Download Cholecystokinin suppresses food intake by inhibiting gastric emptying

Cholecystokinin
suppresses food intake
inhibiting
gastric emptying
TIMOTHY
H. MORAN
AND PAUL R. MCHUGH
Department
of Psychiatry and Behavioral Sciences, Johns
School of Medicine, Baltimure, Mu&and
21205
Macaca mulatta; intestinal hormones; gastric
tiety; hunger; stomach; feeding; intestine
distention;
sa-
PLAYS a critical role in a behavior, then
some of the hormone’s biological characteristics, such as
the stimulus for its secretion, its half-life in circulation,
and its physiological actions in the body, should reveal
how the hormone fits the behavior it serves. Recently
Smith, Gibbs, and associatesproposed that the hormone
cholecystokinin (CCK), released from the small intestine
by the entrance of nutrients, provokes satiety for food
and is part of the natural rhythm of hunger and satiety
in feeding behavior. Their evidence is that exogenous
CCK decreasesfeeding in adult rats (8) and monkeys (7)
and suppressesthe vigorous feeding of these animals that
occurs when food is diverted from their stomachs (sham
feeding) (6, 9). CCK provokes a sequence of grooming
and resting that resembles the behavior of a sated animal
(2) and does not seem to make animals sick (10).
Though an intestinal hormone released by food would
seem an ideal signal to inhibit further food intake, both
the mechanisms whereby CCK inhibits feeding and its
particular place in the sequential characteristics of this
intermittent behavior have been difficult to define. CCK
is known to have a short half-life in circulation (15); yet
IF A HORMONE
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@ 1982 the
American Physiological
Unwersity
satiety is a prolonged event after a meal. Behavioral
inhibition implies a brain event; yet circulating CCK is
unlikely to cross the blood-brain barrier (22) except at
some as yet undiscovered portal. The doses of CCK that
have been used to demonstrate its effect on feeding seem
large and may be in a pharmacological rather than a
physiological range (25).
We have been investigating the peripheral physiological actions of CCK by which it may influence feeding.
Since much of the previous work demonstrated that
gastric distention can inhibit feeding behavior (3,Zl) and
since CCK is one of several intestinal hormones that slow
gastric emptying (4), McHugh (16) suggested that CCK
may act to reduce food intake indirectly through its
capacity to produce gastric distention by retarding the
release of ingested food from the stomach.
From our efforts to test this hypothesis, we report in
this paper than CCK given via two parenteral routes
does have a potent inhibitory effect on gastric emptying
in the rhesus monkey. This effect occurs at physiological
doses, but at these doses its effect on feeding is minimal
unless the stomach is full. Finally both the latency and
duration of action of this hormone on the stomach illuminate its integrative function in feeding. Some of these
data have been previously reported (19, 20).
METHODS
The subjects of these experiments were male rhesus
monkeys (Macuca mulatta) weighing between 5 and 10
kg. They were housed in individual cages in rooms kept
at approximately 70°F and lit by natural daylight. They
had water ad libitum but access to food in the form of
chow pellets for only 4 h/day, (1O:OOA.M. to 200 P.M.).
On this schedule the experiments began between 8:00
and 1O:oOA.M. with animals that fasted overnight for at
least 18 h.
Each monkey was fitted with a light leather jacket
attached to the back of which is a multiflexible stainless
steel cable measuring 3 ft in length and ‘/4in. in internal
diameter extending to the cage wall. A Silastic cannula
(Dow-Corning medical grade tubing 1.9 mm ID) in the
gastric lumen was anchored to the serosal surface of the
greater curvature and passed through the tissues of the
back and out the stainless steel cable. This cannula
permitted infusion and withdrawal of liquids from the
stomach. An intravenous Silastic cannula (0.5 mm ID)
was placed in the right atrium through the internal
Society
R491
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MORAN,TIMOTHY
H., AND PAUL R. MCHUGH. Cholecystokinin suppresses food intake by inhibiting
gustric emptying.
