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Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada M5S 3E2
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: • protein-free, high carbohydrate diet • high protein, low carbohydrate diet • feeding behavior • brain-gut peptide • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,
and some of them have been shown to interact only with specific
nutrients (2)
. For example, the reduced food intake
occurring after preloads of protein (egg albumin) was completely
blocked by pretreatment with the cholecystokinin-A
(CCK-A)4
receptor antagonist (3
,4)
. Because the CCK-A receptor
antagonist did not block the food intake suppression caused by preloads
of cornstarch, corn oil or an amino acid mixture patterned after
albumin, it was concluded that there is a specific interaction between
the CCK receptor and the protein to induce satiety in rats
(3
,4)
.
Glucagon-like peptide-1 (7–36) amide (GLP-1) is a brain-gut
peptide that suppresses food intake both when intravenously infused in
humans (5
6
7
8)
and when administered centrally (via lateral
or 3rd ventricle) (9
10
11
12
13
14
15
16)
and peripherally in rats
(17)
. Its action is blocked by prior treatment with its
specific receptor antagonist, exendin 9–39, in rats
(10
11
12
13
14
,16
,18)
.
The primary metabolic role of GLP-1 appears to be to regulate
carbohydrate metabolism through its effects on glucose-dependent
insulin release, inhibition of glucagon secretion and stimulation of
glycogenesis in the liver and muscle (19
20
21
22
23)
.
Carbohydrate, fat and protein meals cause the release of GLP-1 in
humans (24
25
26
27)
. GLP-1 has also been shown to be released
in rats after ingestion or infusion into intestinal segments of mixed
meals (28)
, carbohydrate (29
,30)
, fat
(31
,32)
and peptones (33)
.
In rats, carbohydrate appears to be the primary stimulant of GLP-1
secretion (34)
. Most carbohydrates including glucose,
galactose and fructose, stimulate GLP-1 secretion in rats
(29
,30
,34
,35)
. Only some fats and bile acids show
stimulatory effects on GLP-1 release (29
,34)
.
Interactions between macronutrient composition and GLP-1 release in determining the feeding response of rats have not been reported. Therefore, the objective of this study was to test the hypothesis that GLP-1 injected into the paraventricular nucleus of the hypothalamus (PVN) exerts a greater interaction with carbohydrate than with protein or fat intake on the regulation of subsequent food intake 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 Laboratories, St. Constant, Quebec, Canada) were individually housed in hanging wire-mesh stainless steel cages in a room maintained at 22 ± 1°C and a 12-h:12-h light:dark cycle (lights on at 0600 h). Upon arrival, rats were allowed free access to nonpurified diet (LabChow #5001; Agribrands, Ontario, Canada) for 24 h/d until fed the experimental diets and to water from spouts of an automated watering system throughout the experiment. For measuring the weights of food cups and spillage, a 40-W red light was on between 1730 and 2100 h.
In some experiments, rats were fed an AIN-93G diet (17.7% protein)
(36)
between 1800 and 0800 h; in other experiments,
the diet was replaced with either a protein-free, high carbohydrate
(CHO) diet or a high protein, low carbohydrate (PRO) diet for the first
2 h (1800–2000 h). The composition of the maintenance (AIN-93G)
diet is shown in Table 1
. The CHO (88.3% carbohydrate) diet and the PRO (50% protein) diet
were isocalorically formulated by adding or removing casein and
L-cystine at the cost of the cornstarch in the AIN-93G diet
(Table 1)
. This study was approved by the University of Toronto Animal
Care Committee.
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GLP-1 (Peninsula Laboratories, San Carlos, CA) was dissolved as 80% peptide content with >97% purity. Because a vial of 0.2 mg GLP-1 contained 160 µg of the peptide, 800 µL of filtrated, deionized water was added to the vial. After the powder was completely dissolved by gentle shaking by hand for 5 min, 40-µL aliquots were frozen on dry ice and vacuum freeze–dried at -70°C for 1 h (Savant Speed Vac SC100 and Vertis Freezemoble 12). The dry powder was stored at -20°C for a maximum of 6 mo until utilization.
