Regulatory Peptides 155 (2009) 6–10

Contents lists available at ScienceDirect

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

Review

Cholecystokinin and gut–brain signalling

Graham J. Dockray ⁎
Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown St, Liverpool L69 3BX, UK

a r t i c l e i n f o a b s t r a c t

Article history: Enteroendocrine cells of the gastrointestinal tract act as a luminal surveillance system responding to either
Received 23 March 2009 the presence or absence of food in the gut lumen. Collectively, their secretory products regulate the course of
Accepted 25 March 2009 digestion and determine the delivery of nutrient to the gut by controlling food intake. Afferent neurons of the
Available online 2 April 2009
vagus nerve are an important target of gut hormones, particularly for control of food intake. The intestinal
hormone cholecystokinin (CCK) stimulates vagal afferent neuron discharge and also controls the expression
Keywords:
of both G-protein coupled receptors and peptide neurotransmitters in these neurons. When plasma CCK
Cholecystokinin
Vagus concentrations are low, for example in fasting, vagal afferent neurons express cannabinoid CB1 and melanin
Leptin concentrating hormone (MCH)-1 receptors, both of which are associated with stimulation of food intake.
PYY Post-prandial release of CCK rapidly down-regulates the expression of both receptors but stimulates the
Ghrelin expression of Y2 receptors in neurons projecting to the stomach. In fasting, there is also increased expression
Receptors in these neurons of the appetite-stimulating neuropeptide transmitter MCH, and depressed expression of the
Nodose ganglion satiety-peptide cocaine and amphetamine regulated transcript (CART). Secretion of CCK decreases
Satiety expression of MCH and increases expression of CART. The neurochemical phenotype of vagal afferent
Gastric emptying
neurons therefore encodes whether or not there has been nutrient ingestion over the previous period. At low
plasma concentrations of CCK vagal afferent neurons exhibit increased capacity for appetite-stimulation,
while post-prandial concentrations of CCK lead to enhanced capacity for satiety signalling. A gatekeeper
function can therefore be attributed to CCK in that its presence or absence influences the capacity of vagal
afferent neurons to respond to other neurohormonal signals.
© 2009 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2. Integrative role of CCK in upper gastrointestinal tract physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3. The neurochemical phenotype of vagal afferent neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4. The gatekeeper functions of CCK on vagal afferent neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5. Modulating the gatekeeper function of CCK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
6. Overview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

1. Introduction organised functional domains: the stomach, proximal small intestine

An impressive range of humoral factors signal changes in the luminal
environment of the gastrointestinal tract [1]. The peptides and amines of
the enteroendocrine cells (EECs) that act as primary transducers in
luminal surveillance are secreted in response to either the presence, or
absence, of luminal stimuli; they have been intensively studied for over a
century. Taken together they can be thought to function in three loosely
⁎ Tel.: +44 151 794 5324; fax: +44 151 1794 5315.
E-mail address: g.j.dockray@liverpool.ac.uk.
and distal small intestine/colon. In each case, the secretory products of
EECs ensure optimal digestion and absorption by controlling the nature
of the luminal contents through stimulation or inhibition of digestive
secretions, and by regulating the delivery of nutrient along the
alimentary tract. In addition, it is now clear that there are many
different immune modulators that respond to infection and inflamma-
tion in the gut wall and that act on some of the same targets as the
products of EEC secretion. Quite recently, a range of lipid mediators has
emerged that also act as gut signals, these include the cannabinoid (CB)1
agonist anandamide which stimulates food intake and the related