Am. J. Physiol. 242 (Regulatory Integrative Comp. Physiol. 11):
FU91-Ft497, 1982.-h
a search for the physiological
mechanisms that could mediate and characterize
a satiety function
for the hormone cholecystokinin
(CCK), we examined in Macaca mulatta the effect of intraperitoneal
injections
(0.1-0.8
pg/kg) and intravenous
infusions (60-240 ng~kg-l~h-l)
of the
C-terminal
octapeptide
of CCK on gastric emptying of saline
test meals. Within these dose ranges, gastric emptying was
inhibited
by this hormone to a degree comparable
with that
produced by intraintestinal
nutrient. The onset of the inhibition
is rapid and its effect brief. At the doses of CCK that produce
gastric inhibition,
CCK would not affect feeding in a fasted
monkey unless the stomach was filled with saline. This result
suggests that a satiety influence of circulating
CCK is an
indirect one. The satiety effect depends upon inhibition
of
gastric emptying, which then leads to gastric distention with
further food injestion. CCK thus can be considered a link in a
chain of physiological
elements producing the short-term
satiety that leads to the appropriate
interruption
of a meal or
bout of feeding behavior.
Hopkins
by
R492
T. H. MORAN
Experiment I. Effects of Intraperitoneal
on Gastric Emptying
0-CCK
Methods. In this experiment we sought to demonstrate
the effect of intraperitoneal injections of 0-CCK on
gastric emptying first by comparing the amount of physiological saline that passed the pylorus 10 min before
with that which passed 10 min after a CCK injection. We
also sought a dose-response relationship to the duration
of any effect. A saline test meal of 150 ml fust established
the control rate for saline emptying over 10 min. Then
0-CCK dissolved in distilled water and in doses of 0.1,
0.2, 0.4, or 0.8 pg/kg was injected intraperitoneally. Five
minutes later a second test meal of 150 ml of saline was
infused into the stomach and left in place as before for a
10-min emptying period. Its emptying rate could be compared with the control rate.
On those occasions in which an obvious inhibition of
gastric emptying was demonstrated with the second test,,
we assessedsequential LO-min gastric emptying rates by
repeatedly filling the stomach with 150-ml saline test
meals permitting a IO-min emptying period, then withdrawing the saline remaining in the stomach. We continued in this fashion until the amount of saline passed
through the pylorus in a lO-min period returned to the
control rate. The time from the CCK injection to this
recovery of rapid gastric emptying was the duration of
the CCK effect. These effects of 0-CCK on gastric emptying were determined in four monkeys.
P. R. MCHUGH
Results and conclusions. In all four monkeys it was
possible to interrupt gastric emptying with intraperitoneal 0-CCK. The duration of this interruption varied
with the dose and the lowest effective dose varied with
the animal.
With the fust test meal (control) in these four monkeys, 88.8 2 1.67 ml (means 2 SE) of saline could be
withdrawn from the stomach indicating that 61.2 ml of
the original 150-ml test meal had passed the pylorus in
the lO-min emptying period (6.1 ml/min.). This confirmed our previous report that physiological saline empties rapidly and exponentially from the stomach of the
rhesus monkey.
At the end of the second test meal, at doses above
threshold, we recovered 145,4 t 0.85 ml of saline indicating that only 4.6 ml had passed the pylorus in 10 min, a
rate of 0.46 ml/min. This rate of 0.4-0.5 ml/min is identical to the rate that the monkey’s stomach delivers
concentrated nutrient loads to the intestine (18). The
thresholds for this inhibitory effect of CCK on gastric
emptying were 0.1 pg/kg for two of the monkeys and 0.4
pg/kg for th e remaining two.
The dose-response curves shown in Fig. 1 display the
duration of this maximal inhibition in each of these four
monkeys against the dose. The individual differences in
threshold and duration of the inhibitory effect are apparent, but an increasing response duration with increasing dosage is also evident in all four monkeys.
