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Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada M5S 3E2 and * Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada M5S 1A8
3To whom correspondence should be addressed. E-mail: harvey.anderson{at}utoronto.ca.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • gut peptide • high protein, low carbohydrate diet • intraperitoneal administration • protein-free, high carbohydrate diet • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. These peptides regulate
both satiety and food intake. But, in addition, some of the peptides
may play a nutrient-specific role. For example, the reduced food
intake seen after preloads of protein (egg albumin) given by gavage is
completely blocked by pretreatment with the cholecystokinin
(CCK)4
-A receptor antagonist devazepide
(2
,3)
. Because devazepide did not affect the food intake
suppression produced by preloads of cornstarch, corn oil or an amino
acid mixture (patterned after egg albumin), it was concluded that there
is a specific interaction between the CCK-A
receptor and protein-induced satiety in rats (2
,3)
.
Similarly, glucagon-like peptide-1 (7–36) amide (GLP-1) may play a
role in the regulation of both satiety and nutrient-specific
feeding responses. GLP-1 is one product of post-translational
processing of the proglucagon molecule in both the intestine and brain
(4
,5)
, and its release from the intestine is stimulated
strongly by carbohydrate (6)
. To date, however, only its
effect on quantity and not composition of food intake has been
measured. GLP-1 mediates satiety and decreases food intake in humans
(7
,8)
and experimental animals (9)
. Central
administration of GLP-1 and its receptor agonist, exendin 4, decreases
food intake in rats (9
10
11
12)
, whereas treatment with the
GLP-1 receptor antagonist, exendin 9–39, increases food intake in
sated rats (9)
.
Although the effect of GLP-1 administered centrally on food intake has
been described, the role of GLP-1 from the intestine in the regulation
of food intake and selection in rats has received little analysis.
Because the half-life of GLP-1 in the circulation of rats is very
short (13)
, GLP-1 has shown little (12)
or no
effect (9
,11)
on food intake when injected subcutaneously
(s.c.) or intraperitoneally (i.p.). Therefore, in the present study, we
used the GLP-1 receptor agonist, exendin 4, and the antagonist, exendin
9–39, to investigate the role of peripheral GLP-1 in the regulation of
food intake. The hypothesis of these studies was that peripheral GLP-1
is a regulator of both food intake and macronutrient selection in rats.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male Wistar rats (Charles River, Quebec, Canada) were housed
individually in hanging wire-mesh stainless steel cages in a room
with a temperature of 22 ± 1°C and a 12-h light:12-h dark cycle
(lights on at 0600 h); they had free access to water throughout
and to pelleted food (Rodent Laboratory Chow # 5001 LabChows,
Strathroy, Canada) for the first 3 d. On d 3 after arrival of the
rats in the animal facility, the pelleted food was removed and replaced
with an AIN-93G (14)
powder diet or with two defined diets
containing either 0 or 50 g protein/100 g. Food was available only from
1800 to 0800 h, but water was provided for 24 h/d. The University
of Toronto Animal Care Committee approved the protocol, and care and
maintenance of the animals conformed to the guidelines of the Canadian
Council on Animal Care.
Diets were formulated to contain either 0 or 50 g protein/100 g based on the AIN-93G diet. The proportion of cornstarch and sucrose to casein (87%, based on the data provided by Harlan Teklad, Madison, WI) in the AIN-93G diet was altered to achieve the 0% (CHO) and 50% protein (PRO) diets. The composition (g/kg) of the AIN-93G, PRO and CHO diets was as follows: casein (200, 575 and 0); cornstarch (597, 216.2 and 699.3); L-cystine (3, 0 and 0); and sucrose (100, 41.2 and 133.2), respectively. The same amount of the following ingredients was added to each of the three diets: soybean oil (70), cellulose (50), vitamin mixture (10), mineral mixture (35), choline bitartrate (2.5) and tert-butyl hydroquinone (0.014).
Nutrient preloads.
