Available online at www.sciencedirect.
com Current Opinion in
ScienceDirect
Review
Sensory, gastric, and enteroendocrine effects of carbohydrates,
fat, and protein on appetite
Richard D. Mattes1, Stephanie R. Hunter1 and Kelly A. Higgins2
Abstract
Carbohydrate, fat, and protein have each been reported as the
most satiating macronutrient. However, rarely is one macro-
nutrient consumed in isolation, and the effects of each are
context dependent. Effects in the oral, gastric, and intestinal
phases of digestion of the macronutrients are reviewed in the
context of their effects on appetite. Because all phases act
synergistically, it is difficult to conclude that any one system or
any one macronutrient is best for controlling appetite. Inde-
pendent of other health concerns related to ingestion of spe-
cific macronutrients, dietary recommendations targeted to
individual preferences will likely be most effective for weight
and appetite management as they will enhance compliance
with a given dietary recommendation.
Addresses
1
Department of Nutrition Science, Purdue University, West Lafayette,
IN 47907, USA
2
Department of Food Science, Purdue University, West Lafayette, IN
47907, USA
Corresponding author: Mattes, Richard (mattes@purdue.edu)
Current Opinion in Endocrine and Metabolic Research 2019,
4:14–20
This review comes from a themed issue on Frontiers in Obesity
Edited by Paolo Sbraccia and Robert Kushner
For a complete overview see the Issue and the Editorial
Available online 26 September 2018
https://doi.org/10.1016/j.coemr.2018.09.002
2451-9650/© 2018 Elsevier Ltd. All rights reserved.
Keywords
Sensory, Cephalic phase responses, Gastric distension, Gut peptides,
Macronutrients, Appetite.
Abbreviations
Free Fatty Acids, FFA; Cephalic Phase Response, CPR; Cephalic
Phase Insulin Response, CPIR; cholecystokinin, CCK; glucagon-like
peptide-1, GLP-1; peptide YY, PYY.
Introduction
The motivation to eat is mediated by numerous cogni-
tive, sensory, endocrine, metabolic, cultural, and
contextual cues. The macronutrients (carbohydrate, fat,
and protein) are chemically distinct and differentially
contribute to energy and nutrient needs. Each has been
the focal point of a theory for feeding regulation. The
Current Opinion in Endocrine and Metabolic Research 2019, 4:14–20
Endocrine and Metabolic Research
glucostatic, aminostatic, and lipostatic theories had
support, but none proved to be a reliable predictor of
appetite or energy intake [1]. Highlights of this evi-
dence base are reviewed here through consideration of
the sensory, gastric, and endocrine effects each macro-
nutrient elicits during ingestion, digestion, and meta-
bolism. Although reviewed here in isolation, under
naturalistic feeding conditions, the primary finding is
appetitive outcomes reflect an integrated complex of
signals, only a portion of which stem from the macro-
nutrients [2,3] (see Figure 1).
Appetitive sensations are labeled according to a widely
accepted lexicon. Hunger is the sensation that moti-
vates the initiation of an ingestive event. It is a predictor
of eating frequency, not portion size. Hunger is viewed
as reflecting an organism’s energy status while the desire
to eat, which is also a determinant of eating frequency,
stems more from cognitive and sensory cues (e.g.,
humans may eat a palatable dessert when no longer
hungry after a meal). Satiation or fullness are terms used
to characterize the sensation that terminates an inges-
tive event. They determine portion size. Hunger and
satiation/fullness are driven by different biological and
environmental cues so are independent, but taken
together, determine energy intake. Satiety is a
commonly used term to characterize the inter-ingestive
event interval. The effects of the macronutrients on
appetite are defined by their influence on these sensa-
tions and the associated consequences of intake.
Cephalic phase responses to the
macronutrients on appetite
Cephalic phase responses (CPR) initiate physiological
processes associated with food digestion and nutrient
absorption and metabolism. They are activated by sen-
sory exposure to food and may enhance or diminish
appetitive sensations [4]. CPR are vagally-mediated and
generally become more robust with increasing sensory
activation in the order of thought < appearance <
odor < taste < mechanical activity. They are also posi-
tively related to food palatability. The responses are
small and transient, but likely act as triggers that
modulate the processes actually involved in nutrient
assimilation. Among the responses are increased saliva-
tion and gastric motility, delayed gastric emptying,
release of gut hormones, and peripheral endocrine
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 Macronutrients and appetite Mattes et al. 15

Figure 1

Carbohydrate, fat, and protein, eaten together as a mixed macronutrient meal, generate oral, gastric, and intestinal signals that, in addition to a
plethora of other biological and environmental factors, influence appetite. Macronutrient effects on appetite are complex. All phases act in
concert so it is difficult to conclude that any one system or macronutrient is best for controlling appetite. CPR – cephalic phase response.

