, administered at subanorectic doses result
in a significant decrease in 24-hour food, but not water, intake as
well as in a marked reduction in body weight in the rat. This
indicates that there is a synergistic interaction between these drugs
in terms of their effects on body energy balance. Since the blockade
of the GLP-1 receptor did not alter the AM 251-induced reduction
in appetite, we conclude that GLP-1 does not mediate the
suppressory effect of the CB1 receptor inhibitor on feeding
behavior in the rat.
Acknowledgements: This work was supported by the grant
No. 0056/B/P01/2011/40 from the National Centre for Science,
Poland.
Conflict of interests: None declared.

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R e c e i v e d : June 10, 2011
A c c e p t e d : August 17, 2011

Author's address: Prof. Dr.Ewa Bojanowska, Department of

Behavioral Pathophysiology, Institute of General and
Experimental Pathology, Medical University of Lodz, 60
Narutowicza Street, 90-136 Lodz, Poland; Phone: 48 42 6306187;
E-mail: ewa.bojanowska@umed.lodz.pl