Acta Physiologica Hungarica, Volume 101 (4), pp.

395407 (2014)
DOI: 10.1556/APhysiol.101.2014.4.1

The role of gut hormones in appetite regulation

(Review)
G Mari1, T Gazibara1, I Zaletel2, M Labudovi Borovi2, N Tomanovi3,
M iri4, N Puka2
1

Institute of Epidemiology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia

Institute of Histology and Embryology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
3
Institute of Pathology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
4
Institute of Physiology, Faculty of Medicine, University of Nis, Nis, Serbia

Received: February 10, 2014

Accepted after revision: June 17, 2014
Eating process is an aggregate of complex and different forms of behavior. Its regulation is based on energy
homeostasis and appetite control which includes two components: the homeostatic and the hedonistic control.
Important signals in appetite regulation are gut-derived hormones. They are produced by enteroendocrine cells in
response to nutrient and energy intake, and achieve their effects by influencing brain structures involved in food
intake regulation. The key brain structure involved in this process is the hypothalamus. Gut hormones reach the
hypothalamus from the circulation or by the vagal nerve via the nucleus of the solitary tract. Among gut peptides,
ghrelin is the only orexigenic hormone, leading to an increase in food intake and body weight. All others, such as
cholecystokinin, glucagon like peptide-1, oxyntomodulin, peptide tyrosine tyrosine or pancreatic polypeptide, are
anorexigenic, leading to decrease in food intake. Also, gut-derived endocannabinoids exert orexigenic effect on
appetite. Keeping in mind the growing problem of obesity, the crucial issue when considering gut derived peptides
is to understand their mechanisms of acting because of potential role in clinical therapy, and discovering long lasting
gut peptides or their analogues, with no or minimal side effects.
Keywords: appetite, ghrelin, cholecystokinin, peptide tyrosine tyrosine, oxyntomodulin, pancreatic polypeptide,
glucagon like peptide-1, endocannabinoids

Regulation of food intake is related to homeostatic and hedonic regulatory mechanisms.

While homeostatic control, which sustains energy balance, is based on negative feedback
control, hedonic mechanisms are driven by reward. Given that the homeostatic system
partially tolerates an increase in food intake, and that the hedonistic mechanisms are based
upon reward, in addition to tasty contemporary food, an increase in obesity incidence is well
comprehensible.
In industrialized countries, for example in the US, more than one-third of adults and
approximately 17% of children and adolescents are obese (17). In the Republic of Serbia, in
2006, one half of individuals older than 20 years, were overweight (body mass index (BMI)
> 25 kg/m2), while 18.3% of people were obese (BMI > 30 kg/m2) (38, 52). Furthermore, an
increase in proportion of overweight and obese children aged 719 years has also been
observed (52).

Corresponding author: Nela Puka

Institute of Histology and Embryology, Faculty of Medicine
Viegradska 26, 11000 Belgrade, Serbia
Phone: +381 11 3607146; Fax: +381 11 3612567; E-mail: nela@dr.com
0231424X/$ 20.00 2014 Akadmiai Kiad, Budapest

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396

Given the complexity and expansion of obesity as well as its relationship with major
chronic conditions (16, 84, 87), the key goal of current research is to ascertain different
factors and their precise roles in mechanisms of appetite regulation, with ultimate goal to
establish an effective obesity therapy.
Important signals in appetite regulation are gut-derived hormones. The aim of this
review is to summarize existing data regarding the most significant brain areas involved in
homeostatic control of appetite and gut hormones mechanisms included in appetite regulation.
Brain areas involved in appetite regulation
The key structure involved in appetite regulation and energy homeostasis is the hypothalamus.
Its main function is to integrate various signals coming from the periphery by vagal afferents
via the nucleus of the solitary tract and by circulation (Fig. 1). Subsequently, these signals
which are further integrated with higher brain centers signals induce specific neuronal
populations to determine instant energy needs, and in return initiate and coordinate appropriate
activities.
21
Higher
brain centers
G
G
P