Within 2 h before injections on experimental days, a vial containing 8 µg of GLP-1 was freshly dissolved in 20 µL of 9 g/L NaCl solution over 5 min by gently blowing air into the solution using its injection cannula attached to a 1-mL syringe via Tygon tubing (see below). The solution was then taken up for injection.
Both deionized water and saline were filtered through a 0.2-µm micropore filter (Gelmann Sciences, Montreal, Canada) to remove pathogens. The injectors and tubing were thoroughly washed with 70% ethanol and dried for a day before use. The stylets were wiped with 70% isopropyl alcohol swabs (Ingram & Bell Medical, Don Mills, Canada).
Anhydrous D-glucose (1.4 g/rat) was obtained from BioBasic
(Toronto, Canada), chicken egg albumin (1.0 g/rat) from Sigma (St.
Louis, MO) and corn oil (Mazola) (2.4 g/rat) from a local supplier.
They were either dissolved or suspended by using a magnetic stirrer in
deionized water (5 mL) and intragastrically provided to rats using a
16-gauge feeding needle (4)
. The amounts of preloads were
based on evidence that when preloaded by gavage, they suppress food
intake in rats for the first 2 h by 
30–40% compared with
control (Peters et al, unpublished data) (4)
. The amount
of GLP-1 (0.2 µg/rat) to be injected was chosen
because it decreases food intake in rats when injected into the PVN
(37
,38)
.
Surgery.
Rats (300 g) under anesthesia with sodium pentobarbital (Somnotol, MTC
Pharmaceuticals, Cambridge, Canada; 40 mg/kg intraperitoneally) were
aseptically implanted with a single 22-gauge stainless steel guide
cannula (Plastics One, Roanoke, VA) 2 mm dorsal to the right side of
the PVN, with coordinates of 1.8 mm posterior to the bregma, 0.5 mm
lateral to the midline and 6.0 mm ventral to the surface of the skull
(39)
using a stereotaxic apparatus (David Kopf
Instruments, Tujunga, CA). The guide cannula was secured to the surface
of the skull with four stainless steel screws and dental cement, and
then a 28-gauge obturator inserted into the guide cannula to prevent
tissue entry. An antibiotic (Penlong XL, 0.03 mL; Pfizer Canada,
London, Canada) was administered intramuscularly to one thigh of the
rats after the surgery. An analgesic (Temgesic, 0.05 mg/kg; Reckett &
Colman Pharmaceuticals, Hull, UK) was provided subcutaneously to
relieve the postoperative pain. For postoperative recovery, rats were
given 1 wk, during which they were closely monitored but no treatments
were given. Allowing rats to have free access to the diet during this
period appeared to contribute to a rapid recovery from the surgery.
Procedures.
To accustom the rats to gavage procedures, from the day after their delivery, each rat received 5 mL of deionized water by gavage. After 1-wk recovery from surgery, handling of rats was resumed each day 2 h before the dark onset. This included weighing, three mock injections and water preloads by insertion of a 16-gauge, 75-mm length, 3-mm ball diameter feeding needle (Fine Science Tools, North Vancouver, Canada) attached to a 5-mL syringe. Beginning a week before behavioral tests, the AIN 93G diet was provided to rats in some experiments from 1800 to 0800 h instead of nonpurified diet; in other experiments, either the CHO diet or the PRO diet was fed for the first 2 h (1800–2000 h) and then the maintenance diet for the rest of the night.
Before injections, each rat was transferred from its own cage to a cardboard box with dimensions of 25 cm x 25 cm x 25 cm; daily body weight and injections were performed in the boxes while rats were allowed to move freely. Injection of substances (in a volume of 0.5 µL) was performed over 50 s using an injection cannula (28-gauge) (Plastics One). The cannula was connected to a Hamilton microsyringe (5.0 µL, #87920) via Tygon Tubing (i.d., 0.19 cm; o.d., 0.20 cm; Cole-Parmer Instrument Company, Vernon Hills, IL). The injection cannula was left in place for an additional 1 min to allow the substances to diffuse into tissues before removal; rats were then returned to their own cages after placement of the obturator. The cannula extended 2 mm ventrally from the tip of the guide to reach the PVN. To minimize drug-carryover effects, each injection day was followed by a 2-d washout period during which no injections were given. Each rat served as its own control. Food was provided in a white china cup, 40 mm in height, and 60 and 70 mm in i.d. and o.d., respectively. Food consumption was measured at 1, 2 and 14 h after food introduction (1800 h) to the nearest 0.1 g with adjustment for spillage.