Glucose (1.0 g) and egg albumin (0.5 g; Sigma Chemical, St. Louis, MO)
were dissolved in deionized water to a total volume of 2.5 mL. Corn oil
(1.5 g = 
1.7 mL; Mazola) was added to 0.8 mL water,
shaken and given in a two-phase mixture. In experiments involving
preloads, all rats received an intragastric preload, in a volume of a
2.5 mL, by gavage 30 min before the onset of the dark cycle (1800 h)
when food cups were presented. The amount of preloads was chosen on the
basis of their equal suppression of food intake during the first 2 h of feeding after gavage (2
,3)
.
Peptide treatments.
Both exendin 9–39 and exendin 4 (California Peptide Company, San Jose, CA) were diluted in deionized water and divided into aliquots before being quickly frozen on dry ice. The aliquots were lyophilized in a freeze dryer and the resulting dried peptide stored at -20°C until used. When needed, freeze-dried peptide was allowed to come to room temperature and reconstituted using PBS (Sigma Chemical) at pH 7.4. The reconstituted peptide was used within 1 h of preparation. All injections were given i.p. in a volume of 0.5 mL. Exendin 9–39 was used at doses of 20 and 50 µg, and exendin 4 of 0.5, 10 and 20 µg.
Procedures.
Before testing, the rats were adapted to the experimental procedures. They were gavaged and/or injected with water and saline, respectively, for 4 d before the adaptation test as follows. On d 1, half of the rats were given a treatment (either preload or injection, or both) and the rest were untreated. On the next day, this testing order was reversed; rats that received treatments on d 1 were left untreated and the rats that received no treatment on the previous day were given treatments. Experimentation began when it was determined that the process of gavaging and/or injecting had no effect on food intake.
Nutrient preloads were provided by gavage at 1730 h. Peptides were injected i.p. at 35 and/or 5 min for 20 µg or 5 min for 50 µg of exendin 9–39 and 35 or 5 min for exendin 4 (0.5–20 µg) before the onset of the dark cycle. At 1800 h, when the dark cycle started, food was provided in a single cup in the studies using the AIN-93G diet or in two cups in selection studies between the CHO and PRO diets. Rats were allowed to select between the CHO and the PRO diets for 10 d before experimentation. Baseline food intake was measured over the final 4 d of this period, and experimentation began once rats were selecting a consistent daily percentage of protein. Food consumption was measured to the nearest 0.1 g with adjustment for spillage at time points.
Design.
In all studies, the rats served as their own control. Experiment 1 was carried out in a repeated-measures design with four preloads (water as control, corn oil, glucose and chicken egg albumin). The rest of the experiments used a within-subject design in which half of the rats received the peptide treatment on d 1 and the rest were treated with saline as control. With one (exendin 9–39) or two (exendin 4) washout days in between, the order of these treatments was reversed; rats that received peptide treatments on d 1 were given saline and rats that received saline were given peptide.
The present study consisted of three main experiments. The effect of nutrient preloads was determined in Experiment 1, and the effect of exendin 9–39 and exendin 4 in Experiments 2 and 3, respectively. Experiments 2 and 3 had three subsets of experiments, which included preload, selection and meal studies.
Experiment 1: food intake suppression induced by nutrient preloads.
The objective of this experiment was to determine the effect of the three nutrient preloads (glucose, corn oil and egg albumin) on subsequent food intake. Because the preloads were to be used in studies defining the effect of exendin 9–39 on suppression of food intake by the preloads, it was desirable for statistical reasons and sample size determination that each preload suppress food intake to a similar extent.
Each rat [n = 14, average initial body weight (BW)
= 344 g] was provided only once with the three nutrient preload
treatments given by gavage (corn oil 1.5 g, D-glucose
1 g, and chicken egg albumin 0.5 g) as well as the control
treatment of water in random order. One washout day was given between
individual nutrient preloads. Preloads were given to rats 30 min before
feeding (1800 h) of the AIN-93G diet after which food intake was
measured at 1, 2 and 14 h. The quantity of the preloads was based
on our previous studies (2
,3)
.