Cir

VN DMN

Gut
Vagu
DVC
Fig. 1. Pathways
gut hormones
to brain
areasincluded
included ininappetite
regulation.
Fig. 1. Pathways
of gutofhormones
to brain
areas
appetite
regulation.
OXM, oxyntomodulin;
CCK, cholecystokinin;
PYY,
peptide
tyrosine;
pancreatic
polypeptide;
OXM, oxyntomodulin;
CCK, cholecystokinin;
PYY,
peptidetyrosine
tyrosine tyrosine;
PP,PP,
pancreatic
polypeptide;
GLP-1,GLP-1,
glucagon
like peptide-1;
DVC,
vagalcomplex;
complex;
postrema;
NTS, nucleus
tractus solitarii;
glucagon
like peptide-1;
DVC,dorsal
dorsal vagal
AP,AP,
areaarea
postrema;
NTS, nucleus
tractus solitarii;
DVN, dorsal
vagal nucleus; ARC, arcuate nucleus; PVN, paraventricular nucleus; VMN, ventromedial nucleus;
DVN, dorsal vagal nucleus; ARC, arcuate nucleus; PVN, paraventricular nucleus; VMN, ventromedial nucleus;
LHA, lateral hypothalamic area. Arrows indicate direction of connections
LHA, lateral hypothalamic area. Arrows indicate direction of connections