Design.
Four experiments were designed in which each rat served as its own control. One group (n = 8) was prepared for Experiment 1, and another group (n = 12) for Experiments 2–4. Both treatment order and group assignment were randomized for each experiment. At 1800 h (meal studies: Experiments 1, 2A and 3A) or 1730 h (preload studies: Experiments 2B, 3B and 4) on experimental days, rats were divided into two groups. One group was injected with GLP-1 (0.2 µg/0.5 µL) into the PVN and the other saline (0.5 µL) at 1800 h (meal studies); in preload studies, injections were made, followed by nutrient preloads given by gavage at 1730 h. Food cups were introduced at 1800 h, and food intake and spillage measured at 1, 2 and 14 h thereafter. After a 2-d washout period, the order of these treatments was reversed, i.e., rats that received GLP-1 on d 1 were given saline and rats that received saline were injected with GLP-1.
Experiment 1. Effect of GLP-1 injection into the PVN on intake of the AIN-93G diet.
To test the effect of GLP-1 injection into the PVN on consumption of the maintenance diet, the AIN-93G diet was provided for 14 h after injections of GLP-1 or saline.
Experiment 2. Effect of GLP-1 injection into the PVN in combination with either the CHO diet or glucose preloads on subsequent food intake.
In Experiment 2A, the CHO diet was provided from 1800 to 2000 h after injections and the AIN-93G diet from 2000 to 0800h. In Experiment 1B, immediately after both GLP-1 and saline injections (1730 h), all rats were gavaged with glucose (1.4 g/5 mL) and 30 min later fed the AIN-93G diet for 14 h.
Experiment 3. Effect of GLP-1 injection in combination with either the PRO diet or egg albumin preloads on subsequent food intake.
The design of these experiments was identical to that in Experiment 2, except that the PRO diet was fed in Experiment 3A and egg albumin (1.0 g) gavaged in Experiment 3B.
Experiment 4. Effect of GLP-1 injection into the PVN and corn oil preloads on food intake.
The design of this experiment was similar to that of Experiments 2B and 3B, except that corn oil (2.4 g/5 mL) was given to all rats by gavage at 1730 h.
Histology.
At the conclusion of the experiments, the rats were injected with 2%
Evans Blue dye (Sigma) in 9 g/L NaCl into the PVN in the same
procedures as peptide injection, and killed by CO2 gas.
Their brains were removed and soaked for several days in 10%
formaldehyde solution in 9 g/L saline and for 2 d in 300 g/L
sucrose solution. After fixation, 40-µm frozen
sections of the brain were cut, mounted on glass slides and
subsequently dehydrated and stained with Cresyl violet (Aldrich,
Milwaukee, WI). To verify the accuracy of the cannula placements, the
sections were examined by light microscopy with reference to the atlas
of the brain of Paxinos and Watson (39)
.
Statistical analysis.
Data analysis was performed by a paired t test using the
SAS System (SAS Institute, Cary, NC). Data were expressed as means
± SEM. All treatment effects were considered
significant at P 
0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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were excluded from the analysis. A
typical placement of cannula in the PVN is shown in Figure 1
. The numbers of rats with cannula placed in the PVN were 6 for
Experiments 1 and 10 (2, outside the PVN) for Experiments 2A–4.
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, Expt. 1).
|
, Expt. 2A) or glucose preloads (Table 2
, Expt. 2B), a
decreased food intake was also found during the 2–14 h period, but not
in the first 2 h. After voluntary consumption of the CHO diet for
2 h (Table 2
, Expt. 2A), intake of the AIN-93G diet from 2 to
14 h was 15.3 g and 9.8 g (t = 3.69,
P < 0.008) after saline and GLP-1 injections,
respectively. Overall food intake during the 14-h access to the diet
was lower after GLP-1 treatment (15.6 g) than after saline (21.4 g)
(t = 5.19, P < 0.002). GLP-1, in
combination with glucose gavage, also tended to suppress food intake
compared with glucose alone (Table 2
, Expt. 2B), with 17.2 g for
saline and 14.2 g for GLP-1 (t = 2.06,
P < 0.078) for 2–14 h, and 20.8 g and 17.8 g (t = 1.93, P < 0.075) for 0–14 h.