Experiment 2.
The objective of this series of experiments was to describe the effect of the GLP-1 antagonist, exendin 9–39, on food intake when given either alone or with nutrient preloads, and on selection of the CHO and PRO diets when given alone.
Experiment 2a: effect of exendin 9–39 (20 and 50 µg) on food intake of the maintenance diet.
Two experiments were conducted. Five minutes before the dark cycle (1800 h), rats (n = 21) were injected with either 20 µg (BW = 224 g) or 50 µg (BW = 243 g) of exendin 9–39 or saline. The AIN-93G diet was presented at 1800 h and food intake was measured at 1, 2, 3 and 14 h.
Experiment 2b: effect of exendin 9–39 on food intake suppression induced by nutrient preloads.
Three separate experiments were conducted. Preloads of glucose (1 g; n = 20, BW = 275 g), corn oil (1.5 g; n = 20, BW = 276 g) and chicken egg albumin (0.5 g; n = 20, BW = 294 g) were given by gavage. Rats were injected i.p. with exendin 9–39 (20 µg) 5 min before and immediately after the nutrient preload (1730 h). Thirty minutes later, they were fed the AIN-93G diet.
Experiment 2c: effect of exendin 9–39 on selection of CHO and PRO diets.
A single dose of exendin 9–39 (50 µg) was injected i.p. 5 min before the rats (n = 14, BW = 394 g) were allowed to select between the CHO and the PRO diet. Because only one injection was given, the dose of the peptide was increased.
Experiment 3.
The objective of this series of experiments was to describe the effect of the GLP-1 agonist, exendin 4, on food intake when given with a glucose preload, and on selection of the CHO and PRO diets when given with or without glucose preloads.
Experiment 3a: effect of exendin 4 (0.5 µg) and glucose preloads on intake of the AIN-93G diet.
To determine the effect of exendin 4 combined with glucose on consumption of the maintenance diet, either exendin 4 (0.5 µg) or saline was injected at 35 min and a glucose preload (1 g) was given by gavage to all rats (n = 13, BW = 370 g) 30 min before presentation of the AIN-93G diet.
Experiment 3b: effect of exendin 4 (0.5 µg) and glucose preloads on selection of CHO and PRO diets.
Exendin 4 (0.5 µg) or saline was injected i.p. 5 min before an intragastric preload of glucose (1 g) was given (n = 13, BW = 352 g). Thirty minutes later, the rats were allowed to select between the CHO and PRO diets.
Experiment 3c: effect of exendin 4 on selection of CHO and PRO diets.
In a within-subject design, each rat (n = 13) was given either exendin 4 (0.5, 10 and 20 µg) or saline 5 min before having access to the CHO and PRO diets. Body weight of the rats was 231, 287 and 324 g for the exendin 4 doses of 0.5, 10 and 20 µg, respectively.
Statistical analysis.
Data were assessed by repeated-measures one-way ANOVA with post-hoc Tukey’s test (Experiment 1) and by paired t test (Experiments 2 and 3). Significance was declared if P < 0.05. Analyses were performed using the Graphpad statistical package (Graphpad Software, San Diego, CA). All data are expressed as mean ± SEM.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Food intake of the maintenance diet by rats was significantly reduced
after all three nutrient preloads compared with water control, during
the 0–1 [F (3, 44) = 10.2, P < 0.01] and 0–2
h [F (3, 44) = 10.9, P < 0.01], with no
differences seen among the three nutrient preloads (Table 1
). During the second hour of feeding, suppression of food intake was
stronger after corn oil and albumin preloads than after water or
glucose treatment [F (3, 44) = 4.48, P < 0.01].