Thus 0-CCK administered intraperitoneally
in this
dose range can exert a maximal inhibition on gastric
emptying. The individual differences in threshold and
duration of the hormone’s effect may be due to several
factors including differential absorption, a complication
of the intraperitoneal route of administration in such
large animals.
P
1
0.1
0.4
0.2
IP O-CM
FIG. 1. Duration
of O-cholecystokinin
of inhibition
(0CCK)
on gastric
l
0.6
0.8
tug/kg)
emptying
at varying
doses
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jugular vein. Anchoring
stitches held it to the strap
muscles of the neck, and it was also led through the
tissues of the back to pass through the cable. We have
described the design of this jacket and the procedures for
gastric and intravenous
cannulation in detail in previous
publications
(I 7, 18).
In all the experiments
studying gastric emptying we
employed the dye dilution, serial test meal method of
Hunt and Spurrell(11).
This method calls for the infusion
into the stomach of a liquid load (test meal) of known
constitution
and volume with phenol red added as a
marker. After a given time (the emptying period), the
duration of which varied with the experiment, the gastric
contents were withdrawn
through the cannula, and the
stomach was washed clean with distilled water. The
volume of the original test meal in these gastric contents
was determined from the volume removed correcting for
any accumulated gastric secretion by measuring colorimetrically
the dilution of the phenol red marker. The
difference between the meal volume infused and withdrawn is the amount of the test meal that passed through
the pylorus during the emptying period. This can be
expressed in ml/min. For all the experiments
reported
here, the test meals were physiological saline (0.9% NaCl)
warmed to 38°C and infused into the stomach by hand
from syringes at a rate of approximately
75 ml/min.
We used the synthetic
C-terminal
octapeptide
(OCCK) for all the cholecystokinin
(Sincalide, Squibb)
experiments; 1.0 lug of 0-CCK is roughly equivalent in its
biological action to 22-25 Ivy dog units of the complete
molecule. We will report doses in both gram and molar
terms; 1.25 ng 0-CCK is 1.0 pmol.
AND
CHOLECYSTOKININ
SUPPRESSES
FOOD
R493
INTAKE
Experiment 2. Interaction
of Intraperitoneal
CCK and Gastric Distention on Feeding
Experiment (3. Intravenous CCK
and Gastric bInhibition
1Methods. IThese results with intraperitoneal
0-CCK
suggest that I a role for CCK in feeding may be mediated
through its effect on gastric emntving. However, the
l
l
l
l
l
l
l
l
l
1. Grums of food eaten in experiment
TABLE
Condition
Time
Feeding,
A,- Control
min
28.8 k 4.0
173.1 k 15.3
10
240
Values
are means
B, Saline
D, CCK
C, CCK
29.6 -+ 3.9
168.8 t, 16.9
t, SE, CCK,
2. Inhibition
TABLE
2
+
Saline
22.5 t 2.7
182.7 AZ10.5
7.8 k 2.0*
149.8 & 21
*P < 0.01.
cholecystokinin.
of gastric emptying
IV 0-CCK
Dose, pm010
kg-‘. tin-’
n
Control
Condition, ml
0.75
1.5
3.0
8
8
8
101.4 * 7.1
95.3 t, 5.0
98.7 k 4.4
CCK
Condition,
ml
74.7 k 2.7
47.8 t, 2.4
6.3 z!z3.1
% Inhibition
23.5 zk 6.0
48.3 t 3.5
91.5 Z!I3.6
Values are means t SE. Gastric emptying
inhibited
by intravenous
O-cholecystokinin
(O-CCK)
expressed
as volume of saline emptied
in
10 min after 150~ml test meal.