Hypothalamus
For a number of years, two hypothalamic regions, ventromedial hypothalamus (VMH) and
lateral hypothalamic area (LHA), were considered to be main structures involved in appetite
regulation. It was based on evidences that lesions of VMH induce hyperphagia and obesity
(46), while the destruction of LHA causes decrease in food intake, even aphagia (2). These
original experiments were the starting point for dual center model: VMH a satiety center
and LHA a feeding center. However, following studies confirmed their important function
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in appetite regulation and reported additional evidence that other areas of hypothalamus, as
well as other neuronal populations within the brainstem, together with the cerebral cortex and
the limbic system are involved in control of hunger and satiety (86, 93, 99, 100, 108).
A major component of the hypothalamus maintaining the energy homeostasis is the
arcuate nucleus (ARC), whose ventromedial part together with the median eminence
represents one of the circumventricular organs (19, 102). Neurons in ARC which co-express
neuropeptide Y (NPY) and agouti-related protein (AgRP) represent orexigenic neurons
whose activation strongly increases feeding (14, 44, 59, 64). Signals from the periphery reach
the ARC, and some of them (such as ghrelin or low glucose level) stimulate NPY/AgRP
neurons, while others (such as leptin or insulin) inhibit their activity (59). Second important
cell population in the ARC with opposite effect is proopiomelanocortin (POMC), as well as
cocaine- and amphetamine-related transcript (CART) peptide expressing neuronal
populations. These neurons have anorexigenic effect on feeding behavior and are activated
by anorexigenic signals, such as leptin or insulin (21, 22, 34, 65) and inhibited by ghrelin
(112). Peptides derived from the POMC act as endogenous ligands for the melanocortin-4
receptor (MC4R) and melanocortin-3 receptor (MC3R) (81, 91). The most significant product
of POMC is the -melanocyte stimulating hormone (-MSH), which binds to MC4R and
MC3R, and activates catabolic pathways, inducing decrease in food intake and increase in
energy expenditure (50). On the other hand, AgRP acts as a MC4R antagonist (83).
Paraventricular nucleus (PVN) receives projections from ARC and other hypothalamic
nuclei and expresses peptides with predominant catabolic effect. The study of Leibowitz and
coworkers (67) demonstrated the development of hyperphagia and obesity after lesion of
PVN. On the other hand, NPY from the ARC released in the PVN stimulates feeding (54).
Dorsomedial nucleus (DMN) receives inputs from the ARC via NPY/AgRP neurons and
from the nucleus of the solitary tract and has an important role in ingestive behavior (99,
100). Its destruction causes hyperphagia and obesity (12).
The dorsal vagal complex
The dorsal vagal complex is the structure in the brainstem composed of three regions: the
nucleus of the solitary tract (NTS), the area postrema (AP) and the dorsal vagal nucleus
(DVN). The NTS receives signals from gastrointestinal tract and sends them towards higher
brain centers, and therefore it is considered as a relay center in the brainstem. Second way of
getting information is through direct connection with AP, another circumventricular organ,
capable to detect circulating hormones and nutrients. Beside this, NTS is able to partially
integrate and process received information input (43). This nucleus, reciprocally connected
with the hypothalamus, sends projections to the amygdala and in addition, it is rich in
neurotransmitters and neuropeptides with (an)orexigenic influence (93, 94, 99, 100, 101).
The amygdaloid complex
The amygdaloid complex (AC), an integral part of the limbic system, receives taste signals
from the periphery via/from the NTS and has intensive reciprocal connections with the
hypothalamus, especially to its lateral area and extensive connections with other brain areas
involved in appetite regulation as well (13, 89, 127). Neurons in AC express several
neuropeptides and receptors involved in appetite regulation (13, 92, 95, 96). Also, lesion of
the basolateral nucleus of amygdala induces hyperphagia and hyperdipsia, while lesions of
the central nucleus induce opposite effects, hypophagia and hypodipsia (37). Based on
previous research it is assumed that the AC acts as a regulator in both hunger and satiety by
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modulating those mechanisms in the hypothalamus. However, recent data showed that
projections from parabrachial nucleus to the central nucleus of the AC, activated by anorectic
hormone CCK or amylin, mediate suppression of appetite (15).
Gut hormones involved in appetite regulation
While eating process is mostly driven by reward, food consumption and body mass are under
control of homeostatic mechanisms (68). Gut derived hormones, along with those released
from adipose tissue are key elements when considering homeostatic control. These hormones
represent a group of more than 20 different peptides involved in regulation of food intake and
energy expenditure. They are produced in enteroendocrine cells, abundantly distributed in
gastrointestinal mucosa with very important roles in controlling digestion, appetite, gut
motility, and metabolism (82). Enteroendocrine cells are capable of sensing content inside
the gastrointestinal tract such are lipids, carbohydrates, amino acids, small peptides or
