Regulatory Peptides 149 (2008) 70–78

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Regulatory Peptides
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / r e g p e p

Effect of protein, fat, carbohydrate and fibre on gastrointestinal peptide

release in humans
L.J. Karhunen a,⁎, K.R. Juvonen a, A. Huotari b, A.K. Purhonen b, K.H. Herzig b,c
a
Food and Health Research Centre, Department of Clinical Nutrition, University of Kuopio, Finland
b
A.I. Virtanen Institute, University of Kuopio, Finland
c
Department of Internal Medicine, Kuopio University Hospital, Kuopio, and Institute of Biomedicine, University of Oulu Medical School, Oulu, Finland

A R T I C L E I N F O A B S T R A C T

Article history: Short-term regulation of food intake controls what, when and how much we eat within a single day or a
Received 15 April 2007 meal. This regulation results from an integrated response to neural and humoral signals that originate from
Accepted 22 October 2007 the brain, gastrointestinal (GI) tract and adipose tissue. In the GI tract, multiple sites including the stomach,
Available online 25 March 2008
duodenum, distal small intestine, colon, and pancreas are involved in this process. Ingested food evokes
satiety by mechanical stimulation and by release of peptides in the GI tract. The intestine in particular plays a
Keywords:
Macronutrients
key role in satiety through various peptides secreted in response to food. Many of the intestinal peptides
Fibre inhibit also gastric emptying thus enhancing gastric mechanoreceptor stimulation. In this review, the current
Intestine knowledge about the effects of different macronutrients and fibre on the release of GI satiety-related
Peptide release peptides in humans is discussed.
Satiety © 2008 Elsevier B.V. All rights reserved.
Humans

1. Introduction in response to ingested food [3]. Many of the intestinal peptides

Short-term regulation of food intake controls what, when and how
much we eat within a single day or a meal. Short-term regulation
results from an integrated response from neural and humoral signals
that originate in different organs: the brain, gastrointestinal (GI) tract
and adipose tissue. Multiple sites in the GI tract, including the
stomach, proximal and distal small intestine, colon, and pancreas are
involved in this process. Signals originating from these sites during
different phases of ingestion (i.e. cephalic, gastric, and intestinal) are
essential for energy homeostasis. Furthermore, there are short- and
long-term regulators of food intake interacting with each other. This
ensures that the energy balance can be maintained even despite the
usually large variation in day-to-day energy intake. The major
regulators of long-term energy balance, such as leptin and insulin,
modulate the sensitivity of an individual to GI satiation signals [1].
Ingested food evokes satiety in the GI tract primarily by two
distinct ways, i.e. by mechanical stimulation and therefore stimulation
of the nerve endings and by release of peptides. Yet, just transient
gastric antrum distension alone did not lead to a reduction in food
intake compared to the control treatment [2]. Post-gastric factors
seem to play a key role in satiety through secretion of various peptides
inhibit also gastric emptying thus enhancing gastric mechanoreceptor
stimulation.
The central nervous system (CNS) receives the GI satiety-related
signals via vagal afferents and humorally through gut-derived
peptides. The hindbrain is the principal central site receiving input
from the GI [4]. The other brain region strongly involved in the
regulation is the hypothalamus. In addition, various limbic and higher
forebrain regions are participating in feeding and energy expenditure
[4]. The access of substances to the CNS from the systemic circulation
is strictly controlled by the blood-brain barrier (BBB) in order to
maintain the optimal neural microenvironment in the brain [5]. There
are also specialized areas called sensory circumventricular organs (e.g.
median eminence, area postrema) which lack the BBB [6]. These areas
serve as crucial sensing regions in the CNS for body homeostasis.
In this review, we summarize the current knowledge about the
main effects of different macronutrients on peptide release from the
human GI tract. A summary is given in Table 1.
2. Peptides released from the stomach
2.1. Ghrelin

⁎ Corresponding author. Department of Clinical Nutrition, University of Kuopio,

Ghrelin is an acylated 28-amino acid peptide hormone produced
Yliopistonranta 1 C, 70211 Kuopio, Finland. primarily by the stomach [7]. Gastric fundus is the most abundant
E-mail address: Leila.Karhunen@uku.fi (L.J. Karhunen). source of ghrelin [8,9]. The second richest site is duodenum and lower

0167-0115/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.regpep.2007.10.008
 L.J. Karhunen et al. / Regulatory Peptides 149 (2008) 70–78
Table 1
Summary of the main findings of the effects of different macronutrients and fibre on
postprandial release of satiety-related gastrointestinal peptides in humans
Peptide Carbohydrate Fibre Fat
CCK Increase Increase Increase
Ghrelin Decrease Blunted or inhibited Decrease/
decrease/decrease/ no effect/
no effect increase
GLP 1 Increase Blunted increase/ Increase
no effect/increase
PYY Increase Increase/no effect Increase
GIP Increase ○ Increase
Insulin Increase Blunted increase Increase
(soluble fibres)
Amylin Increase ○ ○
Pancreatic polypeptide Increase No effect Increase
○: No studies available.
concentrations are expressed throughout the small intestine. In
addition, minor amounts of ghrelin are produced in the lungs,
pancreatic islets, adrenal cortex, placenta, kidney and brain [7,10].