0167-0115/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.regpep.2009.03.015
 G.J. Dockray / Regulatory Peptides 155 (2009) 6–10
Fig. 1. Schematic representation of the neurohumoral factors acting on vagal afferent neurons. Leptin, CCK, PYY3-36 and GLP-1 are associated with stimulation of vagal afferent
pathways leading to inhibition of food intake and, or, gastric emptying. Ghrelin, orexin-A, anandamide and MCH are associated with stimulation of food intake and, or, gastric
emptying; CCK either inhibits expression of their receptors or they inhibit the actions of CCK.
oleylethanolamide which inhibits food intake [2,3]. Exactly how all of
these signalling molecules are integrated is an important issue for
present research.
Nutrient delivery to the small intestine is regulated by varying
the rate of gastric emptying and through control of food intake. In
the latter case, there are inhibitors of food intake from each of the
functional domains mentioned above (stomach: leptin; small
intestine: CCK; ileum/colon: PYY, GLP-1) (Fig. 1) and stimulants
from two of them (stomach: ghrelin; small intestine: anandamide).
The two stimulants are released when the gut is empty and the
inhibitors are directly or indirectly released by luminal nutrients. In
some circumstances gut hormones may act directly on CNS neurons
after delivery in the circulation; however over the last decade or so,
afferent neurons of the vagus nerve have emerged as important
targets of gut hormones, particularly for control of food intake and
gastric emptying. There have been many recent reviews of the
literature on gut hormones and control of food intake [4–7]; the
present account will focus on the relationships between gut
endocrine signals and vagal afferent neurons with a special emphasis
on CCK.
2. Integrative role of CCK in upper gastrointestinal tract physiology
Ingestion of fat or protein rich meals leads to secretion of CCK from
I-type EECs of the upper small intestine. Both in vivo and in cultured
STC1 cells, fatty acids with a chain length greater than 12 carbons are
effective releasers of CCK while those with a chain length b10 C are
largely ineffective [8,9]. In human volunteers, a rise in plasma CCK
concentrations of 3–4 pM can be achieved with modest loads of C12
and is sufficient to inhibit gastric emptying and decrease the intake of
a liquid test meal [10]. In addition to luminal nutrients, it is now clear
that there is also elevated plasma CCK in humans infected with small
intestinal pathogens such as Giardia [11]. Moreover, in a mouse model
of intestinal inflammation due to infection with the nematode Tri-
chinella spiralis, the secretion of CCK was shown to be dependent on
CD4+ T-cells, via the release of IL-4 and IL-13 [12].
The primary actions of CCK are stimulation of pancreatic enzyme
secretion and gall bladder contraction, and inhibition of gastric
emptying and food intake. Collectively, these actions allow optimal
7
digestion of fat and protein in the small intestine by balancing the
capacity to secrete enzyme and bile salt with the delivery of nutrient
substrates. Although there are direct actions of CCK on pancreatic
acinar cells and on gastric smooth muscle cells, it appears that afferent
neurons of the vagus nerve are a target of CCK for reflex stimulation of
pancreatic secretion and inhibition of gastric emptying [13,14]. The
same afferent pathway is thought to mediate the action of CCK in
inhibiting food intake [15]. Many studies have confirmed the
observation of Moran et al. who demonstrated that vagal afferent
neurons express CCK1 (or CCK-A) receptors and that these are
transported towards the periphery [16]. In addition to stimulation of
vagal afferent nerve discharge CCK also controls the expression of both
G-protein coupled receptors and peptide neurotransmitters involved
in controlling food intake thereby regulating the capacity of other
neurohumoral agents to act on this pathway.
3. The neurochemical phenotype of vagal afferent neurons
A wide range of receptors and neuropeptides have been shown to
be expressed by vagal afferent neurons [6,17]. Work by Zhang et al.
established that the neurochemical phenotype of vagal afferent
neurons could be varied depending on experimental treatment.
They showed that vagotomy decreased CCK1 receptor expression
but increased expression of CCK2 (gastrin/CCK-B) and Y2 receptors
[18]; they also showed that vagotomy influenced the expression of
genes encoding the regulatory peptides galanin, NPY, VIP and CCK
itself, which normally exhibit low or moderate levels of expression
[19,20]. Subsequently it has become clear that the neurochemical
phenotype of these neurons exhibits reversible changes in response to
energy restriction.
In rats, withdrawal of food for periods of over 6 h has been shown
to produce changes in both receptor and neuropeptide gene
expression in vagal afferent neurons [21–25]. It is possible to identify
three different patterns of gene expression following manipulation of
energy intake. (a) There are some genes that exhibit broadly similar
levels of expression in nodose ganglion neurons in rats that are fed ad
libitum or fasted up to 48 h (Fig. 2). For example, the expression of
CCK1, orexin type-1 (Ox-R1) and ghrelin receptors (GHS-1) seems not
to be substantially altered with food withdrawal [20,21,26]. (b) Some
8 G.J. Dockray / Regulatory Peptides 155 (2009) 6–10

Fig. 2. Cannabinoid (CB)-1 receptor expression in vagal afferent neurons is increased by energy restriction. A, In situ hybridisation demonstrates expression of CB1 mRNA in neurons
of the nodose ganglion in fasted rats, but not rats fed ad libitum (control). In contrast CCK-1 receptor expression is similar in fasted and fed ad libitum rats. B, Retrograde tracing from
the stomach with True Blue, coupled with double labelling immunohistochemistry indicates that nodose ganglion neurons projecting to the stomach express both CB1 and CCK-1
receptors. Reproduced from Journal of Neuroscience.

genes exhibit increased expression in nodose ganglion neurons in rats
following food withdrawal; examples of this class include the
cannabinoid (CB)1 and melanin concentrating hormone (MCH)1
receptors and MCH itself; each of these is associated with orexigenic
signalling in the CNS. (c) A third group exhibits depressed expression
in fasted rats and is increased by refeeding eg cocaine and
amphetamine regulated transcript (CART) and Y2 receptors both of
which are associated with satiety signalling [21–23,26]. Refeeding of
fasted rats reverses the neurochemical phenotype relatively rapidly
[21–23,25,26]. The neurochemical phenotype of vagal afferent
neurons exhibits, therefore, a simple form of memory by encoding
whether or not there has been nutrient ingestion over the previous
period (Fig. 3).
4. The gatekeeper functions of CCK on vagal afferent neurons
It is well established that CCK stimulates the discharge of vagal
afferent neurons and increases intracellular calcium concentrations
[27–29]. In addition, though, recent work has identified changes in gene
expression dependent on the presence or absence of CCK. Administra-
tion of CCK to fasted rats stimulates expression of CART and Y2
receptors, and inhibits expression of CB1, MCH1 and MCH [21–23,25].
The effects seen with refeeding of fasted rats on expression of CB1,
MCH1 and Y2 receptors, and on the neuropeptides MCH and CART, are
attributable to the action of endogenous CCK since in each case they are
blocked by the administration of a CCK1 receptor antagonist [21–23].
In cultured vagal afferent neurons, the neurochemical plasticity
seen in vivo can be replicated by culturing in media either with or
without fetal calf serum (FCS). For example, in full media (10% FCS)
there is expression of CART but not MCH, while in serum-free medium
there is expression of MCH but not CART [23]. Addition of CCK to
neurons in serum-free medium rapidly restores CART expression and
decreases MCH expression. The action of CCK in stimulating CART
depends on activation of PKC, phosphorylation of CREB and activation
of MAPkinase. The mechanisms of down-regulation are less clear, but
neurons expressing a CREB inhibitor, seem not to demonstrate down-
regulation of MCH suggesting that CREB is on both the stimulatory and
inhibitor pathways downstream of CCK [23].
 G.J. Dockray / Regulatory Peptides 155 (2009) 6–10 9