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Methods. The same four monkeys in which we acquired the dose relationships for the inhibition of gastric
emptying by intraperitoneal
CCK were employed to demonstrate that at these doses, CCK would affect feeding
only if the stomach was full. The four animals were
accustomed to taking’ all their daily food during a 4-h
period. They operated a Lindsey lever to receive 1 g of
Noyes chow pellets. Cumulative records traced the behavior. - _
For this experiment we examined the feeding of these
animals under four different conditions. Condition A:
control feeding in which the animals were under the
influence of no experimental manipulation.
Condition B:
at the beginning of the feeding period, 150 ml of saline
was infused into the stomach. Condition C: 5 min before
feeding, the animal received an intraperitoneal
injection
of a dose of 0-CCK known from experiment 1 to produce
a maximal gastric inhibition
that would extend for at
least 10 min into the feeding period. Condition D: the
same dose of 0-CCK as in condition C was given 5 min
before feeding, but at the onset of feeding period 150 ml
of saline was infused into the stomach. In each of these
conditions we examined the amount of food eaten in the
first 10 min of the feeding period.
We can report on 10 sets of such experiments with
doses of 0-CCK ranging from 0.2 to 0.8 pg/kg. The 0.2pg/kg dose was used only with those two -monkeys in
which this dose did provide a maximal inhibition
on
gastric emptying. The results were analyzed with an
analysis of variance.
Results and conclusions. As shown in Table 1 there
was a prominent effect on feeding in the first 10 min only
in the condition D in which 0-CCK was combined with
a saline load to the stomach [F (9,1) = 11.523; P <
0.011. The slight reduction with CCK alone (condition C)
did not reach significance. No significant effects were
found at 240 min. No difference was found across the OCCK dose range.
Thus we can say that a 150-ml intragastric load of
saline alone has neither short- nor long-term effects on
feeding. Under this condition saline is emptied rapidly,
and it does not produce a sustained distention of the
stomach. Likewise it is possible to choose doses of CCK
capable of inhibiting the stomach maximally that do not
affect food intake significantly when given alone to a
fasting animal with an empty stomach. Only when these
doses of CCK and a 150~ml saline load to the stomach
are combined do these ineffective stimuli show a potent
effect on feeding. Since at these doses of CCK we did not
find a dose-response effect on the magnitude of gastric
inhibition, but on the duration that this maximal effect
is sustained, we did not expect and did not find a dose
effect on the feeding in the IO-min test period.
intraperitoneal
route of delivery is an unsatisfactory
method for examining such dynamic effects as latency
and duration of action of CCK on either the gut or
behavior. Knowledge of these aspects and increasing
confidence that we are dealing with physiological doses
would be crucial in confirming this view.
In anoth .er four monkeys weighing 6-10 kg and prepared with both intrajugular
and intragastric cannulas,
we replicated the methods of infusion of 0-CCK and the
dose ranges employed by Debas et al. (4) in the dog to
establish the physiological actions of this hormone. Infusions of solutions of 0-CCK in saline at rates of 0.75,
1.5, and 3.0 pmol kg-’ min-’ (60, 120, 240 ng kg-’ h-‘)
were sustained for 70 min through the intravenous cannula by means of a Harvard constant-inf&ion
pump.
After 60 min of infusion, the stomach was filled with a
150~ml saline test meal that WaS left in for an emptying
period of 10 min. Simultaneo usly with the termination of
the hormone infusion the gastric contents were removed,
and the rate of delivery of saline in ml/min were calculated for that 10,min period and compared with control
rates. The degree of inhibition
could be indicated by
expressing the reduction in emptying rate produced by
CCK as a percent of the control rate.
Results and conclusions. As shown in Table 2,OCCK
did inhibit gastric emptying of saline in a dose-related
fashion; 0.75 pmol. kg-la min-’ produced a 25% inhibition,
1.5 pmol kg-’ min-’ a 50% inhibition, and 3.0 pmol kg-’
mine1 an inhibition essentially identical to that produced
by nutrients in stomach and intestine. These graded
results with a mean dose (Da) of 1.5 pmol‘ kg-’ min-’
are identical to those reported by Debas et al. (4) for
inhibition of gastric emptying in the dog. Since these are
the CCK doses that produce a similar graded stimulation
of pancreatic secretion, they argued that gastric inhibition should be considered one of the physiological functions of that hormone.