Ghrelin receptors are expressed widely in the brain and peripheral
tissues, especially in the pituitary, stomach, intestine, pancreas,
thymus, gonads, thyroid and heart [11]. Ghrelin crosses the BBB and
stimulates food intake by acting in the brain on the hypothalamus,
hindbrain/caudal brainstem and mesolimbic reward centers.
Ghrelin can exert various biological actions and was originally
identified as the natural ligand for the growth hormone secretagogue
receptor. However, the role of ghrelin in the regulation of energy
homeostasis is generally viewed as its most important function [11].
Ghrelin is the only mammalian substance that has been shown to
increase appetite and food intake when delivered to humans [12–14].
Ghrelin can exert this effect whether injected peripherally or centrally.
Contrary to GI satiety peptides, ghrelin increases GI motility and
decreases insulin secretion. Circulating ghrelin levels typically rise just
before and fall shortly after a meal. Ghrelin has thus a role in mealtime
hunger and meal initiation. Accordingly, ghrelin enhances food intake
by increasing the number of meals initiated without altering meal
size. Preprandial ghrelin secretion seems also to be a cephalic re-
sponse participating in the anticipatory processes preparing the body
for food ingestion [15].
Ghrelin has also a role in the long-term regulation of energy bal-
ance and body weight. Circulating ghrelin levels respond in a com-
pensatory manner to body weight changes; diet-induced weight loss
increases, weight gain decreases the circulating levels of ghrelin [16].
2.1.1. Nutrients and ghrelin release
The postprandial ghrelin response is affected by macronutrient
composition of a meal. However, when the calorie content of meals is
varied but the volume, macronutrient distribution, and all other fea-
tures are kept constant, the depth and duration of postprandial ghrelin
suppression are dose-dependently related to the number of ingested
calories [17]. Thus, more energy-rich meals suppress ghrelin more
than lighter ones. Based on the recent findings, it also seems that
postprandial suppression of ghrelin is not mediated by nutrients in
the stomach or duodenum but rather results from post-ingestive
increases in lower intestinal osmolarity (via enteric nervous signaling)
as well as from insulin surges [11]. The release of ghrelin seems also to
depend upon the length of small intestine exposed since no
postprandial decrease was seen if less than 60 cm from the upper
isolated part of the small intestine was exposed to glucose [18]. Pure
stomach expansion, by e.g. ingestion of water, is not a sufficient
condition to modify ghrelin secretion [19,20].
Among different macronutrients, carbohydrates might be the most
effective in suppressing postprandial ghrelin concentration [21,22].
71
Decreased concentrations have been seen after intravenous and oral
administration of glucose [19] as well as after ingestion of simple (e.g.
maltodextrin) or complex (e.g. exopolysaccharide) carbohydrates [20].
Protein Different carbohydrate preloads suppress ghrelin concentrations in
proportion to their energy content. Nevertheless, the crucial experi-
Increase
Decrease/ ments fully answering the question about the postprandial effects
increase/ of different macronutrients on ghrelin release have not been performed
no effect yet and therefore it is too early to conclude the ranking order of
Increase
different macronutrients in suppressing postprandial ghrelin secretion.
Increase The effect of dietary fibre on postprandial ghrelin is not fully
No effect/ understood due to a limited number of studies as well as a wide range
increase of fibres with different physical and chemical properties. Increased
Increase fibre content of the meal has been shown both to decrease
postprandial ghrelin concentration as well as to inhibit the decrease.
○
Increase In one study, consumption of a small amount (4 g) of non-caloric
soluble psyllium fibre with water was as effective of suppressing
postprandial plasma ghrelin concentrations in healthy subjects as the
585-kcal mixed meal [23]. In contrast, no postprandial ghrelin
decrease was seen after ingestion of the 300 kcal meal enriched
with a considerable amount (23 g) of psyllium-fibre [24]. Similarly, no
postprandial decrease in ghrelin was reported after intake of a non-
caloric liquid containing 21 g of guar gum [25]. A soluble arabinoxylan
fibre (6 g) enriched breakfast induced a shorter postprandial decrease
in ghrelin when compared to a control breakfast [26]. Also enrichment
of bread with 10 g of insoluble wheat fibre blunted the postprandial
decrease in ghrelin concentration whereas the same amount of in-
soluble oat fibre did not [27]. In our recent study, postprandial ghrelin
concentration decreased similarly after puddings enriched with 10 g
insoluble wheat fibre or 10 g oat fibre (partly soluble) (Juvonen et al.
unpublished). Addition of insoluble carob fibre (5, 10 or 20 g) to a
liquid meal decreased acylated ghrelin without dose-dependent ef-
fects but failed to affect total or non-acylated plasma ghrelin in
comparison to a non-fibre meal [28]. This suggests that the discrepant
results obtained in different studies could also be ascribed to the
differences in the type of ghrelin measured.