No difference in food intake among the four treatments was found during
the rest of the night, 2–14 h [F (3, 44) = 2.74, P
0.05], indicating that suppression of food intake by nutrient
preloads occurred during early evening feeding.
|
Neither 20 nor 50 µg of exendin 9–39 affected food intake
of the AIN-93G diet at any time (Table 2
).
|
Exendin 9–39 decreased the consumption of the maintenance diet by rats
during the second hour after the glucose gavage (Fig. 1
), but not at any time after corn oil and albumin preloads (Table 3
).
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Baseline food intake and selection patterns were consistent with those
of a previous report (15)
, with rats selecting 32 ± 2% protein over five baseline days. The total food intake was reduced
by the peptide treatment during 0–2 and 0–14 h (Fig. 2
). The primary effect of exendin 9–39 on the food intake occurred
within 2 h after meal initiation and was due to a decreased intake
of the CHO diet during the 0–0.5, 0–1 and 0–2 h periods of feeding
(P < 0.05). A decrease in intake of the PRO diet was
apparent only for the cumulative measurement of 0–14 h.
|
When the AIN-93G diet was provided to rats after a glucose gavage, the
injection of exendin 4 reduced food intake during 2–14 and 0–14 h
(Fig. 3
).
|
When preloaded with glucose, the rats given exendin 4 reduced
consumption of the PRO diet during 0.5–1, 0–1, 1–2, 0–2 and 0–14 h
(P < 0.05; Fig. 4
). No change in intake of the CHO diet was observed. As a result, it was
the reduced intake of the PRO diet that contributed to the decreased
total food intake during the 1–2, 0–2 and 0–14 h (P
< 0.05; Fig. 4
).
|
The average food intake over 4 d of baseline measurement was 8.6 ± 1.0 g for the CHO diet and 14.4 ± 0.8 g for the PRO diet. The rats selected an average of 31 ± 3% protein by weight over the baseline period.
Intake of the PRO diet was reduced (P < 0.05) by 0.5
µg of exendin 4 during the intervals of 0–0.5, 0–1, 0–2
and 0–14 h. Consumption of the CHO diet was not affected (Table 4
). When 10 µg of exendin 4 was given, a reduction in intake
of the CHO diet occurred during 2–14 h, and intake of the PRO diet was
reduced during the early (0–0.5, 0–1, and 0–2 h) feeding intervals
as well as over the total day (0–14 h). Exendin 4 (20 µg)
decreased total food intake by 50% and increased intake of the CHO
diet during 0.5–1, 1–2 and 0–2 h (P < 0.05), but
reduced it by two thirds for the rest of night (2–14 h), resulting in
reduction by about half in intake of the CHO diet for the 0–14 h. In
contrast, intake of the PRO diet was decreased by 70% in the first
2 h of feeding, and cumulative intake (0–14 h) was reduced by
65%. The rats given the highest dose of exendin 4 (20 µg)
were lethargic and for some rats administered the 10 µg
dose, a decrease in activity was apparent.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The effect of exendin 9–39, given either centrally or peripherally, on
macronutrient selection has not been reported. As shown by the present
results, rats given an i.p. injection of exendin 9–39 decreased
consumption of the CHO but not the PRO diet when allowed to select from
these two choices (Fig. 2)
. Because the antagonist suppressed intake of
the single diet after glucose but not corn oil or egg albumin preloads,
these results suggest that blocking GLP-1 activity leads to a selective
feeding response to the carbohydrate portion of the diet.
Central injection of exendin 9–39 increases food intake in sated rats
(9
,16)
. In contrast, peripheral injection decreased food
intake (Figs. 1
, 2)
. At present, no explanation can be offered for this
apparent contradiction in response between centrally and peripherally
administered exendin 9–39.
The effect of exendin 4, the agonist, on macronutrient selection has
not been reported. Given centrally, exendin 4, like GLP-1, decreases
food intake (12
,17
,18)
. In the present study, rats
injected i.p. with exendin 4 decreased food intake, but, at least at a
low dose, they selectively suppressed intake of the PRO diet.