responses [5]. Each macronutrient can induce a CPR,
but the responses elicited are dependent on the
macronutrient. The most intensively studied is the ce-
phalic phase insulin response (CPIR). Sugars stimulate
a CPIR [6]. Select low calorie sweeteners are effective
stimuli for a CPIR (saccharin and potentially sucralose,
but not aspartame [6e8]), indicating that the CPIR is
not triggered by sweetness alone. Modified sham
feeding of fat can stimulate a serum triglyceride peak,
and the release of insulin, GLP-1, and CCK, and inhi-
bition of ghrelin, but the magnitude varies based on
chain length and saturation [9]. Protein has been shown
to induce a CPIR and cephalic pancreatic polypeptide
response [4]. Weakening learned associations between
taste and post ingestive consequences of ingestion via
consumption of low energy food substitutes (i.e., de-
livery of sweetness without carbohydrate energy) is
postulated to disrupt CPRs and increase energy intake
[4]. However, little work has been undertaken in
humans and a diminished CPIR was not found in rats
repeatedly exposed to saccharin [10]. Despite different
responses to each macronutrient, CPR respond to food
independently of macronutrient [4]. The degree to
which CPR influences appetite is not established [4].
Orosensory effects of the macronutrients
on appetite
The sensory properties of foods interact with the sen-
sory systems of individuals to generate a range of sen-
sations that, when placed in the context of a culture and
personal experience, result in perceptions. Each sensory
system transduces a different set of stimuli (e.g.,
chemicals for taste, smell, and chemical irritation;
electromagnetic radiation for vision, pressure waves for
audition, etc.) and collectively they result in a percept

www.sciencedirect.com Current Opinion in Endocrine and Metabolic Research 2019, 4:14–20

16 Frontiers in Obesity
called flavor. The sense of taste has traditionally been
defined as extremely limited; comprised only of the
qualities of sweet, sour, salty, bitter, and umami. How-
ever, recent work has challenged this view with accu-
mulating evidence supporting the ability to detect fatty
acids, starch, calcium, CO2, phosphate, H2O, and
possibly others. Historically, taste has been the sense
most closely tied to nutrition. There are teleological
claims linking the primary qualities with specific nutri-
ents. Sweetness is a signal for the presence of carbohy-
drate, a desired energy source; saltiness indicates the
presence of electrolytes, umami is an indicator of pro-
tein; sour aids identification of vitamins or avoidance of
strong acids; and bitter is a warning signal to reject
toxins. Recent findings related to fat suggest that while
there are essential fatty acids and fat plays numerous
vital roles in the body, the sensation that fatty acids
impart is unpleasant and most likely leads to avoidance
rather than consumption. In contrast, the mouthfeel of
triglycerides is appetitive. While there is an innate
sensitivity and hedonic response to each of these qual-
ities, these can be overridden by dietary experience.
Humans learn where various qualities should occur in
the food supply and at what intensity.
Whether innate or learned, the sensory properties of
foods are consistently rated as the primary driver of food
choice. However, the effects of palatability on appetite
are mixed. Intake of palatable foods reportedly promotes
overconsumption of that food [11,12]. Conversely,
palatability may aid weight management [13], because it
improves dietary adherence. Foods high in sugar, fat (as
triglycerides), or mono-sodium glutamate are generally
rated as highly palatable but, there is no consensus that
one macronutrient’s influence on palatability has a larger
effect on appetite than any other [11].
Diets of varying macronutrient composition are often
promoted for weight loss. However, there is no signifi-
cant difference in weight loss between such diets when
compared directly. In a one year, parallel-arm trial, adults
with overweight or obesity were assigned to follow the
Atkins diet (carbohydrate restriction), Zone diet
(macronutrient balance), Weight Watchers diet (energy
restriction), or Ornish diet (fat restriction) [14]. All
diets led to modest weight loss with no significant dif-
ferences between them. Although palatability was not
assessed, weight loss was positively associated with diet
adherence rather than macronutrient composition.
Adherence decreased over the course of the year for all
diets, with the Atkins and Ornish diets (more restric-
tive) having higher attrition rates than the Zone and
Weight Watchers diets. Another study produced similar
results [15]. Therefore, deciding on an energy-
restricted diet that can be adhered to by a patient will
be more beneficial for weight loss than recommending a
diet because of its macronutrient composition.
Current Opinion in Endocrine and Metabolic Research 2019, 4:14–20
Overall, sensory influences on CPR and appetite are not
closely aligned to the macronutrient content of diets. If
a particular dietary macronutrient mixture is prescribed,
attention should be given to its acceptability as any diet
that is not adhered to is of limited value.