The so far reported studies on the effects of protein on postprandial
ghrelin have also given contradictory results. In some studies, post-
prandial ghrelin concentrations have not changed [29] or have even
increased after the ingestion of protein-rich meal [25,30] or a phys-
iologic dose of essential amino acids [31,32]. In contrast, a high-
protein test breakfast (enriched with milk-based proteins) [33,34] or
liquid preloads of whey, casein, soy and gluten [35,36] caused a pro-
longed suppression of ghrelin as compared to carbohydrate. The type
of protein might thus play a role in modulating postprandial ghrelin
release. Decreased postprandial ghrelin levels have quite consistently
been found after milk-based proteins [37] whereas increased levels
reported after meat proteins [25,30]. Nevertheless, although the kine-
tics of the ghrelin response to ingested proteins and carbohydrates
differ, the overall magnitude of suppression after isocaloric intake of
these two macronutrient types could be relatively similar [11]. Ghrelin
concentrations were equivalent among people consuming isocaloric
high- vs. normal-protein diets with constant fat content [38]. Thus,
calorie for calorie, carbohydrates and proteins might also suppress
postprandial ghrelin levels equally.
Intravenous lipid infusion seems not to affect ghrelin concentra-
tions [39,40]. After oral ingestion of a high-fat meal, ghrelin
concentrations have been shown to decrease [21,29] or to increase
[41]. If decreased, the decrease has been characterized by a slower
return to baseline than after a high-carbohydrate meal [42,43]. Latest
studies have also indicated that fat-induced suppression of ghrelin is
dependent on fat digestion [44]. The effect of intraduodenal fatty acids
on ghrelin secretion seems also to be dependent on fatty acid chain
length [45,46]. Fatty acid with 12 carbon atom length (C12, lauric acid)
markedly suppressed plasma ghrelin compared with a fatty acid with
10 carbons (C10, decanoic acid) which had no effect. Similarly, in a
recent study long-chain fatty acids (sodium oleate, 18 carbon atoms)
72 L.J. Karhunen et al. / Regulatory Peptides 149 (2008) 70–78
inhibited ghrelin whereas medium-chain fatty acids (sodium capry-
late, 8 carbon atoms) was ineffective [46].
3. Peptides released from the small intestine and colon
3.1. Cholecystokinin (CCK)
Plasma cholecystokinin (CCK) is derived almost completely from I
cells in the duodenal and jejunal mucosa of the small intestine [47].
Selective processing of the proCCK, a 115-amino acid precursor, leads
into multiple bioactive CCK forms of different lengths [48,49]. The
major circulating forms in human are CCK-58, -33, -22 and -8, all
ligands for the CCK receptor 1 (CCK1R) [50]. CCK is also found in the
enteric nervous system and CNS where it serves as a neurotransmitter,
predominant form of CCK released by the neurons being CCK-8 [48].
CCK1R predominates in the GI system, whereas the CCK receptor 2 is
located in the CNS and in the stomach. CCK1R mediates CCK-induced
satiation [51]. This receptor is expressed on vagal afferents in the
duodenum and stomach, and peripheral CCK administration increases
vagal-afferent firing, as well as neuronal activity in the hindbrain
region receiving visceral vagal input. CCK1R is expressed also in the
hindbrain and hypothalamus indicating that CCK might relay satiation
signals to the brain both directly and indirectly.
The inhibitory effect of CCK on food intake has been confirmed in
numerous species, including humans. It is however short-lived, lasting
less than 30 min. Accordingly, CCK inhibits food intake within the
meal by reducing meal size and duration but does not affect the onset
of a next meal [52,53]. CCK has thus an important role in the causal
chain leading to satiation or meal termination.
The satiating effect of CCK is mediated through activation of vagal
afferent mechanosensitive fibers in the stomach and in the duode-
num. Gastric distention augments the anorectic effects of CCK in
humans [54]. However, evidence suggests that CCK causes satiation
also through mechanisms additional to enhancing gastric distention
signals, including activation of duodenal chemosensitive fibers [55]
and activation of CCK1R in the pyloric sphincter causing pyloric
contraction and slowing down gastric emptying.
3.1.1. Nutrients and CCK release
CCK is released in response to nutrients in the duodenal lumen, fat
and protein producing a greater postprandial release than carbohy-
drates [56,57]. Nevertheless, also intragastric or intraduodenal glucose
infusion increases plasma CCK levels in humans [18,58]. The response
is rapid and seen within 15 min of ingestion. The CCK increase after
carbohydrates is, however, quite short-lived and returns close to
baseline within 1 h [36].
Fibre content of the meal also affects postprandial CCK release.
Different dietary fibres, including hydrolyzed guar gum [59], beta-glucan
in barley pasta [60] or fibre in bean flakes and fibre mostly from oatmeal
and oat bran [61] have been shown to produce greater postprandial CCK
levels with prolonged elevations than low fibre meals or placebo.