Fig. 3. The neurochemical phenotype of vagal afferent neurons depends on energy intake. In rats fed ad libitum (right) there is expression of Y2 receptors and the satiety-peptide
CART in vagal afferent neurons projecting to the stomach, but not MCH-1 and CB1 receptors or MCH. After energy restriction for 6–48 h there is progressive up regulation of MCH-1
and CB1 receptors, and MCH, with loss of Y2 receptors and CART; these changes are reversed by refeeding or administration of CCK. The abundance of CCK-1, Ob-r, GHS-1 and Ox-R1
receptors seems to be similar in fed and fasted rats.

The actions of CCK in controlling Y2 receptor expression are
interesting. When rats are fasted there is a progressive loss of
expression of Y2 receptors with a t1/2 of about 12 h. However, even
after 48 h of food withdrawal there is a small population of neurons in
which expression is preserved that amounts to 5–10% of the total
population in the mid and caudal regions of the nodose ganglion.
Studies combining retrograding tracing with immunohistochemistry
have shown that the neurons exhibiting loss of Y2 receptors with food
restriction mostly project to the stomach, whereas the vagal afferent
neurons serving the ileum and colon continue to express these
receptors during food withdrawal. The endogenous ligand of Y2
receptors is PYY3-36 produced by secretion of PYY from EECs
predominantly located in the ileum and colon. The vagal afferent
neurons projecting to these regions are therefore expected to be
exposed to locally high concentrations of PYY3-36, and receptor
activation is not dependent on CCK, while those to the stomach
presumably respond to PYY3-36 delivered as a hormone in the
circulation and signalling is subject to prior stimulation of receptor
expression by CCK. It is worth noting that the action of PYY3-36 both
in delaying gastric emptying and in stimulating fos expression in brain
stem neurons (which is a putative marker of vagal afferent excitation)
is CCK-dependent [25,30]; these observations are therefore consistent
with the role of CCK in controlling Y2 receptor expression in vagal
afferent neurons serving the stomach.
Together, these data indicate that CCK is able to switch the
neurochemical phenotype of vagal afferent neurons between two states.
At low plasma concentrations (through energy restriction), the vagal
afferent pathway exhibits increased capacity for appetite-stimulation,
while post-prandial concentrations of CCK lead to enhanced capacity for
satiety signalling. Thus a gatekeeper function can be ascribed to CCK in
so far as its presence or absence influences the capacity for responding to
other neurohormonal signals.
5. Modulating the gatekeeper function of CCK
The action of CCK in stimulating vagal afferent neuron discharge
and inhibiting food intake is potentiated by gastric distension, leptin
and urocortin [28,29,31–34]. In contrast, orexin-A and ghrelin inhibit
the action of CCK on these neurons [35,36]. During the immediate
post-prandial period when CCK concentrations are rising and ghrelin
concentrations are falling, vagal afferent neurons are exposed to both
and interactions between the two are therefore possible. Although in
principle the peptide obestatin derived from the ghrelin precursor is
also likely to be secreted alongside ghrelin, recent work suggests it has
no effect on CCK-satiety signalling [37]. The action of CCK in down-
regulating CB1, MCH1 and MCH is inhibited by prior administration of
ghrelin [26]; similarly, CCK-stimulated increases in CART and Y2
receptor expression are blocked by ghrelin administration [23]. In
cultured vagal afferent neurons, ghrelin has been shown to act by
excluding phosphoCREB from the nucleus [23]. The cellular mechan-
isms are unknown but merit further study.
6. Overview
Vagal afferent neurons seem able to adopt two states: one
associated with expression of signalling molecules associated with
inhibition of food intake, the other with signalling molecules
associated with stimulation of food intake. These states are deter-
mined by energy intake over the previous day or so. In addition to the
acute actions of CCK on vagal afferent neurons, it seems that there are
10 G.J. Dockray / Regulatory Peptides 155 (2009) 6–10
also longer term effects over hours or even days in which CCK switches
neurons between the two states. Manipulation of these states could
provide a novel therapeutic target for the control of food intake and
the treatment of obesity.
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