Since the maximal dose 3.0 pmol. kg-‘. min-’ produced
an inhibition
on gastric emptying similar to that seen
with concentrated nutrient, and yet this dose is below
previously reported doses for satiety in the rhesus (7), we
chose it or the Dso (1.5 pmol kg-’ emin-1) as the doses to
R494
T. H. MORAN
combine with a gastric load to demonstrate
an interaction
in satiety between these two physiological
events (CCK
secretion and gastric distention) that occur with feeding.
Experiment 4. Interaction
Between Intravenous
CCK and Gastric Distention in Satiety
of food eaten
grams
4
Condition
Feeding
The,min
B, Saline
A, Control
10
45*5
20
30
40
50
60
120
240
84
107
128
!41f
147
177k
212
Values
are means
48
79
108
123
136
144
162
207
t
*
t
12
13
10
9
t, 13
16
AZ 16
k
t
t
-+
t
k
k
f
6
10
11
13
12
15
13
14
& SE. See Fig+ 2.
D, CCK
Saline
C, CCK
38 A
73 t,
97t,20
112 A
136 k
156t,27
175 t,
212 2
13*4*
29 t,
47*
66*
91 k
105t
149t
198k
8
15
23
27
28
22
+
9t
15'r
21*
20
21
20
21
tP < 0.01.
*P < 0.05.
our interventions
(saline fill or CCK) on feeding and
discern whether it is their interaction
that has a clear
influence. We carried out seven sets of these experiments
in four monkeys (6 at 3.0 pmol~kg%nin-I;
one at 1.5
and analyzed the results with an analpmol kg-’ l in-‘)
ysis of variance.
Results and conclusions. Table 3 shows the results at
several intervals into the feeding session. There were no
significant main effects of either saline or CCK. However
there was a significant interaction between saline in the
stomach and intravenous
CCK extending through the
first 40 min of the feeding period.
Figure 2 shows the feeding for the 1st h for conditions
A-D (control, intragastric saline, intravenous CCK alone,
and intravenous
CCK plus intragastric
saline). The saline
alone and the CCK alone had no significant effect, but
their combination showed an obvious inhibition on feeding. This effect was temporary
and gradually
disappeared. As shown in Table 3 and Fig. 2 all groups eventually consume similar amounts by the end of the 4-h
feeding session.
These results are the same as those with intraperitoneal 0-CCK and demonstrate
that with amounts of CCK
that inhibit gastric emptying, it is the combination of the
hormone and the distention of the stomach that is critical
for the inhibition of food intake in the fasted animal. For
such an interaction
the dynamics of action of this hormone on the stomach, particularly
the latency and duration of activity of a dose within the physiological range,
would likely be important.
Experiment 5. Latency and Duration
of 0-CCK on Gastric Emptying
of Action
Methods. In five experiments
on two monkeys with
both intravenous
and intragastric
cannulas, we infused
0-CCK intravenously
after the characteristics
of gastric
emptying of saline had been established. For this purpose
100-ml saline loads (with phenol red marker) were instilled into the stomach and left for a 2-min emptying
m- . - . a CONTROL
A
w
e
200
.
.
n
- 4 SALINE
CCK
- +
T
SALtNE+CCK
m
FIG. 2. Cumulative
feeding records of
monkeys
under 4 different
conditions:
control,
after an intragastric
saline load
of 150 ml, after an infusion
of O-cholecystokinin
(O-CCK),
with combination
of O-CCK
and intragastric
saline load.