Protein is a strong stimulus for CCK release. CCK levels remained
elevated longer after liquid whey, casein, soy and gluten or after a whey
protein meal compared to glucose and lactose [34–36]. Gastric
emptying time was also reduced after a whey protein meal. Higher
CCK responses after proteins (whey, casein) also correlated with satiety
but did not affect food intake [35]. The postprandial CCK release has
been greater after whey than casein [62]. Whey was also more satiating
than casein. Digestion of proteins is required to effectively stimulate
CCK release in humans. Proteins may stimulate CCK release via
inhibition of trypsin digestion of intestinal CCK releasing peptides [63].
Lipids significantly stimulate CCK release [64,65]. In order to
stimulate CCK secretion triglycerides must be hydrolyzed to fatty
acids. The length of the fatty acid carbon chain determines CCK release
[66]. Most authors have shown that in humans long chain fatty acids,
carbon chain length N10 C, are the most potent stimulants for CCK
release [66–69]. Furthermore, C12 as compared with C10 suppressed
appetite and energy intake [69].
High fat intake seems to have long-lasting effect on CCK: after a
high-fat evening meal CCK concentrations remained elevated until to
the following morning [70]. High-fat, low-carbohydrate feeding does,
however, reduce CCK-induced satiety, possible due to a down-regu-
lation of vagal CCK1R [71].
3.2. Glucose-dependent insulinotropic polypeptide (GIP)
Glucose-dependent insulinotropic polypeptide/gastric inhibitory
polypeptide (GIP) is a 42-amino acid polypeptide that shares the
insulinotropic effect with glucagon-like peptide 1 (GLP-1) to potentiate
meal-induced insulin secretion from the pancreas [72]. GIP is released
from the intestinal K cells in response to the presence of nutrients in
the intestinal lumen. GIP-secreting K-cells are found predominantly in
the duodenum but can be detected throughout the GI tract [73].
Secretion of GIP is closely correlated to the secretion of GLP-1, although
the mechanism underlying this co-secretion is still unclear.
The predominant stimulus for GIP release is nutrient intake and
GIP concentration increases within 5–15 min after nutrient ingestion
[74]. The concentration peaks 30–60 min postprandially depending on
meal size and composition [75]. GIP is rapidly degraded by the pro-
teolytic enzyme dipeptidyl-peptidase 4 (DPP4) yielding the biologi-
cally inactive fragment of GIP (GIP3–42) [76]. After the cleavage GIP has
lost its incretin effect. Circulating GIP represents a mixture of active
(GIP1–42) and inactive GIP (GIP3–42).
In addition to the role of GIP in the regulation of endocrine
pancreatic secretion and thus glucose metabolism, GIP exerts various
peripheral effects on adipose tissue and lipid metabolism in the
postprandial state. As an anabolic hormone GIP stimulates lipoprotein
lipase activity [77] and promotes fatty acid incorporation into adipose
tissue [78], thereby leading to increased lipid deposition and fat
storage. GIP does not affect gastric emptying in humans [79].
3.2.1. Nutrients and GIP release
The major stimuli for GIP release are dietary fat and carbohydrates
[80–85]. Protein seems to have no effect [82,84], although some evi-
dence exists indicating that the intraduodenal administration of
amino acids [86] can stimulate GIP release. The carbohydrate-free
meal composed of protein and fat also stimulated PP [87].
Among different carbohydrate sources, glucose, but not fructose,
increased GIP concentration, although they both were equally effec-
tive in suppressing food intake in the following test meal [88].
Moreover, equivalent portions of carbohydrate either in simple
(glucose) or complex forms (boiled brown rice or barley) stimulated
GIP release differently — the largest following glucose and the smallest
after a barley meal [84]. In addition, fat stimulates GIP release. Among
different fats, olive oil induced higher concentrations of GIP than did
butter [89] suggesting that postprandial GIP release might be affected
by the saturation of the fatty acids.
3.3. Glucagon-like peptide 1 (GLP-1)
Glucagon-like peptide 1 (GLP-1) is cleaved from proglucagon
expressed in the gut, pancreas, and the brain [90]. Post-translational
cleavage of proglucagon leads into different breakdown products de-
pending on the tissue. In the intestine, the process results in the end
products of glicentin, GLP-1 and GLP-2. Glicentin (also known as
enteroglucagon) is then further cleaved to oxyntomodulin [91]. In the
pancreas, the end product of proglucagon is glucagon. Although
several of these peptides are implicated in satiation, the strongest
evidence has been demonstrated for GLP-1 and oxyntomodulin [3].
However, since to our knowledge, there are no published human
studies on the effects of different nutrients on postprandial oxynto-
modulin release in humans, it is not discussed here in more detail.
 L.J. Karhunen et al. / Regulatory Peptides 149 (2008) 70–78
GLP-1 is an incretin hormone released by L cells in the distal small
intestine and colon in response to food intake [84,92]. In L cells GLP-1
colocalizes with oxyntomodulin and peptide YY (PYY). In human
plasma, two equipotent bioactive forms, GLP-17–36 amide and GLP-17–
37, are detected, GLP-17–36 amide being the most abundant form.
