Am J Physiol Gastrointest Liver Physiol 304: G1038–G1043, 2013.
First published April 11, 2013; doi:10.1152/ajpgi.00060.2013.
Specific food structures supress appetite through reduced gastric
emptying rate
Alan R. Mackie,1 Hameed Rafiee,2 Paul Malcolm,2 Louise Salt,1 and George van Aken3,4
1
Institute of Food Research, Norwich Research Park, Norwich, United Kingdom; 2Norfolk and Norwich University Hospital,
Norwich, United Kingdom; 3NIZO Food Research, Ede, The Netherlands; and 4Top Institute Food and Nutrition,
Wageningen, The Netherlands
Submitted 27 February 2013; accepted in final form 5 April 2013
appetite; dairy food structure; gastric retention; cholecystokinin
OVER THE LAST 30 YEARS, there has been a steady rise in obesity
and related health issues, such as diabetes. Type 2 diabetes and
obesity are now major public health problems, with over 50%
of the adult population being overweight and 1 in 20 having
diabetes in the UK (2). Type 2 diabetes is associated with
weight gain, and both diabetes and weight gain are associated
with aging. A range of approaches have been used to address
the increase in obesity based around dieting, but the continued
increase in the prevalence of obesity suggests that a greater
understanding of the mechanisms involved in controlling appetite and satiety is needed (33). Nutrition studies have started
to look in detail at how specific macroscopic food structures
are broken down in the gastrointestinal (GI) tract and how they
release their nutrients (12, 23, 30). Such studies have shown
that one of the major factors influencing nutrient release is the
control of GI flow (21). In this regard, nutrient sensing in the
small intestine has also been shown to be important and acts
through the release of GI hormones such as cholecystokinin
(CCK), GLP-1, and PYY. Studies looking at the sensing of
specific nutrients such as protein and lipids have shown that
Address for reprint requests and other correspondence: A. R. Mackie,
Institute of Food Research, Norwich Research Park, Colney Lane, Norwich,
UK (e-mail: [email protected]).
G1038
intra-duodenal protein (29) or fat (18 –20) can contribute to the
suppression of energy intake. Thus understanding the rules that
link food structure to GI flow, nutrient sensing, and satiety
responses will be of primary importance in designing foods
that are acceptable to the consumer and that provide the
required physiological responses for maintaining health.
A number of studies have investigated the effect of food
structure on gastric emptying and appetite regulation. At the
most basic level, simple protein solutions have been assessed
for their ability to affect gastric retention. In a study using dairy
proteins, whey was compared with casein and cross-linked
casein (10, 11). Both casein and whey were more potent in
lowering postprandial glucose than the cross-linked protein,
which had a less pronounced peak in insulin and significantly
lower CCK release. Clemente et al. (4) studied the effects of
structure on nutrient release for a range of dairy-based foods
and showed that Mozzarella cheese was able to delay the peak
in plasma triglycerides compared with milk. They also demonstrated a significantly faster reduction in antral volume as
assessed by ultrasound, which may, however, not be directly
related to a reduced gastric emptying time as suggested by the
authors. Lipids form another group of macro nutrients that
affect GI flow, and of particular interest for this are systems
used to control the release of lipids. In a study comparing
stable and unstable emulsions (21), gastric emptying was
slower for an acid-stable emulsion, although the rate of energy
delivery to the duodenum was not different up to 2 h. The
acid-stable emulsion also induced increased fullness and decreased hunger and appetite. The use of emulsion systems with
tailored release properties is increasingly being considered to
control hyperlipidemia (3, 24, 33).
These studies demonstrate the importance of food structure
in the modulation of postprandial satiety-related physiology.
Indeed, foods such as fresh whole fruits and vegetables, whole
grain bread, and meat are digested more slowly and as a
consequence are more satiating than foods that have a softer,
more highly processed structure (25). However, a review of a
cross section of these types of studies in which food structures
have been developed to enhance satiety (35) shows that we are
still a long way from fully understanding the complex process
of satiety, which involves physiological processes of the entire
metabolism as well as psychological and social processes,
although progress is being made in all these areas.
In this study, we have attempted to confirm that food
structure alone can impact satiety and to determine the role of
gastric retention and nutrient sensing as indicated by CCK
secretion. The design of the meals in this study was based on
the concept that gastric emptying is regulated by the caloric
density of the chime delivered to the small intestine and the in
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Mackie AR, Rafiee H, Malcolm P, Salt L, van Aken G. Specific
food structures supress appetite through reduced gastric emptying rate.