Several aspects of the design of the present studies require comment
with respect to interpretation of the data. First, the evidence
provided herein for peripheral GLP-1 involvement in macronutrient
selection is indirect. Because of the short half-life of GLP-1, we
used an agonist and an antagonist as treatments, assuming that the
vagus is involved in the transmission of GLP-1–mediated satiety
signals from the gut to the brain (19)
. Indeed,
intraportal injections of physiologic and pharmacologic doses of GLP-1
have been shown to facilitate the afferent impulse discharge rate of
the hepatic vagus (20)
. Because this same report did not
find exendin 9–39 and exendin 4 to affect the discharge rate of the
vagus, there is some uncertainty about their mechanisms of action and
therefore the extent to which their effects on food intake reflect the
action of peripheral GLP-1 (20)
.
Second, the primary purpose of the preload studies was to determine
whether there was an interaction between the antagonist, exendin 9–39
and the composition of the preloads in affecting subsequent food
intake. We previously showed that preloads of protein or carbohydrate
given to rats modify both total food intake and diet choice
(1
,21
,22)
. In addition, we showed that suppression of food
intake by preloads can be modified by agonists and antagonists. For
example, injection of the CCK-A antagonist
devazepide blocks the food intake suppression induced by protein
(chicken egg albumin) preloads in rats (2
,3)
. Because
individual macronutrients vary in their stimulation of GLP-1 release,
it was predicted that concurrent treatment with the peptides would
provide an indication of which of the macronutrients utilizes GLP-1 in
altering food intakes. In the present study, exendin 9–39 caused a
further reduction in food intake from the AIN diet after the glucose,
but not after the albumin or corn oil preloads (Fig. 1
, Table 3
).
Therefore, these results support the hypothesis of a
nutrient-specific interaction between the nutrient source and the
effect of GLP-1 on food intake. Why exendin 4 also enhanced the effect
of a glucose preload on food intake from the AIN diet remains
unexplained. It was expected that the agonist would have an effect
opposite to that of the agonist.
The goal of Experiment 1 was to define the dose of each of the
macronutrients that, when given as preloads, would decrease food intake
to a similar extent. As reported, this was achieved (Table 1)
. The
importance of utilizing macronutrient doses that suppressed food intake
similarly in early feeding is directed by consideration of treatment
effect and sample size. For example, if the same quantities of each
macronutrient were given on a weight basis, protein would suppress food
intake more than carbohydrate and fat, and carbohydrate more than fat
(3)
. Thus the magnitude of response to the drug treatment
may be modified by the extent of satiety caused by the macronutrient.
This in turn would influence the sample size required to test the
interaction between preload composition and drug treatment. We chose to
standardize the early feeding response to each of the macronutrients,
thereby allowing the use of the same sample size and the same group of
rats for all tests. Of course it remains possible that the treatment
effect would be different if higher quantities of each preload were
used to provide a greater degree of satiation in the rats at the start
of the feeding period.
Third, although the two-choice diet selection experiments provided
evidence that the agonist and antagonist influenced the rats’ choice
of protein vs. carbohydrate, the effect of these peptides on the rats’
response to fat remains undetermined. The preload studies with exendin
9–39 and corn oil suggest that fat might be little or no interaction
between fat and GLP-1 in the regulation of food intake. This
observation must be interpreted with caution because fat stimulates
GLP-1 secretion (23
24
25)
, and the effect of GLP-1 on
insulin secretion and lipogenesis in adipose tissue (26)
indicates that it may play a role in fat metabolism and intake. We
recently found that a corn oil preload resulted in a transient
enhancement (0–2 h) of the anorectic effect of GLP-1 (200 ng) injected
into the hypothalamic paraventricular nucleus (PVN) (27)
.