Both peptides are rapidly inactivated in the circulation by N-terminal
cleavage by DPP4 yielding GLP-19–37 and GLP-19–36amide. Thus C-
terminally directed antibodies utilized in some plasma GLP-1 measure-
ments do not distinguish between the active GLP-1 forms and
biologically inactive metabolites. Due to rapid degradation of active
GLP-1 by DPP4 the plasma levels of the intact hormone are very low and
thus assays quantitating also the primary metabolite may be more useful
as an estimation of L-cell secretion [93]. In humans, almost all of
intestinal GLP-1 is C-terminally amidated, and assays directed against
the amidated C-terminus reflect total intestinal GLP-1 secretion. The
differences in the primary antibodies in addition to methodological
aspects in plasma extraction procedures used may explain the variation
in the GLP-1 levels reported in the literature.
Due to its rapid degradation the effect of GLP-1 on food intake is a
typical short-term effect. GLP-1 is thought to play an important part in
the “ileal brake”, a mechanism regulating the flow of nutrients from
the stomach into the small intestine [94]. In addition to the ileal brake,
GLP-1 is an incretin hormone and accentuates glucose-dependent
insulin release, inhibits glucagon secretion, and increases pancreatic
ß-cell growth [72,95,96].
The mechanisms underlying GLP-1-induced anorexia are not fully
understood but involve vagal and possibly direct central pathways.
Anorectic effects are mediated specifically by GLP-1 receptor (GLP1R).
GLP1R is expressed in the gut, pancreas, brainstem, hypothalamus,
and vagal-afferent nerves [90]. The peptide can cross the BBB, but it
seems unlikely that physiologically relevant quantities of endogenous
peripheral GLP-1 evade peripheral DPP4 degradation and cross the
BBB. GLP-1 is also produced by brainstem neurons that project to the
hindbrain and hypothalamus.
3.3.1. Nutrients and GLP-1 release
Plasma concentrations of GLP-1 rise rapidly within minutes after
food intake [75]. Ingested nutrients stimulate GLP-1 secretion thus by
indirect neural mechanisms, in addition to a direct effect on the
enteroendocrine L cells in the distal intestine [97].
Carbohydrates are strong stimuli of GLP-1 release consistent with
the role of GLP-1 as incretin [84,85,97]. Nevertheless, differences in the
GLP-1 responses between different carbohydrates have been reported:
after equivalent portions (75 g) of glucose or complex carbohydrates,
(brown rice or barley) plasma GLP-1 concentrations increased only
after glucose [84]. Among different monosaccharides, oral glucose
seems to have a bigger effect on GLP-1 release than fructose, although
glucose and fructose have similar effects on appetite [98].
Dietary fibres modify the postprandial GLP-1 response. Elevated,
inhibited and unaffected GLP-1 responses have been reported, possible
related to the type or amount of dietary fibre. A galactose and guar gum
containing meal increased and extended GLP-1 release [99]. In contrast,
resistant (pregelatinized) starch produced a smaller GLP-1 response
than digestible starch [100]. Whole-kernel and whole-meal rye bread
and dark durum pasta produced smaller GLP-1 responses than low-
fibre wheat bread and rye bread containing oat β-glucan concentrate
[101]. In our own study, a test meal enriched with a considerable
amount (23 g) of soluble psyllium fibre in combination with soya
protein completely abolished the postprandial GLP-1 response, but not
when protein was replaced with carbohydrate (Karhunen et al. un-
published). A smaller amount of psyllium fibre (1.7 g) did not modify
postprandial GLP-1 responses [102], nor did pea fibre [103].
Protein stimulates GLP-1 release, even more than carbohydrates
[34,38]. Among meals rich in protein, fat, carbohydrate or alcohol,
GLP-1 responses were the highest after a protein rich meal [104]. A
high-protein dairy product enriched with a whey protein isolate
73
stimulated GLP-1 secretion more than a high-carbohydrate meal,
although subjective sensations of hunger and ad libitum energy intake
during the lunch were not significantly different between the meals
[34]. Among different protein sources, whey protein has been shown
to increase postprandial GLP-1 secretion as well as satiety more than
casein [62].
GLP-1 concentration increases also after fat [85], although the
increase is delayed when compared to carbohydrates [84]. Fats rich in
monounsaturated fatty acids (i.e. olive oil) induced higher GLP-1
concentrations than butter [89]. The effect of fatty acid saturation on
GLP-1 response has, however, not been observed in all studies [105].
The postprandial GLP-1 response to intraluminal fats may also depend
on the chain length of fatty acids [69]. Fatty acid with 12 carbon atoms
(C12, lauric acid) stimulated GLP-1, whereas the shorter one (C10,
decanoic acid) did not [69].