Am J Physiol Gastrointest Liver Physiol 304: G1038 –G1043, 2013. First
published April 11, 2013; doi:10.1152/ajpgi.00060.2013.—The aim of
this study was to determine the extent to which gastric layering and
retention of a meal could be used to reduce appetite using the same
caloric load. Liquid (control) and semi-solid (active) meals were
produced with the same protein, fat, carbohydrate, and mass. These
were fed to 10 volunteers on separate days in a crossover study, and
subjective appetite ratings, gastric contents, and plasma cholecystokinin (CCK) were assessed over a period of 3 h. The active meal
showed food boluses in the stomach persisting for ⬃45 min, slower
emptying rates, and lower plasma CCK levels over the first hour.
After the first hour, both gastric emptying rates and plasma CCK
levels were similar for both systems and slightly increased compared
with the unfed situation. Despite the lower plasma CCK levels for the
active meal over the first hour, this meal reduced appetite more than
the control meal over the 3 h of the study. For a moderately increased
plasma CCK level in the fed state, appetite was correlated with the
volume of gastric contents rather than gastric emptying rates or
plasma CCK. This suggests that enhanced gastric retention was the
key factor in decreasing appetite and was probably mediated by a
combination of intestinal nutrient sensing and increased viscosity in
the stomach.
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APPETITE SUPPRESSED BY INCREASED GASTRIC RETENTION
Table 1. The nutritional composition of the two meals used
in the study
Fat, g
Carbohydrate, g
Protein, g
Total, g
Sodium, mM
Energy, kCal
Weight of meal, g
Control Meal
Active Meal
27.5
6.1
25.3
58.9
20
373.1
500
27.5
6.1
25.3
58.9
64
373.4
500
MATERIALS AND METHODS
The meals. The two meals used in the study were prepared under
food grade conditions. The homogeneous meal referred to in this
article as the control meal was made as follows. An emulsion was
made comprising 27.5 g of sunflower oil and 242.5 g of 1.24% sodium
caseinate solution in a blender (BL450 series, Kenwood). The shear
cycle comprised 30 s at the low shear setting, 30 s of rest, 30 s at the
high shear setting, 30 s of rest, and 30 s at high shear setting. The
emulsion was then mixed with 199.5 g of a solution containing 1.24%
sodium caseinate and 10% whey protein isolate (Bipro, Davisco).
Sugar (6.1 g) was then added to the emulsion along with a few drops
of vanilla flavoring. The emulsion was stored at 4°C until use (⬍24 h).
The structured meal referred to as the active meal was prepared by
mixing 88 g of finely grated Gouda cheese (Waitrose Essential Dutch
Gouda) and 73 g of low-fat yogurt (Waitrose Essential low-fat
yogurt), both of which were purchased from the local supermarket.
The meal was consumed with 339 ml of bottled water, which was
stored with the cheese and yogurt mixture at 4°C until use (⬍24 h).
The sodium content of the active meal was 64 mM based on a
concentration in the cheese of 2.1%, whereas the sodium content in
the control meal was 20 mM based on the protein content. Figures for
the nutrient content of the meals are given in Table 1. As far as
possible, the two meals were isocaloric, the only differences being the
higher salt content and the large degree of proteolysis of the proteins
introduced into the active meal with the cheese.
Imaging of gastric contents. The gastric contents of the volunteers
were determined using a conventional 1.5-T magnetic resonance
imaging (MRI) scanner (Siemens Avanto 1.5T). Imaging used a
TRUFISP (fast imaging with steady-state precession) protocol developed to scan the stomach in a breath-hold of the order of 15–25 s,
Table 2. Timing of clinical activities relative to consumption
of the meal (min)
Activity
MRI Scan
Blood Drawing
VAS Questionnaire
1
2
3
4
5
6
7
8
9
10
⫺15*
5
25
45
65
85
105
125
145
165
⫺10*
10
20
35
60
90
120
150
180
⫺5*
15
30
40
55
95
115
155
185
*Premeal was not considered to be critical, so these values are largely
indicative.