GLP-1 injection had no effect on food intake when given with the PRO
diet or albumin preloads. No difference in food intake occurred over
14 h between the saline and GLP-1 treatments (Table 2
, Expts. 3A
and 3B) (P > 0.05). When the PRO diet was fed for the
first 2 h, food consumption from 2 to 14 h was 14.6 g
after saline vs. 13.5 g after GLP-1 (P < 0.45),
and the total 14 h intake was 22.0 g vs. 20.6 g
(P < 0.41), respectively (Table 2
, Expt. 3A). Similar
results were seen after albumin preloads, with food intake from 2 to
14 h of 14.9 g for saline vs. 13.7 g for GLP-1
(P < 0.49) and 20.1 g vs. 19.8 g
(P < 0.84) for the total 14 h intake (Table 2
,
Expt. 3B).
When GLP-1 was combined with corn oil, a slight but significant
reduction was detected only for the cumulative 0–2 h food intake
(Table 2
, Expt. 4). Food consumption was as follows: 0–1 h, 2.3 g
(saline) vs. 1.9 g (GLP-1) (t = 2.18,
P < 0.072); 0–2 h, 3.9 g vs. 3.3 g
(t = 3.08, P < 0.03).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The decreased intake of the maintenance diet after GLP-1 is in general
agreement with previous reports. However, the time course of the
response is not. Intracerebroventricular injection of GLP-1 suppresses
feeding behavior in both food-deprived and freely fed rats
(9
10
11
12
13
14
15
16
,18
,41)
, a result that is abolished by pretreatment
with its receptor antagonist, exendin 9–39 (16)
.
Suppression of food intake from a nonpurified diet has been found to be
rapid, within 2 h of GLP-1 injections (9
10
11
12
13
14
15
16
,18
,41)
.
McMahon and Wellman (37
,38)
recently reported a reduction
in food intake of a palatable liquid meal or pelleted nonpurified diet
within 1 h after GLP-1 (0.2 µg) injection into the
PVN of fed rats.
The primary effect of GLP-1 on food intake in the present study
occurred from 2 to 14 h (Table 2
, Expt. 1). It is unlikely that
our observation resulted from a delayed diffusion rate of the GLP-1
injected in the PVN to bind to its receptors because GLP-1 injection
combined with the corn oil preload resulted in a reduction in food
intake over 0–2 h (Table 2
, Expt. 4). An explanation likely resides in
the feeding method. McMahon and Wellman (37
,38)
injected
GLP-1 (0.2 µg/rat) into the PVN of freely fed rats in
experiments that were performed during the day, starting 4 or 2 h
before dark onset, respectively. In the present study, however, the
rats were deprived of food daily for 10 h, and food was available
only from 1800 h (dark onset) to 0800 h the next morning.
GLP-1 (0.2 µg/rat) was injected either 30 min before or at
the dark onset, depending on the experiment. Because of food
deprivation during the day and the normal surge in feeding activity of
rats as they enter the night time feeding period, rats in this study
started to eat immediately after the peptide was injected and food
provided.
The present results suggest that the action of GLP-1 on feeding
behavior is enhanced by signal(s) arising after carbohydrate, but not
protein consumption (Fig. 2
) (Table 2
, Expts. 2A–3B). Carbohydrate ingestion increases release of
GLP-1, a potent insulin secretagogue, inhibits glucagon secretion, and
stimulates glycogenesis in the liver and muscle and lipogenesis in
adipose tissue (21)
. Because insulin release enhances
glucose uptake by tissues and increased metabolism of glucose has been
associated with food intake control mechanisms, it is reasonable to
expect that the action of GLP-1 would be enhanced by CHO intake. GLP-1
alone resulted in a 20% reduction in consumption of the AIN diet for
2–14 h but led to a 36% decrease when the CHO diet was fed. This
enhancement was not seen after other treatments (glucose, 17%;
albumin, 8%, PRO, 9% decrease; but corn oil, 19% increase) (Fig. 2)
.
|
,42
,43)
. Thus it is likely that glucose
directly activates these mechanisms, resulting in the enhancement of
the negative effect of GLP-1 injected into the PVN on food intake.