proteins, including bile components involved in emulsification and digestion of lipids.
Anumber of different sensors located on the apical surface of enteroendocrine cells have
been established. Among them are various G-protein coupled receptors, atypical protein
kinase C, calcium sensing receptors, but some of them are still undefined. Final result of
receptor activation or nutrients uptake is release of hormones from basolateral secretory
vesicles. Among gut hormones, ghrelin is the only one with orexigenic effect, while all others
belong to group of hormones with anorexigenic acting. Gut derived hormones may influence
food intake and energy expenditure directly from the blood stream, through brain areas
lacking in blood-brain barrier, or indirectly by vagal afferent neurons, taking part in shortterm regulation of hunger and satiety (105). On the other hand, peripheral adiposity signals
have a role in long-term appetite regulation (118). In this regard, the most significant
hormones are leptin and insulin. Levels of these hormones reflect the status of energy stores
in organism. Both, leptin and insulin activate anorexigenic neurons in the ARC, leading to
decrease in food intake and energy expenditure. Leptin is the peptide secreted primarily from
the adipose tissue. Its secretion is pulasatile, and after releasing it binds to ObR receptor,
widely distributed in CNS, particularly in ARC of hypothalamus. This process initiates
activation of different signal pathways which mediate leptin acting, in both feeding and
satiety center (85). Insulin is produced in pancreatic -cells, and released after meal. It binds
to insulin receptors in crucial brain structures involved in appetite regulation exerting its
anorexigenic effect. All of these signals coming from periphery are being integrated with
those from CNS regions in key brain structures involved in control of feeding behavior:
hypothalamus and brainstem.
Ghrelin
Ghrelin is a 28 amino acid peptide produced in endocrine cells of the stomach (60). Ghrelinproducing cells have been identified also in the pancreatic islets, intestine, kidney, placenta,
lung, testis and ovary, as well as in the ARC (30). It is the only gut-derived orexigenic
hormone, inducing an increase in food intake and body weight. Many studies suggest that
ghrelin is involved in meal initiation. The release of ghrelin is pulsatile, and dependent on
food intake. It is the highest before meals and rapidly decreases after food intake (25). The
level of ghrelin is the highest during fasting, while the long-term increased levels are found
in individuals who had a loss in body weight. Concentration of this hormone is low in obese
people. Gastric bypass is also associated with noticeably suppressed ghrelin levels, possibly
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taking part in the weight-reducing effect after this surgical procedure (26). Both peripheral
and central administration of ghrelin enhances the c-fos expression in brain regions involved
in appetite regulation, including NPY/AgRP neurons in ARC, neurons in PVN and DMN as
well as neurons of NTS and AP in the brainstem (47, 66, 104). Ghrelin stimulates NPY, AgRP
and orexin neurons, mainly in the ARC of the hypothalamus, presumably through the
modulation of the mTORC1/S6K1 pathway (117). New data also indicate that ghrelin exerts
its orexigenic action through the regulation of hypothalamic carnitine palmitoyltransferase
1A (CPT1C) and ceramide metabolism (98). In contrast, ghrelin inhibits neuronal populations
with anorexigenic effect, such as POMC and corticotropin-releasing hormone (CRH) neurons
(23). These effects are mediated by growth hormone secretagogue receptor (GHS-R) (6) and
it is generally acknowledged that ghrelin targets POMC neuronal population via GHS-R-1a
expressing presynaptic NPY neurons (103). Nevertheless, a recent study clearly suggests that
POMC neurons may be a direct target for ghrelin (107).
Cholecystokinin
Cholecystokinin (CCK) is a gut hormone generated from pro-CCK by posttranslational
modification. It is co-expressed with PYY, and acts as an anorexigenic peptide, inducing
decrease in food intake and body weight and increase in perception of fullness (58, 69, 78).
Furthermore, CCK regulates gastric emptying, gall bladder contraction and pancreatic
enzyme release (33, 110). Studies have shown that CCK is one of the factors responsible for
meal termination (40). This peptide is released after meal from the enteroendocrine cells in
duodenum and upper small intestine (90). Stimulus for its release is the presence of proteinand fat-rich food (70). The circulatory half-life of CCK is several minutes, while its levels are
increased after meal and reduced during fasting. After peripheral administration of CCK in
rodents there is evident dose dependent decrease in food intake and decrease in meal size, but
at the same time there is an apparent reduction in locomotor activity which usually follows
fasting period (3). There have been two types of CCK receptors isolated so far, CCK1 and
CCK2 (80). The majority of CCK anorexigenic effect is accomplished through CCK1 subtype
receptor on vagal afferent fibers (11). In addition, this subtype is widely distributed on the
periphery and brain areas that influence feeding behavior. Moreover, a study by Little et al.
provided new information about the role of CCK and CCK-1 receptor in brain reaction to