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vitro observation (34) that liquid food emulsions can be designed to either form a creaming or sedimenting energy-rich
phase in the stomach. This feature can be used to control the
timing of energy release from the stomach, which in case of a
sedimenting energy-rich layer would induce increased satiety
compared with meals that remain homogeneous under gastric
conditions. In the present study, we wanted to test this concept
by comparing two isocaloric (same fat, protein, and carbohydrate content) meals to assess the impact of food structuring on
gastric retention and short-term appetite regulation. Because
we did not want to be dependent on the process of gastric
acidification since the mechanism that would produce a sedimenting protein and fat-rich phase in the stomach, we constructed a sedimenting system in the form of a slurry of small,
dense cheese particles. These cheese particles were suspended
in yogurt to form a thick semi-fluid. Detailed information about
the dissolution of structures in the stomach and the volume of
gastric contents were obtained by MRI, allowing the persistence of structure to be correlated with gastric flow rates,
appetite, and CCK secretion.
depending on the fullness of the stomach [reptitition time (TR)/echo
delay time (TE) 3.5/1.5 ms; field of view 24 ⫻ 32 cm; matrix 154 ⫻
256; slice thickness 0.5 cm]. This yields contiguous 5-mm axial slices
through the stomach, enabling calculation of total stomach volume.
Both transverse and coronal images were acquired to ensure that the
gastric volume could be accurately defined. Total volumes of gastric
contents (excluding gas) and the nature of layers formed as a result of
sedimentation were determined at each time point using free-hand
tracings of the region of interest around the stomach contents for each
5-mm-thick slice, and from this the total stomach volume was calculated using cardiac ventricular volume measurement software (Siemens Argus workstation). This involved assessment of the position of
the pylorus. Each scan took ⬃5 min, and between scans the volunteers
underwent minimal physical movement and remained seated upright
close to the scanner. From the variation of the gastric volume with
time, we deduced an apparent emptying rate, which gives and impression of, but is not precisely the same as, the rate at which the food
emptied from the stomach, because of the inhomogeneous distribution
of the food material inside the stomach and because of the simultaneous addition of gastric secretion.
Visual analog scales. We assessed volunteer satiety with a selfreported visual analog scale (VAS) technique (32). Before the meal
and at specific time intervals post-meal, as given in Table 2, the
volunteers completed a five-question satiety questionnaire with a VAS
for each of the following questions: 1) “How hungry are you?” 2)
“How full do you feel?” 3) “How satisfied do you feel?” 4) “How big
is your desire to eat?” 5) “How thirsty are you?” The analog scores for
each question were then converted to numeric scores based on the
following: 1) 1 ⫽ not at all hungry, 10 ⫽ very hungry; 2) 1 ⫽ not full
at all, 10 ⫽ very full; 3) 1 ⫽ not satisfied at all, 10 ⫽ very satisfied;
4) 1 ⫽ no desire to eat at all, 10 ⫽ very big desire to eat; 5) 1 ⫽ not
thirsty at all, 10 ⫽ very thirsty.
Determination of CCK. At the start of each study session, volunteers were fitted with a cannula so that blood could be drawn
periodically. At each required time point, 4 ml of blood was drawn
and stored on ice for ⬍2 h before being centrifuged. Blood was
collected into tubes (Vacutainer K2 EDTA, Becton Dickenson) containing 170.9 ␮l of aprotinin (Sigma-Aldrich), and, after centrifugation for 10 min at 1,500 g and 4°C, the plasma was removed and
stored in prelabeled tubes at ⫺80°C. The plasma was subsequently
analyzed for CCK content using a radio-immunoassay (RIA) (27, 28)
performed by the TNO organization in The Netherlands.
The study method. The crossover study was designed to assess
differences in gastric emptying, satiety indicators, and levels of the GI
hormone CCK. The study included only male volunteers aged between 20 and 50 yr and with a body mass index (BMI) between 19 and
30. The mean age of the cohort was 35 yr, and the mean BMI was
24.7. All 10 volunteers recruited to the study were apparently healthy
and provided written, informed consent before taking part in the
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APPETITE SUPPRESSED BY INCREASED GASTRIC RETENTION
subsequent scans being undertaken as laid out in Table 2. The
volunteers were asked to repeatedly complete a VAS satiety questionnaire and have a 4-ml sample of blood drawn, and the timing for these
are given in Table 2.
Data analysis. SPSS for Windows software (SPSS for Windows,
version 19.0) was used to analyze the data. The results are expressed
as means and SE, with a P value of ⱕ0.05 (two-sided) as a criterion
for the statistical significance. The statistical significance of the data
was determined from differences in the areas under the curves using
a paired two-sided t-test (1).