3.4. Peptide YY (PYY)
Peptide tyrosine–tyrosine (PYY) is a member of the pancreatic
polypeptide-fold (PP-fold) family including neuropeptide Y (NPY) and
pancreatic polypeptide (PP) [106]. PYY is synthesized and released in
response to food intake primarily from the endocrine L-cells from the
distal parts of the GI tract, especially ileum, colon and rectum [107].
Yet, smaller amounts of PYY are also found in the upper small
intestine. Based on animal observations, PYY is present also in the
CNS, with PYY immunoreactive nerve terminals in the hypothalamus,
medulla, pons, and spinal cord. Receptors mediating the effects of PYY
belong to the NPY receptor family and include Y1, Y2, Y3 Y4 and Y5.
Among other functions, PYY mediates ileal and colonic brakes,
mechanisms that ultimately slow gastric emptying and promote
digestive activities to increase nutrient absorption [108]. PYY is in-
volved in a wide range of digestive functions including regulation of
insulin secretion and glucose homeostasis [109]. Postprandially re-
leased PYY is rapidly cleaved by DPP4 to PYY3–36. Full length PYY
activates receptor types Y1, Y2 and Y5, while PYY3–36 activates re-
ceptor types Y2 and Y5 [106]. This change in target activity is
important for the different effects of PYY on digestive and feeding
behavior. However, very little information is available with respect to
circulating molecular forms of PYY [110].
3.4.1. Nutrients and PYY release
Plasma concentration of PYY increases after meals and decreases
after fasting consistent with a meal-related signal of energy home-
ostasis [111]. PYY secretion occurs even before nutrients have reached
the PYY-releasing cells. The postprandial PYY secretion is thus
biphasic, stimulated initially by atropine-sensitive neural projections
from the foregut, followed by direct nutrient stimulation in the gut.
Nutrients stimulate PYY release within 30 min of ingestion of a
meal, reaching usually a maximum within 60 min [107]. The release of
PYY is proportional to calorie intake; the greater the energy intake, the
greater the PYY release. However, also meal composition affects
postprandial PYY release. Plasma PYY concentration is not altered by
gastric distension [2], water loading [112] or sham feeding [113].
Dietary fat, carbohydrates and protein all stimulate PYY release but
to different degrees and time-courses [106]. Adrian et al. [107] found
that fat (as double cream) elicited the largest increase in postprandial
PYY concentration, protein (as steamed cod) a more moderate
increase whereas glucose solution caused only a transient and
minor release. Higher PYY release after lipids than carbohydrates
has been reported also by others [114,115]. In contrast, Pedersen-
Bjergaard et al. [112] reported that PYY concentration increased after
proteins and carbohydrates while there was only a slight rise after a fat
meal. In a recent study Batterham et al. [116] showed that in normal-
weight and obese humans, high-protein intake induced the greatest
release of PYY, as well as most pronounced satiety, followed, in the
following order, by fat and carbohydrates. Interestingly, in the same
74 L.J. Karhunen et al. / Regulatory Peptides 149 (2008) 70–78
study PYY null mice were selectively resistant to the satiating and
weight-reducing effects of protein and developed obesity that was
reversed by PYY treatment.
Different fats elicit different PYY release. Especially fat hydrolysis
and fatty acids chain length seem to be crucial in this process [46]. 12-
carbon fatty acids (lauric acid) stimulated PYY release, while C10
(decanoic acid) had no effect [45]. Similarly, perfusion of long-chain
triglycerides (sodium oleate, C18) increased the plasma PYY concen-
tration, whereas medium-chain triglycerides (sodium caprylate, C8)
stimulate PYY release to a lesser extend [117] or not at all [46].
Moreover, plasma PYY levels were consistently higher after ingestion
of oleic acid-enriched liquid mixed meal than after ingestion of
linoleic acid (sunflower oil) enriched meal [118]. Ileal infusions of oleic
acid solutions induced a dose-dependent increase of PYY [108].
Soluble psyllium-fibre (23 g) enriched meals induced slower but
more prolonged increase in plasma PYY concentration as compared to
eucaloric meals with no added fibre (Karhunen et al. unpublished).
However, there might be differences in the postprandial PYY re-
sponses between different fibre types. In a recent study, postprandial
PYY release was greater after insoluble oat-fibre (13.5 g) enriched
bread or white wheat bread than after the eucaloric intake of bread
with insoluble wheat fibre (13.4 g) [27]. In our own study,
postprandial PYY responses did not differ after eucaloric puddings
enriched with the same amounts (10 g) of wheat (insoluble) or oat
(partly soluble) fibre (Juvonen et al. unpublished).
Stimulatory effect of protein on PYY has been seen after different
protein solutions of similar energy density (whey or casein: whole
protein versus hydrolysate) [119]. Ingestion of fermented milk resulted
in a slightly greater PYY concentrations compared with whole milk, but
after crossover whole milk meal resulted in higher PYY concentrations
than fermented milk [120]. Soy isoflavone supplementation for eight
weeks increased plasma PYY concentrations in healthy postmenopausal
women [121], whereas the increased soy protein content of a single
mixed meal did not modify the PYY release [24].