\
0
1’0
2b
3b
4b
TIME (mid
5b
io
1
240
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3. Cumulative
for experiment
P. FL MCHUGH
l
Methods. As in experiment 2 we chose a 4-way design
with four monkeys
employing both their gastric and
jugular cannulas. As before the animals were fasted overnight and were prepared for a 4-h feeding session. In
design A, an intravenous
saline infusion was begun 60
min before the feeding period and ran through the first
10 min of the feeding. We followed the feeding over the
4 h with a cumulative recorder attached to the Lindsey
lever. This constituted
the control condition. In design
B, at the time feeding began, a load of 150 ml of physiological saline was delivered into the stomach seeking a
saline load effect. In design C, we infused 0-CCK intravenously for 60 min before and 10 min into the feeding
period but did not fill the stomach, seeking a CCK effect.
In design D, we combined the features of designs B and
C (the infusion of CCK and the gastric load of 150 ml of
saline) seeking an interaction effect.
We can, in this fashion, document any main effects of
TABLE
AND
CHOLECYSTOKININ
SUPPRESSES
FOOD
R495
INTAKE
period. A 3-min interval permitted the full removal of the
saline, and then another lO@ml load was infused to be
left in for another 2 min. This series of infusions and
withdrawals
every 5 min was continued until the basal
level of gastric emptying was established clearly. Usually
this required just two test meals. Under control conditions in 2 min the stomach emptied 15 ml of the original
100 ml averaging 7.5 ml/min.
Then simultaneously with delivering the next saline
test meal we started the intravenous infusion of 3 pmole
kg-l min-’ of 0-CCK, the dose previously established as
having the maximal inhibitory effect on emptying. This
infusion was sustained for varying periods of 10, 15, or 20
min, during which we continued to assess the gastric
emptying of 100 ml of saline every 5 min.
Finally, simultaneous with the delivery of another test
meal, we disconnected the CCK pump and so abruptly
ended the infusion of hormone. We continued, however,
the saline test loads every 5 min until control emptying
rates reappeared.
Results and conclusions. Figure 3 depicts the characteristic result. Saline emptied rapidly prior to the CCK
infusion. An effect on gastric empyting was evident with
the infusion of CCK even with the first 2-min saline test
load; as the emptying rate fell from 7.5 to 6 ml/min.
During the rest of the infusion period gastric emptying
was less than 1 ml/min. This is the limit of our power to
determine and represent an essential interruption of the
delivery of saline through the pylorus. Yet again when
the hormone was discontinued, there was an immediate
increase in gastric emptying in the fist 2-min test meal,
and no apparent inhibition on gastric empyting remained
in the test meal begun 5 min after the CCK infusion
ceased.This pattern of rapid onset and offset of inhibition
with intravenous CCK (almost an endocrine “square
wave”) was seen in all five experiments,
The onset of the gastric inhibition by CCK was rapid,
and its duration beyond cessation of infusion was brief.
These results are consistent with the known brief halflife of CCK in the circulation (15).
o-CM IV
3.0pmdes/Lg/min
l
The methods for study that we have employed in this
investigation are all standard techniques. The hormone
preparation O-CCK is the active principle of the naturally occurring hormone, which possessesthe full biological activity including an effect on feeding demonstrated
in the monkey (7).
The gastric load of 150 ml that we have made our
standard test meal for both the physiological and behavioral experiments is a sizable but far from excessive load
in these animals. When they are drinking liquid nutrients,
rhesus monkeys of this weight can imbibe this volume in
less than 1 min and have been observed to ffl their
stomachs with as much as 500 ml of glucose and water.
The technique that we have devised for demonstrating
gastric inhibition depends on our repeated demonstration
that physiological saline empties rapidly from the stomach of the rhesus monkey when unimpeded and uses the
Hunt and Spurrell method (11) to follow saline test meals
to discern any change in this emptying with the experimental manipulations. The Hunt and Spurrell method
,
0
T
10
20
30
40
Time (miff)
FIG. 3. Typical
example
of temporal
characteristics
and recovery
of gastric emptying
of saline that results
venous infusion
of O-cholecystokinin
(O-CCK),
of inhibition
from an intra-
(11) does permit the demonstration of load retention as
distinct from the intragastric accumulation of secretions.