glucose (73). Namely, this research has shown lessening of blood oxygenation leveldependent (BOLD) signal, which is CCK1-receptor independent in the hypothalamus and
brainstem, the key brain areas regulating feeding behavior. Otherwise, a CCK1-receptor
dependent raise of BOLD signal has been observed in motor cortex (73).
Peptide tyrosine tyrosine
Peptide tyrosine tyrosine (PYY) belongs to a PP-fold family of proteins, which has PP fold
structural motifs. Pancreatic peptide and NPY are also clustered in this group, and all of them
act via NPY receptors (71). This peptide is produced in the endocrine cells of the distal ileum,
colon, and rectum in response to the nutrient intake. The most important stimulus for PYY
release in rodents is protein ingestion (9). In healthy humans, high protein food meals increase
circulating concentrations of PYY, more than meals rich in carbohydrate or fat (124).
However, in obese people low-carbohydrate, high-fat diet was shown to give the highest
levels of PYY (35). Nevertheless, recent results indicate that PYY levels start to rise within
about 15 minutes of any caloric ingestion (39), before the nutrients reach distal parts of the
gut, possibly suggesting some other neural or hormonal mechanisms for its release. There are
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two circulating forms of PYY: PYY336, the predominant form, and PYY136 (41). The effects
of the predominant form are mostly achieved through binding to Y2 receptors (56). This
receptor is widely expressed in various brain regions, such as the brainstem areas, nucleus
accumbens, amygdala, hypothalamus, hippocampus (116) and it has been shown that
peripheral administration of the Y2 receptor agonist PYY3 36 in rodents, induces neuronal
activation in multiple brain regions (115). The role of PYY in appetite regulation is
anorexigenic: its peripheral administration reduces appetite, food intake and subsequently
body weight (18, 125). Also, in humans, PYY336 enhances energy expenditure (114). In
addition, there is evidence that PYY reduces food intake and body weight by influencing the
ARC of the hypothalamus (8). It is also believed that PYY delays gastric emptying in mice
(120) and increases water and electrolyte absorption in the colon of dogs (74). Hence, plasma
levels of PYY are the lowest during fasting, and rise after food intake.
Oxyntomodulin
Oxyntomodulin (OXM) is a 37 amino-acid anorexigenic peptide hormone, derived from
preproglucagon, and cosecreted with GLP-1 from the enteroendocrine cells in response to a
meal (122). Administration of OXM has been shown to inhibit food intake and body weight
gain in rodents (27). Central administration of chicken OXM suppresses food intake and
increases plasma concentrations of glucose and corticosterone in chicks (49). Also,
subcutaneous or intravenous administration in human reduces food intake (20). Therefore,
this hormone is considered as a satiety signal. In overweight and obese people OXM increases
energy expenditure and decreases energy intake (126). Some studies have demonstrated that
OXM acts primarily in the hypothalamic ARC (32), by increasing -MSH, which afterwards
acts via melanocortin receptors as well as by increasing c-fos expression (28). It acts via
GLP-1 and glucagon receptors (105). However, it is believed that majority of OXM acting is
mediated by GLP-1 receptor (5), since co-administration of a GLP-1 receptor antagonist
blocks the anorectic actions of OXM (27). Comparing to GLP-1 peptide, although OXM has
weak affinity for this receptor, it is similarly potent as a GLP-1 in exerting its effects mediated
by GLP-1 receptor. New data suggest that chronic body weight-lowering effects of OXM
involve not just the activation of GLP-1 receptor, but also the activation of glucagon receptor
(GCGR) (63). Oxyntomodulin also mimics many of the actions of GLP-1, including inhibitory
effect on gastric acid secretion and gut motility (76).
Pancreatic polypeptide
Pancreatic polypeptide (PP) belongs to PP-fold family. This peptide is released from PP
cells of endocrine pancreas, also in colon, in response to ingestion of food, but its secretion
in addition is regulated by the vagal cholinergic mechanism (1, 109). The levels of PP fall
during fasting, and rise after meal in proportion to the caloric load, remaining elevated for up
to 6 hours (1). Data indicate that PP decreases food intake after peripheral administration in
humans and rodents (10, 77). Furthermore, PP stimulates energy expenditure and subsequently
induces a state of negative energy balance (4). Anorexigenic acting of PP peptide is mediated
by NPY Y4 receptor subtype expressed in ARC, PVN, AP, NTS and DVN (7, 111). In Y4
receptor knockout mice, i.p. injection of PP was unable to induce ARC c-fos activation (72),
emphasizing the importance of this receptor. In the study by Yulyaningsih et al. (128), it has
been observed that PP exerts its effects in regulation of feeding behavior via NPY6 receptors
in mice. Reduced expression of orexigenic peptides, NPY, ghrelin and orexin in the
hypothalamus after peripheral administration of PP indicates a central mechanism of action
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and hypothalamus involvement (4). Bearing in mind the results from vagotomised animals,
that indicate abolished appetite reduction after PP application, it can be concluded that this
peptide exhibits its effects via vagus nerve and the brainstem, too (4). Recent study has