Gastric effects of macronutrients on
appetite
Gastric distension resulting from food ingestion is
detected by mechanoreceptors in the stomach. Gastric
satiation effects stem primarily from the extent and
time course of distension (often measured by gastric
emptying time). This is regulated by gastric and intes-
tinal neural and endocrine signaling [16,17]. The
macronutrient content of a meal affects gastric satiation
indirectly through enteroendocrine control of gastric
emptying mediated by gut peptides such as cholecys-
tokinin (CCK) and glucagon-like peptide-1 (GLP-1).
Gastric distension and intestinal nutrient feedback
systems can act independently, but under naturalistic
eating conditions, they act synergistically to induce
satiation. CCK and GLP-1 slow gastric emptying,
enhancing the magnitude and duration of gastric
distention effects. In addition, CCK increases the
sensitivity of gastric mechanoreceptors and enhances
vagal signaling activity [18,19]. Ghrelin, the only pro-
posed orexigenic hormone, is secreted primarily from
the stomach, though the validity of ghrelin as a hunger
hormone is questionable (discussed below) [20,21].
While intraduodenal administration of all macronutri-
ents increase plasma concentrations of CCK, free fatty
acids (FFA) are the most potent stimuli. Hydrolyzed
protein stimulates CCK release to a lesser degree and
carbohydrates are least effective [22]. Increasing energy
content of fat, carbohydrate, and protein loads increases
GLP-1 release, but a relative potency of macronutrients
for GLP-1 secretion is difficult to quantify because of
the different patterns of release [22]. Glucose (but not
fructose) and amino acids cause a rapid rise in GLP-1
concentrations. Complex carbohydrates produce a
blunted response compared to glucose [23]. GLP-1
concentration increases are delayed but sustained
longer with protein and fat intake [24,25]. Isovolu-
metric, isoenergetic glucose, protein, and FFA emul-
sions administered intragastrically typically yield similar
gastric volume curves. However, there is evidence that
gastric emptying is slower for fat compared to other
macronutrients [26,27]. This is attributed to the action
of CCK released with intestinal FFA exposure. In
addition, free lipids “cream” to form a separate upper
layer of gastric fluids that empties slower than other
gastric contents [28]. Select trials actually document
slower gastric emptying with high carbohydrate loads
compared to high fat loads [16,29], but do not match
loads for energy content and osmolarity, respectively;
both of which affect gastric emptying [30,31].
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There is some evidence that consumption of a high-fat
diet diminishes fat-induced satiation by accelerating
gastrointestinal transit time and decreasing sensitivity
to CCK, GLP-1, and peptide YY (PYY) (see
Refs. [26,32]). Consumption of high-fat diets for two
weeks accelerated gastric emptying of high-fat meals
[33] and increased post-prandial CCK [34]. Despite
these changes, appetitive sensations were not different
from a high-carbohydrate meal [33] and energy intake at
an ad libitum meal was not different compared to pre-diet
energy intake [34]. A high-fat diet may affect gastric
emptying and gut peptide release, factors that affect
satiation. However, this does not reliably translate to a
difference in energy intake.
In summary, gastric distension effects on satiation are
largely macronutrient independent. The duration of
gastric distension is dependent, in part, on nutrient-
sensitive gut peptide release, but the effects of these
hormones under naturalistic eating conditions are not
robust. It is also noteworthy that complete gastrectomy
is associated with short-term reduced appetite and
energy intake [35], but over time there is accommoda-
tion for the reduced gastric satiation effects [36]. There
are multiple systems that regulate appetite besides the
stomach, and these systems may play a larger role in
long-term energy regulation.
Intestinal effects of macronutrients on
appetite
Gut peptides are released in anticipation of eating
events [4], but more robustly in response to nutrients
entering the gastrointestinal tract. The prevailing view
is that these peptides are biomarkers of appetitive
sensations. Reportedly, ghrelin promotes an increase in
hunger and food intake, whereas CCK, PYY, GLP-1, and
more than 20 other peptides as well as leptin (adipose
tissue hormone) and insulin (pancreatic hormone)
purportedly elicit a decrease in appetite and food intake
(see Refs. [37,38]). However, evidence suggests these
peptides primarily modulate digestive processes rather
than appetite. Exogenous administration of CCK, GLP-
1, and PYY do lead to reductions in energy intake and
administration of ghrelin does increase appetite and
energy intake. However, results from these trials do not
translate to a regulation of energy intake in a naturalistic
feeding environment and most gut peptides (with the
exception of CCK) do not meet the criteria for a phys-
iological role in feeding [37,39,40].