RESULTS
study, which was approved by the local research ethics committee
(Approval 11/EE/0192). Each volunteer attended the study center on
two occasions at least 7 days apart and consumed a different meal on
each occasion. The order in which the meals were consumed was
randomly allocated. All volunteers were able consume all of the test
meals within 5 min.
On each study day, volunteers were asked to eat their breakfast at
home (before 9:00 AM). They were allowed to drink as much water
as they need but only until 10:00 AM. After this time, no further
consumption was allowed. The experimental protocol was started at
between 1:30 PM and 2:00 PM, which corresponds to the first time
point in Table 2. After initial formalities, each volunteer had a cannula
inserted into an arm ready for blood drawing. They then underwent
the first MRI scan, a 4-ml sample of blood was drawn, and they were
asked to complete a VAS questionnaire (baseline measurements). The
volunteer consumed the meal, allocated at random. Immediately after
the meal was consumed, the second MRI scan was performed, with
Table 3. Mean areas under the curve ⫾ SE of the visual-analog
scale data collected for the control and active meals
Hunger
Fullness
Satisfaction
Desire to eat
Thirst
Control Meal
Active Meal
P Value
6,187 ⫾ 697
4,345 ⫾ 627
4,616 ⫾ 711
6,561 ⫾ 685
7,518 ⫾ 358
4,477 ⫾ 592
6,538 ⫾ 635
6,759 ⫾ 647
4,787 ⫾ 701
5,598 ⫾ 659
0.002053
0.004911
0.00881
0.007301
0.001126
P values shown are based on a paired, two tailed t-test.
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Fig. 1. Visual-analog scale (VAS) score data for hunger (A), fullness (B), and
thirst (C) for the control (broken line) and active (solid line) meals. Mean and
SE values are shown.
Satiety. The impact of the two meals on the scores for
hunger and fullness are shown in Fig. 1, and the areas under the
curves (AUC) summarized in Table 3. There is a significant
difference in the hunger scores for the two meals, with the
active meal reducing hunger more than the control meal at
virtually every time point, although the slopes of the two
curves are very similar. Statistical analysis of the AUC for the
two data sets yielded a P value of 0.002 (Table 3). A similar
pattern is seen for the fullness data, with the active meal
eliciting a higher fullness score at every time point, although
the difference was more pronounced over the first 45 min after
ingestion. Interestingly, the liquid control meal gave the highest fullness score at the first point collected after the meal was
consumed, whereas after the active meal the second time point
was highest. Although this difference was not statistically
significant, it may indicate a slightly slower onset of the
sensation of fullness with the active meal. The VAS determination of satisfaction and desire to eat very much reflect the
data in Fig. 1, A and B, as can be seen from the AUC data in
Table 3. Given the composition of the active meal and the
relatively high salt content, it might be expected that the VAS
thirst data would show a high value for the active meal.
However, the data in Fig. 1C shows consistently lower thirst
scores for the active meal at every post-meal time point.
CCK modulation. The mean levels of CCK measured in the
blood of the volunteers after consuming the two meals is
shown in Fig. 2A. The data for both meals is an average for
nine of the volunteers, since the data from the active meal for
one was clearly an outlier (data not shown). It is clear that
differences in the release of the hormone were only seen in the
first hour after consumption of the meal. After the first hour,
serum CCK levels were increased from 0.6 pmol/l in the unfed
state to ⬃1 pmol/l during gastric emptying for both meals. In
the case of the control meal, there was a steep rise to a
maximum of 1.6 pmol/l at 25 min post-ingestion. In fact, the
data for the control meal fell into two different groups, as
shown in Fig. 2B. One group of five volunteers with a maximum in CCK concentration of 2.2 pmol/l and another with four
APPETITE SUPPRESSED BY INCREASED GASTRIC RETENTION
G1041
Fig. 2. A: blood plasma concentrations of CCK measured before and after consumption of the control (broken line) and active (solid line) meals. B: two groups of
controls: those showing a significant increase in CCK at
30 min (n ⫽ 5; broken line) and those that did not (n ⫽
4; solid line). Mean and SE values are shown in both
graphs.
presented markedly different emptying rates, with the control
meal emptying more than twice as fast as the active meal (P ⫽
0.0058, paired, two-tailed t-test). From 60 min onward, the
emptying rates of the two meals were very similar at ⬃2
ml/min, showing that the cause of the 30-min difference in
gastric half-times of 69 min and 100 min for the control meal
and active meal, respectively, was behavior in the first 45 min
after ingestion.