Fourth, the doses of exendin 9–39 and exendin 4 may have been
inappropriate. As noted earlier, there have been no reported studies of
the effect of exendin 9–39 on food intake and very few reports of the
effect of exendin 4 given peripherally. It is possible that the dose
chosen for exendin 9–39 (20 or 50 µg) was inadequate to
affect intake in food-deprived rats. However, central injection of
exendin 9–39 also failed to affect food intake from a single diet in
food-deprived rats (9)
. Selection of an appropriate
dose was also compromised by a lack of information on the half-life
of exendin 9–39 when injected peripherally in rats. In humans it is
30 min (28)
. Nevertheless, for the purpose of the
present study, the doses selected were sufficient to affect feeding
behavior of the rats. Exendin 9–39 further reduced food intake in
response to carbohydrate preloads and decreased carbohydrate intake
when rats were given a choice between the CHO and PRO diets.
For exendin 4, the dose of 0.5 µg was based on a report
that 0.1–100 µg/rat caused a dose-dependent decrease
in the food intake of diabetic fatty Zucker rats when given i.p. twice
daily (18)
. When given with a glucose preload, this dose
was sufficient to enhance suppression of AIN-93G diet intake (Fig. 3)
and to reduce PRO consumption selectively when rats were given diet
choices (Fig. 4)
. Similarly, when injected independently of preloads,
it caused a selective reduction of the PRO diet (Table 4)
.
Clearly, it was fortuitous that we used the smaller dose because we
observed that the doses of both 10 and 20 µg suppressed
activity of the rats. This was a surprising observation because these
amounts are within the range of doses administered i.p. by others in
food intake studies in rats (17
,18)
. Yet, no comment has
been made previously of the more general adverse effect of these doses
on behavior.
Although the results of this study suggest that peripheral GLP-1 may be
a component of macronutrient-specific feeding behavior, the
physiologic mechanism remains undetermined. Two aspects of GLP-1 action
might provide some evidence that GLP-1 could modify
macronutrient-specific feeding behavior. First, blocking GLP-1
action with exendin 9–39 would be expected to modify glucose
metabolism. The primary metabolic role of GLP-1 appears to be in the
regulation of carbohydrate metabolism in the periphery through its
effects on glucose-dependent insulin release, inhibition of
glucagon secretion and stimulation of glycogenesis in the liver and
muscle (29
30
31
32
33)
. Glucose metabolism is believed to be one
of the regulators of food intake (1)
.
Second, GLP-1 may slow the rate of protein digestion and absorption by
decreasing gastric acid secretion, gastric emptying and pancreatic
secretion (34
35
36)
. A prolonged presence of protein and
peptides in the intestine would be predicted to prolong the release of
CCK in rats (37
,38)
. Because CCK mediates the satiating
effects of proteins (2)
, it is possible that exendin 4
indirectly stimulates a decrease in protein intake via this mechanism.
In support of the hypothesis that GLP-1 functions in
macronutrient-specific feeding responses, we also found that the
effect on food intake of GLP-1 injected into the PVN was influenced by
the macronutrient content of the food consumed. Carbohydrate enhanced,
protein blocked and corn oil had a transient effect on the suppression
of food intake caused by GLP-1 in the PVN (27)
.
In summary, the results obtained indicate that exendin 9–39 affected the feeding response after preloads of glucose, but not after protein or fat. When the rats were allowed a choice between the carbohydrate and protein diets, exendin 9–39 reduced intake of the carbohydrate diet, whereas exendin 4 reduced intake of the protein diet. Therefore, peripheral GLP-1 might have a role in the regulation of macronutrient-regulated feeding behaviors as well as in the regulation of total food intake in rats.
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FOOTNOTES |
|---|
2 Supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada.
4 Abbreviations used: BW, body weight; CCK, cholecystokinin; CHO, protein-free, high carbohydrate diet; GLP-1,
glucagon-like peptide-1 (7–36) amide; PRO, high protein, low carbohydrate diet; PVN, paraventricular nucleus.
Manuscript received November 1, 2000. Initial review completed December 15, 2000. Revision accepted May 9, 2001.
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