Physiological concentrations of ghrelin, GLP-1, and PYY
are likely not sufficient to elicit hunger or satiation/
fullness effects under naturalistic eating conditions
[41,42]. Ghrelin peaks are entrained to meal patterns
and rise in anticipation of customary eating times [20].
GLP-1 has also been associated with anticipatory activ-
ity in rats [43], although not consistently across trials
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Macronutrients and appetite Mattes et al. 17
[44]. Additionally, feelings of hunger can occur without
the release of ghrelin [45]. Even CCK, which induces
satiation (i.e. decreases meal size) has limited to no
effect on satiety (i.e. intermeal intervals or eating fre-
quency). The trials that monitor energy intake in
response to exogenous gut-peptide administration are
typically short-term (less than 24 h in duration), but
satiety signal fidelity may diminish with chronic
administration. Repeated administration of CCK to rats
negated its effect on total energy intake. This was
attributed to either a tolerance for elevated blood CCK
concentrations [46], recovery of total food intake by
increasing eating frequency [47], or a diminished
learned association between endogenous CCK and
satiety. Repeated injections of CCK to rats prior to
intake of a sucrose drink initially reduced consumption
of the drink, but consumption of the sucrose drink was
similar to rats receiving a saline injection after ten days.
However, the satiating effect of CCK was maintained
among rats receiving intermittent injections, suggesting
the learned association between CCK and satiation was
still functional [48]. Gut peptides modulate digestion,
nutrient absorption, and metabolism; including stimu-
lating gallbladder contraction, altering circulating insu-
lin and glucagon concentrations, regulating gastric and
intestinal motility, adipogenesis, and lipolysis. Thus, the
release of gut peptides plays a large role in preparing for
nutrient ingestion, digestion, and storage [22] and
appetite may only be a byproduct. The initiation,
termination, and magnitude of an eating event is
dependent on a plethora of cognitive, sensory, endo-
crine, metabolic, and cultural factors. Therefore, gut
“satiety” peptides contribute minimally to energy
intake regulation.
Macronutrients vary in their potency to stimulate gut
peptide release, but due to the lack of reliable effects of
these peptides on appetite, differences in macronu-
trient exposure do not correlate with changes in appe-
tite and energy intake. Numerous studies have
compared gut peptide release between loads of varying
macronutrient composition, yet relatively few trials
concurrently measure appetitive sensations and energy
intake in response to fat, carbohydrate, or protein loads
[49e53]. When isoenergetic high protein, fat, and car-
bohydrate loads were consumed by healthy individuals,
PYY and GLP-1 were higher following the high-protein
load compared to the high-fat and high-carbohydrate
loads. However, these differences had no effect on
appetitive sensations or energy intake at the subsequent
meal [49,50]. Generally, though not uniformly, similar
elevations of CCK, GLP-1, and PYY concentrations are
observed for high-fat versus high-carbohydrate loads but
the loads do not differentially affect appetitive sensa-
tions or energy intake [51,52].
Experiments that use intraduodenal macronutrient in-
fusions to provide information about the mechanisms by
Current Opinion in Endocrine and Metabolic Research 2019, 4:14–20
18 Frontiers in Obesity
which the macronutrients affect gut peptide release
eliminate the oral and gastric effects that contribute to
satiation and satiety [54,55] under naturalistic feeding
conditions. In a pooled analysis of nine trials investi-
gating ingestive responses to intraduodenal protein and
lipid, there was no association between PYY or CCK
concentrations and energy intake; only GLP-1 concen-
trations were associated with decreased energy intake
[56]. Additionally, fats, proteins, and carbohydrates
stimulate release of a mixture of gut peptides. Because
they may act synergistically and in combination with
gastric distension to induce satiety, the administration
of single nutrients intraduodenally may yield limited
insights on the satiety response compared to a mixed-
macronutrient oral load.
Conclusion
Sensory, gastric, and intestinal signals are part of a
complex system that reportedly regulates appetite and
feeding. Carbohydrates, fats, and proteins have different
taste qualities, cephalic phase responses, effects on
gastric emptying, and efficacy for gut peptide release
when ingested in isolation. However, rarely are these
macronutrients consumed alone. In the context of diets,
there is limited evidence of differential effects of the
macronutrients on appetite or energy intake. There are
reasons to prescribe diets of differing macronutrient
composition, but there is no clear advantage of one
mixture over another with respect to modulation of
appetite.
Conflict of interest statement
RDM serves on advisory boards of the Grain Food
Foundation and Con Agra Brands and currently receives
research support from the Almond Board of California
and Welch’s. KAH and SRH have no conflict of interest
to report.
Acknowledgements
This work was supported by USDA Hatch Project # IND030455. The
funding source had no involvement in the interpretation or writing of the
report.
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