DISCUSSION
In the study described in this article, we have used two
iso-caloric meals with different structures, semi-solid vs. liquid, to assess the impact of food structure on gastric emptying
rates and short-term perception of appetite. We have used MRI
to assess not just gastric volume but also the persistence of
macroscopic structure in the gastric compartment, any layering
formed, and its subsequent persistence. The active meal had a
gastric retention half-time 30 min longer than the control meal.
Although this seems to be in disagreement with a study
showing that a mixed solid/liquid food empties faster and is
less satiating than the same meal after homogenization to a
“soup” (22), in that case the authors suggested that the mixed
solid/liquid system initially emptied the liquid portion, which
had a low energy density and in this way more quickly reduced
the gastric volume and hence the sensation of fullness. Another
study demonstrated faster gastric emptying when the viscosity
of a meal was increased by adding pectin (30). However, in a
study comparing liquid and semi-solid meals, the latter was
more satiating, even though there was no difference in CCK-8
or GLP-1 secretion (36). It has also been shown that the
detection of fat in the duodenum can significantly reduce
hunger, increase fullness, and delay gastric emptying (20).
There are a number of feedback mechanisms that control
gastric emptying, but one of the important ones involves the
Fig. 3. MRI images of the active meal in the
stomach (outlined) 5 min after consumption (A)
and the control meal in the stomach (outlined) 25
min after consumption (B).
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volunteers where all the values were close to 1 pmol/l over the
first 2 h. The data from both control groups was significantly
different from that for the active meal over the first 25 min
(P ⫽ 0.029, paired, two-sided t-test). The CCK levels generated by the active meal were significantly lower than the
control meal for at least the first 40 min post-ingestion.
Gastric emptying and layering. The data shown above has
been governed to a large extent by the behavior of the two
meals in the gastric compartment. To assess this, we have used
MRI as illustrated in Fig. 3. Figure 3A shows the active meal
in the stomach 5 min after ingestion, and individual boluses of
cheese are clearly visible as dark regions in a fairly homogenous surrounding medium. The other image in the figure shows
the control meal in the same volunteer some 25 min after
consumption. In this image, layering of the gastric contents is
clearly visible as the fat in the control meal starts to cream,
leaving a darker, higher fat content region as an upper layer.
We have measured the time over which these structures formed
and persisted.
The structures in Fig. 3 reflect the heterogeneous and changing nature of the gastric contents and highlight the challenges
in interpreting gastric retention times. The structures seen in
Fig. 3A were persistent over the first 45 min after ingestion, and
this time scale is typical of what was seen in the volunteers
more generally. The layering seen in Fig. 3B tended to be
persistent for rather longer and was typically still visible up to
105 min after ingestion. In addition to assessing intra-gastric
layering, we measured mean gastric volume over the time
course of the study, and the data are given in Fig. 4. After
ingestion, there was little difference in the volume of gastric
contents between the two meals for the first 25 min. The active
meal showed a slightly higher volume at 5 min, but this was
not statistically significant. The active meal also emptied
slightly faster over the first 25 min, but again this was not
statistically significant. Between 25 and 45 min, the two meals
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APPETITE SUPPRESSED BY INCREASED GASTRIC RETENTION
Fig. 4. A: mean volumes of gastric contents as a function
of time before and after consumption of the control
(broken line) and active (solid line) meals. B: the gastric
emptying rates (derivatives) calculated from the individual volume data. The data are the mean and SE values.
CCK-regulated control of the emptying rate became fully
effective. This would also explain why the active meal also
generated a significantly higher feeling of fullness over the
same period: since plasma CCK levels were similarly elevated
in both cases, the remaining volume in the stomach would have
been sensed by the distension mechanoreceptors, signaling
more fullness for the active meal compared with the control
meal, extending over the whole time of gastric emptying.
Although the greater feeling of fullness persisted for the
duration of the study, the differences seen after 45 min were
much reduced and only just statistically significant. As discussed above, CCK works through activation of vagal afferent
mechanosensors in the stomach and in the duodenum. Consequently, the satiating effect of gastric distension increases the
anorectic effects of CCK in humans (14).