Second, GLP-1 signaling appears to depend on both the afferent and
efferent fibers of the vagus through which the information is
transmitted and integrated into the nucleus tractus solitarius (NTS)
and then other brain sites such as the PVN. The PVN and the arcuate
nucleus (ARC) express GLP-1 receptor mRNA and are intensively
innervated by GLP-1 immunoreacitve nerve fibers from GLP-1 perikarya in
the NTS (44
45
46
47)
. For example, the delayed gastric
emptying elicited by GLP-1 is lost after either vagal denervation with
capsaicin in rats (6)
or vagotomy in humans
(48)
and pigs (49)
. Thus, the suppressive
effect of GLP-1 on gastric motility may account in part for
GLP-1–induced satiety. Third, the circulating GLP-1 is able to enter
the brain by crossing the blood-brain barrier (BBB)
(50)
and binds to its receptors in several brain regions
in which the BBB is relatively leaky. Among those are the subfornical
organ, area postrema, median eminence and pituitary
(23
,51
,52)
, which have a high density of GLP-1 receptors
(51)
as well as close neuroanatomical connections with
hypothalamic areas such as the PVN and ARC (53)
. Fourth,
GLP-1 has been shown to interact with a variety of neurotransmitters in
the brain, such as neuropeptide Y (NPY) (13
,16)
,
corticotrophin-releasing hormone (CRH) (54)
and leptin
(10
,53)
. Because both NPY and CRH are associated with
carbohydrate intake (55
,56)
, for example, GLP-1 may
suppress food intake by suppressing the elevation of NPY found after
food intake and increasing corticosterone in plasma via activation of
the CRH neurons in the PVN (54
,56)
. Injection of CRH into
the PVN, but not elsewhere in the hypothalamus, reduces NPY-induced
feeding (57)
.
Food intake was suppressed by 17% during the 2–14 h period compared
with saline when GLP-1 was combined with glucose gavage, whereas an
36% reduction in food intake was observed after treatments of GLP-1
and the CHO diet. The weaker feeding response after GLP-1 with glucose
preloads, compared with the CHO diet, may be accounted for by the
smaller size, the bolus nature of the glucose preloads and perhaps the
30-min delay between these treatments and presentation of the AIN-93G
diet. Evidence has shown that GLP-1, and thereby insulin, is rapidly
released in response to intragastric loads of glucose in rats and
reaches a peak within 5 (58)
or 30 min (59)
.
Because glucose preloads were given 30 min before feeding in the
present study, a peak of GLP-1 release caused by glucose preloads may
have passed, whereas consumption of the CHO diet would have continued
to stimulate GLP-1 release over the 2-h feeding interval, resulting in
a stronger suppression of subsequent food intake.
Protein intake prevented the decrease in food consumption caused by
GLP-1, implying that protein consumption interrupts the pathways by
which GLP-1 reduces food intake. It has been speculated that protein is
a weak stimulant of GLP-1 release in rats, as it is in humans
(24
,25)
, with little interaction occurring between
peripheral and central actions of GLP-1, although the effect of protein
ingestion on GLP-1 release and the time course in rats has not been
reported (34)
. It seems likely that signals arising from
GLP-1 release may have been surpassed by others derived from protein
consumption, which itself strongly suppresses food intake through other
mechanisms (unpublished data)5
(3
,4)
. For example, CCK is strongly released in response
to the presence of protein in the upper small intestine
(60)
and both central and peripheral injections of CCK
robustly suppress food intake (61)
. We recently showed
that CCK-A receptors are involved in the reduced food intake
occurring after preloads of protein (egg albumin) (3
,4)
.