demonstrated that PP directly interacts with PYY and induces Ca2+ signaling in the nodose
ganglion neurons of the vagal afferent nerves of mouse, which suggests that the effect of PP
on nodose ganglion neurons may be implicated in suppression of feeding (53). New data
have also shown that short-term exercise training increases postprandial PP concentrations in
obese people (55), but there was no difference in postprandial secretion of PP after a liquid
meal intake, between aerobically trained and untrained healthy males with sedentary lifestyle
(75). In addition, inhibitory effects on gall bladder motility and secretion of pancreatic juice
have been reported in humans (42).
Glucagon like peptide-1
Glucagon like peptide-1 (GLP-1) is a preproglucagon derived hormone produced by
endocrine cells of the gastrointestinal tract, mainly as a result of glucose ingestion (45). There
are two identified forms of GLP-1: GLP-1737 and GLP-1736 amide. Circulating
concentrations of GLP-1 are low during fasting period, and rise after meal. Also, the level of
GLP-1 may rise in anticipation of a meal (123). New data show that in healthy individuals,
high protein food meals, increase circulating concentrations of GLP-1, more than meals rich
in carbohydrate or fat (124). Acute administration of GLP-1, peripheral or central, reduces
food intake (121), and chronic administration decreases weight gain (79). In addition, GLP-1
reduces gastric motility and inhibits gastric acid secretion. Its effects are mediated by GLP-1
receptor, localized in the pancreas and many other tissues and organs: kidney, lung, heart,
gastrointestinal tract, arteries and arterioles and CNS (62, 97). It has been shown that GLP-1
achieves its effects centrally, through ARC, PVN and supraoptic nucleus of the hypothalamus
(113), but in part by vagus nerve and the brainstem (51). After releasing from GLP-1
producing cells, it is rapidly degraded by dipeptidyl peptidase IV (DPPIV), as well as
oxyntomodulin, resulting in short plasma half-life (105). Besides the appetite regulation, the
main task of GLP-1 is regulation of blood glucose level. It is achieved by increasing insulin
(36) and inhibiting glucagon secretion (61), acting as an incretin and potent insulin
secretagogue (31). In patients with type 2 diabetes, GLP-1 secretion is diminished and
therefore it is considered as a possible cause of decreased insulin secretion (57). Also, GLP-1
delays gastric emptying, and decreases appetite and food intake (48). Moreover, GLP-1 is
currently the most successful gut hormone to be exploited for therapeutic purposes in humans.
It is used for treatment of type 2 diabetes because of its incretin effect (122).
Endocannabinoids
Beside gut hormones, members of the endogenous endocannabinoide system are also found
in the gastrointestinal tract. Main endocannabinoids included in appetite regulation are
anandamide (arachidononyl ethanolamide) and 2-AG (2-arachidononyl glycerol). These
chemical compounds act as endogenous agonists on two types of G-protein-coupled receptors:
cannabinoid CB1 and CB2 receptors, that are also expressed in gastrointestinal tract, mainly
in the enteric nervous system but in the epithelium too (88, 106). Activation of CB1 receptors
plays a role in controlling many gastrointestinal functions, such as motility and gastric acid
secretion, while activation of CB2 receptors has an important role in immune system
functioning (106). Studies have shown that central administration of endocannabinoids in
crucial brain areas involved in control of feeding behavior (hypothalamus or nucleus
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accumbens), activates CB1 and causes stimulation of food consumption (29). On the other
hand, blockade of these receptors has anorectic effects on appetite (29). In addition, members
of the endocannabinoid family provide neuromodulatory control of orexigenic and
anorexigenic transmission (24). Also, it has been observed that this regulation is changed
during the state of obesity because of influence of leptin on restructuring glutamatergic and
GABAergic synapses (24). In some studies it has been shown that CB1 is present on vagal
afferent fibers, mediating transmission of orexigenic signals to the central brain areas
controlling hunger and satiety (119). Consequently, levels of anandamide and 2-AG are high
during fasting periods, and low after food intake. Changes in concentrations of
endocannabinoids are mostly influenced by leptin and ghrelin, hormones with key roles in
regulation of food intake and energy expenditure. In addition, it is believed that these changes
have a major task in control of releasing the most important peptides and neurotransmitters
in appetite regulation (29).
Conclusion
Gut hormones, along with pancreatic peptides and adipose tissue hormones have fundamental
role in appetite regulation by influencing activity of key brain areas involved in food behavior,
reaching them directly from the blood stream or via vagus nerve. The crucial issue when
considering gut derived peptides is their potential role in clinical therapy. According to this,
fundamental task is discovering long lasting gut peptides or their analogues, with no or
minimal side effects in order to provide effective treatment of obesity.
Acknowledgement
This work was supported by the Ministry of Science and Development of the Republic of Serbia (grant No. 175061
and 175087).

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