4. Peptides released from the pancreas
4.1. Insulin
Insulin is the major endocrine and metabolic polypeptide hormone
secreted by the ß cells of the endocrine pancreas and one of the key
adiposity signals in the brain influencing energy homeostasis [122].
Plasma insulin concentrations are in direct proportion to changes in
adipose mass. Insulin concentrations are increased at positive energy
balance and decreased at the times of negative energy balance. Ad-
ditionally, plasma insulin concentrations are largely determined by
peripheral insulin sensitivity which is related to the amount and
distribution of body fat. Insulin thus provides information to the CNS
about the size and distribution of the adipose mass to regulate
metabolic homeostasis [1].
4.1.1. Nutrients and insulin release
The endocrine cells of the pancreatic islets respond rapidly to the
nutrients in the blood stream [123]. Only small monomeric molecules
such as monosaccharides, long-chain fatty acids, L-amino acids and
ketone bodies are affecting secretion while large polymeric nutrients
such as glycogen or triglycerides do not. Neither do metabolic end
products or intermediates such as lactate, pyruvate, glycerol, and
citrate affect insulin secretion.
Glucose is the well known and most powerful stimulator of insulin
secretion and independent of other fuels while it can potentiate other
stimuli [124]. Circulating glucose concentrations higher than 5 mM
stimulate insulin release with the highest release rate at glucose
concentrations ranging from 5 mM to 10 mM [123,125]. Accordingly,
dietary glucose causes a greater insulin release than an equal amount
of e.g. starch [126]. In contrast, the digestible carbohydrate fructose
does not stimulate insulin secretion. Amino acids and fatty acids are
ineffective in the absence of glucose, or stimulate insulin secretion
only weakly when circulating glucose concentrations are low (i.e. in
fasted state).
Indigestible complex carbohydrates, i.e. diverse forms of dietary fibre,
may exert metabolically beneficial effects on postprandial insulin action.
After ingestion of high fibre containing food products, insulin secretion is
clearly attenuated compared to pure glucose ingestion [126]. Thus, dietary
fibre can delay nutrient absorption. Moreover, the extreme fluctuations
between the fed and fasted states seen with low fibre intake are
dampened by high fibre diets. Accordingly, consumption of foods high
in fibre is associated with beneficial effects on insulin sensitivity and
insulin resistance [127–129]. This effect has been seen especially after
soluble viscosity-producing fibres, such as oat β-glucan, although
insoluble fibres, primarily from the cereal products, have also been
associated with lower incidence rates of e.g. cardiovascular diseases.
Several studies have suggested that diets low in glycemic index may
improve insulin sensitivity [130,131].
Proteins are secretagogues for insulin as well though there seems
to be variation in postprandial insulin responses after different kind of
dietary proteins [132]. Milk proteins have been shown to produce
larger postprandial insulin responses than fish (cod) or plant (soya)
proteins. Furthermore, whey leads to higher insulin concentrations
compared to casein [133]. This is suggested to be due to fast digestion
of whey protein leading to increased levels of stimulatory amino acids
in plasma [134]. Amino acids like alanine, glutamine, lycine along with
branched chain amino acids (leucine, isoleucine, valine) stimulate
insulin release [123,135,136]. However, amino acid stimulated insulin
release requires permissive levels of blood glucose (2.5 mM to 5 mM).
The only exception is leucine, which stimulates insulin secretion even
in the absence of glucose. Arginine stimulates insulin secretion in vitro
[137] and when administered intravenously in high amounts [138,139]
but in contrast when ingested orally in doses obtainable from a large
beef meal no stimulation was observed [140].
Short-term elevation of plasma free fatty acids stimulates insulin
secretion [123]. Elevation of non-esterified fatty acids upon fasting is
required for the glucose stimulated insulin release [141]. The chain length
and saturation degree of fatty acids could play a role in stimulatory
capacity, i.e. saturated long-chain fatty acids (especially palmitate and
stearate) had the highest capacity to stimulate insulin secretion, whereas
the medium-chain saturated fatty acids were not as potent in the isolated
perfused rat pancreas model [142]. However, when free fatty acids are
chronically elevated, the insulin secretion capability of pancreatic β-cells is
disturbed [143]. Chronic elevation of free fatty acids is initially increasing
insulin secretion in low glucose concentration, but subsequently, impair-
ing the insulin response to high concentrations of glucose [144]. In
addition, the association of elevated free fatty acids, obesity and type II
diabetes is well established [145].
4.2. Amylin
Additionally to insulin, pancreatic β-cells secrete a 37 amino acid
peptide hormone amylin — also known as islet amyloid polypeptide,
IAPP [146]. Amylin is an anorexigenic peptide shown to reduce meal
size as well as the number of meals [147,148]. The inhibitory effect of
amylin on food intake is thought to be due to the inhibition of gastric
emptying [149]. Amylin is stored in same granules as insulin and
cosecreted in response to stimuli evoking insulin release [150]. Amylin
inhibits gastric acid and glucagon secretion [148]. Hence, amylin is
considered to be required for the proper function of insulin in the
control of nutrient flux by its ability to regulate nutrient appearance
and postprandial glucose concentrations.