Our results then indicate that CCK is a potent inhibitor
of gastric emptying in the monkey. It does so at dose
levels that are identical to the range found effective for
gastric inhibition in the dog by Debas et al. (4), a dose
range that these other investigators concluded was the
physiological range for the hormone because the D50 for
stimulating pancreatic secretion was the same.
This dose range of CCK though is below that previously reported to inhibit feeding in the monkey (25).
Nonetheless a potent inhibitory effect on feeding can be
produced by CCK in this range if the experiments are
designed to combine a gastric load with it. In these fasted
monkeys only when the stomach has a significant load in
its lumen, a load retained because of the action of the
hormone, does CCK at these dose ranges produce an
inhibition on feeding. From these data we propose that
circulating CCK has a satiety effect in its physiological
range when it leads to gastric distention by restricting
the flow of food from the stomach through the pylorus.
It is our view (16) that CCK is part of an integrative
chain of physiological elements controlling food intake.
Once its secretion is provoked by the entrance of nutrients into the intestine, it reduces gastric emptying and
helps to permit gastric distention as feeding persists.
Feeding is unaffected until the distention of the stomach
has reached some level where the visceral afferent neuronal supply from the stomach signals such distention
and inhibits further feeding.
Several objections to this interpretation can be raised.
First Gibbs et al, (9) have inhibited feeding and produced
a sated state with CCK in animals that are sham feeding
and whose stomachs can not distend because they are
constantly emptying through a gastric f=tula. Yet the
dose of CCK that these investigators must give to produce satiety is greater than in our experiments and may
well be outside the physiological range (6). A pharmacologic action of CCK in sham feeding may still depend
on some aspect of change in the physiology of the stomach or pylorus, since these structures are in place in
sham-fed animals. As well, pharmacologic amounts of
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DISCUSSION
I
R496
H. MORAN
AND
P. R. MCHUGH
supply has been taken to relieve the organism for some
period of a need to seek more food. CCK acts to facilitate
this storehouse
function and in its secretion from the
intestine does not interrupt feeding directly.
In fact the observations
of Kissileff et al. (12) that
CCK infused into humans reduces the ultimate size of
the meal taken, but does not affect the rate of feeding, is
just what could be expected from this indirect mode of
action of CCK in satiety. The Kissileff experiments were
all done on fasted subjects whose stomachs presumably
were empty. The subjects eat to fill the stomach at a
constant rate. As we have demonstrated,
gastric emptying would be inhibited by CCK infusion and the amount
of food passing the pylorus reduced in the CCK condition.
Feeding, though, would proceed until the stomach is
distended in both the control and CCK conditions. This
distention would be of the same degree at a smaller meal
size under the CCK infusion because of the more complete retention of the meal. Hence, the demonstration
that CCK affects meal size but not feeding rate, Third,
this view that CCK and gastric distention are linked to
inhibit feeding can explain why intermeal intervals are
better predicted by the size of the preceding meal than
is meal size predicted by the duration of the preceding
intermeal interval (13). There are many features that can
affect meal size, i.e., schedule, taste, expectation,
and
past learning, but the state of the stomach (its distention
sustained by slow emptying) may provide visceral signals
that render the search for the next meal less insistent
and thus prolong the intermeal interval after a large meal
and vice versa after a small one.
Finally, this view makes contact with the classical
studies of Cannon and Washburn
(3) and others (I, 23)
of the relationship
of gastric distention to feeding. They
demonstrated
that mechanical distention of the stomach
inhibited food intake. Our proposal for CCK in satiety
places those observations
into an integrative physiology.
It views the satiety that interrupts
a given meal as the
behavioral
outcome of a succession
of physiological
events, hormone secretion and gastric distention,
that
occur in sequence during feeding.