The results showing that corn oil preloads in conjunction with GLP-1
slightly, but significantly decreased food intake only during early
feeding are consistent with the time course of GLP-1 release after corn
oil consumption. Fat, including corn oil, enhances GLP-1 release after
ingestion (32
,62
63
64)
. GLP-1 secretion peaks within 5 min
and lasts for 1 h after the infusion of corn oil (3–4 mL) into the
proximal segment of rat duodenum (32)
. In pigs, a peak of
GLP-1 release was observed at 60 min after fat infusion (soybean oil)
into the duodenum, followed by a gradual decrease without significant
difference from baseline at 90 min (63)
. Thus, peak action
of GLP-1 after corn oil gavage would be expected in the first 2 h
of food access.
To confirm that the GLP-1 was biologically active over the duration of
these studies, we measured the effect of the peptide GLP-1 (lot #:
802902) on heart rate (beats/min) in male Wistar rats
(65
,66)
at the end of the series of experiments. Rats (470
g) were anesthetized as described previously (67)
. After
20 min, heart rate (beats/min) was measured every 3 min for 1 h
using Pulse Oximeters (Nonin 8600V, Nonin Medical, Minneapolis, MN).
Approximately 20 min after a constant baseline was observed, GLP-1 (2
µg/0.5 mL saline) or saline (0.5 mL) was injected
intravenously via the tail vein over 2 min (2 rats each group). GLP-1
injection increased heart rate in both rats (8% at 12 min and 16% at
6 min after the injection), whereas saline injection did not.
Therefore, the failure to see a feeding response to the GLP-1 when
given with protein preloads or the PRO diet cannot be explained by the
absence of biological activity of the preparation. Furthermore, GLP-1
activity was also found in the final experiment in which it enhanced
food intake suppression by a corn oil preload (Table 2
, Expt. 4).
Central injection of GLP-1 has been shown to cause conditioned taste
aversion (CTA). When intracerebroventicular GLP-1 at 1.0 or 3.0
µg was followed by immediate oral infusion of saccharin,
rats reexposed to GLP-1 and saccharin after several days rejected the
saccharin after the 3.0 µg dose (41)
. It is
unlikely that the reduced food intake in the present study resulted
from CTA by GLP-1. For example, McMahon and Wellman (38)
showed previously that a 0.2 µg GLP-1 injection (the same
amount used in the present study) into the PVN did not cause CTA in
rats. Moreover, we did not observe any consistent pattern of eating
over a series of experiments that might be interpreted as a CTA
response. Because no suppression in food intake was seen in rats
treated with GLP-1 and protein, it is unlikely that the decreased food
intake after GLP-1 injection resulted from CTA.
Studies conducted to date on the effect of GLP-1 provided centrally to experimental animals have tested total food intake from a single diet. Because GLP-1 exerts a critical effect on carbohydrate metabolism and its effect on subsequent food intake is enhanced by carbohydrate intake, it may be that central GLP-1 also plays a role in regulating macronutrient selection and intake. Evidence for this possibility is supported indirectly by recent studies of the effect of peripheral injections of a GLP-1 agonist and an antagonist. When rats were given a choice between CHO and PRO diets, and received intraperitoneal injections of the GLP-1 receptor antagonist, exendin 9–39, a selective decrease was observed in intake of only the CHO diet, whereas a GLP-1 receptor agonist, exendin 4, caused a selective decrease in intake of only the PRO diet (Peters et al, unpublished data).
We concluded that the effect of GLP-1 injected into the PVN on food intake is influenced by the macronutrient composition of the food consumed. Carbohydrate enhances, protein blocks and corn oil has a transient effect on the suppression of food intake caused by GLP-1 in the PVN.
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ACKNOWLEDGMENTS |
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|
FOOTNOTES |
|---|
2 Supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada.
4 Abbreviations used: ARC, arcuate nucleus; BBB,
blood-brain barrier; CCK-A, cholecystokinin-A; CHO,
protein-free, high carbohydrate diet; CRH,
corticotrophin-releasing hormone; CTA, conditioned taste aversion;
GLP-1, glucagon-like peptide-1 (7–36) amide; NPY, neuropeptide Y;
NTS, nucleus tractus solitarius; PRO, high protein, low carbohydrate
diet; PVN, paraventricular nucleus of the hypothalamus.
Manuscript received November 14, 2000. Initial review completed February 22, 2001. Revision accepted March 16, 2001.
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