4.2.1. Nutrients and amylin release
The effects of nutrients in amylin secretion are similar to that of
insulin [151]. In humans, plasma amylin concentrations rise after a
 L.J. Karhunen et al. / Regulatory Peptides 149 (2008) 70–78
glucose load [152], a meal rich of carbohydrates [153] and after mixed
meals [154,155]. Instead, to our knowledge there is only one published
human study on the effects of dietary fat on amylin showing no
differential effects on postprandial amylin after moderate changes in
dietary fatty acid profile [156].
4.3. Pancreatic polypeptide (PP)
Pancreatic polypeptide (PP) belongs to the same PP-fold peptide
family that includes neuropeptide Y (NPY) and PYY. PP is secreted by F
cells of the endocrine pancreas comprising approximately b5% of islet
volume [157]. Other sites of PP expression include exocrine pancreas,
colon and rectum [158]. The main function of PP is thought to be the
inhibition of exocrine pancreas. Secretion of PP is controlled by the
parasympathetic nervous system and therefore used as a marker of
activation of pancreatic parasympathetic nerves [159,160]. Atropine
almost completely blocks PP secretion [161]. PP has been shown to
affect energy balance by suppressing food intake and gastric emptying
[162,163].
Pancreatic polypeptide is secreted in a biphasic manner in
proportion to food intake [164]. The main stimulus for the release of
PP is the activation of the parasympathetic nervous system by food
intake [158]. The quantity of PP release is related to the nutritional
state: there is little release in the fasting state but increased through-
out phases of digestion [165,166]. There is evidence that sham feeding
and even sole water ingestion stimulate PP secretion [167–170].
4.3.1. Nutrients and PP release
Different dietary factors potentiate PP release and several studies
have reported increased postprandial PP levels after mixed meal
conditions [44,165,169,171,172]. Glucose as well as starch ingestion
stimulates PP [173–176]. However, indigestible carbohydrates seems
to have no effect on PP release. Diets supplemented with dietary fibre
(20 g/d; apple pectin, alpha-cellulose) over a four week period had no
relevant effects on postprandial PP concentrations [177,178]. Negative
results have been demonstrated also in later studies performed with
other dietary fibres (5 g, guar gum) [179], (20 g, guar gum) [180], (15 g
of pectin/ methylcellulose) [181]. In contrast, soy polysaccharide (10 g)
has been shown to attenuate PP concentrations [182].
Protein-rich meals stimulate PP secretion [183,184] in a dose
dependent manner [185] due to increased levels of circulating amino
acids. However, only 35% of postprandial PP levels can be ascribed to
the rise of plasma amino acids [184] suggesting that other neural and/
or endocrine factors contribute to the release. Indeed, the stimulatory
effect of dietary protein on postprandial PP release has been seen even
in the sham-fed condition [167].
Dietary fat increases postprandial PP as well (a standard breakfast
40% fat [186]; a 466 kJ standard, oral high-fat liquid test meal
containing 50 g long-chain triacylglycerols [168]). In contrast, daily
supplementation with excess fat (as cream and peanuts) over a three
week period led to decreased postprandial PP levels [187]. Similarly,
reduced fasting concentrations of PP were observed in the following
morning after a high-fat evening meal [70].
5. Conclusions
This review summarizes the current knowledge about the effects
of dietary protein, fat, carbohydrate and fibre in the gastrointestinal
peptide release in humans with the emphasis on the satiety-related
peptides. It clearly demonstrates that composition of diet modifies
neuroendocrinological physiology and different macronutrients exert
diverse postprandial effects. The amount of existing literature is,
however, still limited, and the study designs used varied significantly
in respect of the amount and composition of tested foods as well as the
characteristics of study subjects. This all makes it challenging to
compare the studies and summarise the results. It should be noted
75
that also other characteristics, such as chemical, physical and sensory
properties as well as the structure of food, can modify the postprandial
responses. These effects need to be considered and further examined
in order to fully understand gastrointestinal peptide release by macro-
nutrients. Moreover, the precise relationships between various GI-
peptides and appetite are still unclear, as for example differences seen
in gastrointestinal peptide secretions are not always followed by
corresponding changes in appetite sensations or food intake. This
might, at least in part, be attributed to the large inter- and intra-
individual variation typical for appetite ratings. Nevertheless, in the
current obesity epidemic a better understanding of the factors regu-
lating gastrointestinal peptide release and thus food intake is urgently
needed to modify our food products in order to be able to better treat
this epidemic on a populational level.
Acknowledgments
This study was supported in part by grants from the Academy of
Finland (110525,118191,118281) (to L.J.K, K.R.J., K.H.H, A.H), the
Technology Development Centre of Finland (Tekes) (to L.J.K.), Nordic
Innovation Centre (Weighty-project) (to L.J.K.) and Novo Nordisk
Foundation (to K.H.H.), and the Jalmari and Rauha Ahokas Foundation
(to A.K.P).
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