This concept now promotes a search for the particular
actions of the proposed links in this integrative
chain
from intestine to stomach to brain and behavior. Smith
et al. (26) have demonstrated
that gastric vagotomy will
interfere with CCK satiety, and thus provide evidence
that it may be afferents in the vagus nerve that signal
the distention of the stomach. But the quanti tative relation of intestinal nu trient to C:CK relea se, the nature of
the changes in the stomach and pylorus produced by this
hormone that inhibits emptying, the location of receptors
that could mediate these changes in the viscera and any
similar roles of other visceral hormones are all questions
crucial to further comprehension
of this integrative physiology and evaluation of this hypothesis for satiety.
The authors thank Lee Riley III for expert technical
help, Dr. James
Wirth for advice on our statistical
assessment,
and Gretchen
Stitt for
the illustrations.
The work is supported
by National
Institutes
of Health Grant AM19302.
Received
9 July
1981; accepted
in final form
13 October
1981.
Downloaded from http://ajpregu.physiology.org/ by 10.220.32.247 on June 17, 2017
CCK may provoke feeding inhibition through other sites
of action of the hormone.
Della-Fera
and Baile (5) present results that would
appear to challenge our view of the action of CCK in food
satiety by demonstrating
the inhibition on feeding with
intracerebral
injections of CCK. However,
we are not
claiming to describe all the sites of action of CCK but
only the likely mechanism
and actions of circulating
intestine-derived
CCK. A central CCK action linked to
CCK that is itself originating from intracerebral
sites is
not sought or excluded by our findings.
Finally, it has been noted that other hormones of the
intestine, particularly
secretin (25), are known to inhibit
gastric emptying but so far have not been shown to
provoke satiety. This is a critical question, but one that
must be approached by the same combination of physiology and behavior that we have employed for CCK. It
seems unlikely that a hormone that inhibits gastric emptying will not show some of these effects on feeding, since
we and others have so often shown that gastric distention
is a sufficient
stimulus for feeding inhibition.
Quigley
(24), in fact, demonstrated
that the transplanted
denervated stomach is inhibited in its activity by nutrients
placed in the intestine predicted over 25 yr ago that such
a hormonal role would be found. Yet the physiological
dynamics of the hormonal action must be documented
and that information
employed to show that the behavioral test is occurring
in a comparable
setting. Since
different hormones are released in response to different
nutrients in the intestine, it would seem probable that
CCK is only one of several hormones that is to be fitted
into this integrative chain for feeding control (14). The
presence of other hormones provoked by food may combine with the exogenous CCK in experiment 4 to prolong
the inhibition on feeding beyond the infusion time.
But accepting the importance
of these objections for
further work, consider now the view proposed. First we
have a hormone with a brief half-life in circulation and
a very brief effect on the function in question, gastric
emptying. CCK’s release from the intestine will promptly
interrupt the delivery of further nutrient into the intestine and so avoid the flooding of the intestinal
and
postintestinal
compartments
with nutrients.
Yet after
absorption of nutrient, CCK’s effect will promptly
disappear leading to a further delivery through the pylorus
of the gastric contents and further secretion of the hormone. In this fashion a regulated supply of nutrients
passes through the pylorus. These characteristics
that
render CCK an appropriate
integrative
agent in the
delivery of nutrients to the intestine can give it a role in
the inhibition of food intake, but mediated through the
gastric distention that it will sustain. Second, the requirement that there is a linkage between
CCK and the
stomach for the physiological dose of CCK to produce an
inhibition on feeding explains why the fast release of this
hormone, which will occur with the first passage of food
into the intestine, does not stop feeding immediately.
If
this occurred, meals would be restricted
to tiny bouts
interrupted
by short satiety periods and feeding would
be a repetitive “on and off’ activity like breathing. The
stomach is the storehouse for a meal, and permits a single
period of feeding to continue until an adequate caloric
T.
CHOLECYSTOKININ
SUPPRESSES
FOOD
INTAKE
R497
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