In summary, in the study reported here, the more structured
active meal supressed the initial secretion of CCK compared
with the liquid control meal, presumably because, for the active
meal, initially a more viscous layer containing food boluses
was present in the antrum, preventing significant early emptying. Thus a larger volume was retained longer in the stomach,
leading to an increased sense of fullness. Altogether, this
suggests that a nutrient-induced increase in serum CCK levels
did not have a direct role in the control of appetite sensation in
the active meal. In contrast, the liquid meal showed a peak in
both emptying rate and plasma CCK at 30 min, related to the
initial quick emptying of this meal. This is the first time that
macroscopic structure persistence and formation have been
linked to satiety via gastric retention and CCK secretion. The
results suggest that, for the studied situation in which the
plasma CCK level is moderately increased during nutrientcontrolled gastric emptying, gastric retention was the key
factor in decreasing appetite rather than the detection of nutrients in the duodenum and that plasma CCK was not directly
linked to suppression of either gastric emptying or appetite.
This study paves the way for further work to assess the role of
other GI hormones and the impact of even more persistent
structures.
GRANTS
The work in this article was funded by Top Institute for Food and Nutrition
through project B1007 and BBSRC through their core strategic grant to the
Institute of Food Research.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
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peptide hormone CCK. Detection of nutrients in the proximal
small intestine by I-cells leads to the release of CCK, which
plays a key role in regulating a range of intestinal responses
that integrate and optimize the digestion of fat and protein (15).
CCK is released in response to nutrients in the duodenum, with
fat and protein producing a greater postprandial release than
carbohydrates (13). This regulation includes three physiological effects of threshold levels of plasma CCK, which are a
stimulation of pancreatic secretion through relaxation of the
sphincter of Oddi; gall bladder emptying through contraction
of the gall bladder and a modulating effect on gastric emptying
(7–9, 15, 17, 31). Normally, following ingestion of a meal,
CCK levels rise rapidly from a resting value of ⬃1 pmol/l to a
peak of 6 – 8 pmol/l during the first 15 min and then decline to
a submaximal level, which is maintained for up to 2 h after
eating (16, 17, 26). This peak in plasma CCK is responsible for
gall bladder contraction (7). In the present study, the observed
effect of the meals on CCK blood levels was smaller than
typically observed for liquid emulsions (e.g., peaking to 8
pmol/l). This might be due to the relatively high viscosity of
both meals in this study, which impeded the initial fast emptying found for thin liquids. The role of plasma CCK concentrations on inhibition of gastric motility and emptying seems
more complex. CCK probably stimulates the mechanoreceptors in the gastric wall that signal gastric distension, which
through the enteric nervous systems stimulates neurons that
ultimately lead to a relaxation of the gastric fundus, a
reduced motor activity of the antrum, and a reduced gastric
emptying rate (14). The same type of effect is also induced
by osmotic pressures in the duodenum (typically caused by
sugars) and acidity (from the chime), independent of the
CCK regulation (5–7).
Most significantly, in the present study, the main difference
in empting rates occurred up to ⬃50 min after ingestion, when
the apparent emptying rate of the control meal was more than
twice that for the active meal. This coincides with the time over
which semi-solid parts of the active meal were seen to persist.
Over this same time period, the rate of CCK secretion was
significantly supressed relative to the control meal, apparently
related to a reduced release of energy in the form of protein and
fat during this time period. In fact, the observed steady-state
emptying rate of ⬃2 ml/min for both meals after 60 min
translates to an emptying rate of ⬃1.5 kcal/min, which is
typical for energy-controlled gastric emptying. Thus it seems
that the body was better able to control the initial emptying rate
of the active meal at an appropriate energy release rate than the
control meal. This might be because the less viscous control
meal had already emptied by a substantial amount before
APPETITE SUPPRESSED BY INCREASED GASTRIC RETENTION
AUTHOR CONTRIBUTIONS
Author contributions: A.R.M., P.M., and G.v.A. conception and design of
research; A.R.M. and L.S. performed experiments; A.R.M., H.R., and P.M.
analyzed data; A.R.M., H.R., P.M., and G.v.A. interpreted results of experiments; A.R.M. prepared figures; A.R.M. drafted manuscript; A.R.M., P.M.,
and G.v.A. edited and revised manuscript; A.R.M., P.M., and G.v.A. approved
final version of manuscript.
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