REVIEW

CURRENT
OPINION Cholecystokinin
Graham J. Dockray

Purpose of review
Cholecystokinin (CCK) controls nutrient delivery to the small intestine by inhibiting food intake and gastric
emptying. This review deals with recent work shedding new light on how and when.
Recent findings
Intestinal I-cells release CCK in response to dietary lipid and protein through mechanisms involving the
G-protein-coupled receptors GPR40 and calcium-sensing receptor. Vagal afferent neurons are a primary
target of CCK and are now recognized as an important site of integration of peripheral signals regulating
ingestion. In addition to regulating vagal afferent nerve discharge, CCK also controls the expression of
receptors and peptide neurotransmitters by these neurons; these actions are potentiated by leptin and
inhibited by ghrelin. The responses of vagal afferent neurons to CCK are attenuated in obesity. Studies of
human central nervous system responses using functional magnetic resonance imaging indicate activation
of brainstem, hypothalamus and motor cortex by ingested fatty acid that is inhibited by a CCK-1 receptor
antagonist. CCK may also play a role in adaptive responses in pancreatic islets by maintaining b-cell mass
and acting as an incretin in certain circumstances.
Summary
CCK mediates inhibition of food intake in response to ingested lipid and protein; resistance to CCK occurs
in obesity and may contribute to altered mechanisms regulating food intake.
Keywords
I-cell, obesity, satiety, vagal afferent neurons

INTRODUCTION smooth muscle, but vagal afferent neurons are an

Ingestion of food activates a neuro-endocrine pro-
gram directed at matching delivery of nutrients to
the small intestine with the capacity for their diges-
tion, absorption and assimilation. The program
includes sensing mechanisms for nutrients and ot-
her food components in the gut, signalling to the
central nervous system to regulate ingestive behav-
iour and autonomic efferent pathways, control of
secretion by the stomach and pancreas, gallbladder
contraction, control of nutrient mixing and pro-
gression along the gut by changes in motility and
signalling to the endocrine pancreas to activate
hormonal mechanisms regulating nutrient utiliz-
ation. An impressive diversity of humoral mediators
has been implicated in these events and there are
many examples of overlapping functions. In recent
years, however, cholecystokinin (CCK) has emerged
as an important integrator of upper small intestinal
function that acts by inhibiting food intake and
gastric emptying and by stimulating pancreatic
enzyme secretion and gallbladder contraction. It
is well established that there are direct effects of
CCK on pancreatic acinar cells and gallbladder
important target for control of food intake and
gastric emptying. In the last year or so, progress
has been made in understanding the mechanisms
of CCK release, its actions on vagal afferent neurons
and the changes in signalling that occur in obesity.
Several recent reviews have dealt with different
aspects of the biology of this system [1–5].
RELEASE MECHANISMS
Fatty acids and protein in the small intestine have
been recognized for over 60 years to stimulate CCK
release, probably by acting directly on intestinal
Physiological Laboratory, Institute of Translational Medicine, University of
Liverpool, Liverpool, UK
Correspondence to Graham J. Dockray, Physiological Laboratory, Insti-
tute of Translational Medicine, University of Liverpool, Crown Street, P.O.
Box 147, Liverpool L69 3BX, UK. Tel: +44 151 794 5324;
e-mail: g.j.dockray@liverpool.ac.uk
Curr Opin Endocrinol Diabetes Obes 2012, 19:8–12
DOI:10.1097/MED.0b013e32834eb77d

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Number 1
February 2012

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

KEY POINTS

CCK is released by long-chain fatty acids and aromatic
amino acids via GPR40 and calcium-sensing receptor.

fMRI studies in humans indicate that ingestion of lipid
activates hypothalamus and brain stem mainly by
release of CCK.

Vagal afferent neurons are a key target of CCK which
stimulates expression in these neurons of cocaine and
amphetamine regulated transcript protein (CARTp) and
Y2 receptors and inhibits expression of melanin
concentrating hormone and cannabinoid receptor-1
(CB1) receptors.

Leptin potentiates the action of CCK on vagal afferent
neurons; resistance to CCK and leptin in these neurons
is an early feature of diet-induced obesity.

Studies in mice null for CCK or the CCK-1 receptor
reveal novel roles in adaptive mechanisms in the islets
of Langerhans and in vagal afferent signalling.
I-cells. The cellular mechanisms are now becoming
clearer. The availability of transgenic mice express-
ing green fluorescent protein (GFP) under the con-
trol of the CCK gene promoter has facilitated the
preparation of highly enriched populations of CCK-
expressing I-cells using fluorescence-activated cell
sorting. This approach has identified expression in
I-cells of GPR40 which is a G-protein-coupled recep-
tor responding to long-chain fatty acids. Agonists of
GPR40 such as linoleic acid increased intracellular
calcium and CCK release in GFP-labelled cells,
whereas in cells prepared from GPR40/ mice both
responses were inhibited; moreover, in vivo, the
increase in CCK secretion in response to olive oil
was reduced by about 40% in GPR40/ mice [6 ]. A
&
similar approach has indicated a role for the extra-
cellular calcium-sensing receptor (CaSR) in media-
ting the effect of aromatic amino acids on CCK
release. Two groups have identified CaSR expression
in GFP-labelled I-cells, and have shown that aro-
matic amino acids stimulate intracellular calcium
fluxes via a CaSR-dependent mechanism [7,8]. In
addition, the release of CCK in response to a pep-
tone meal was reduced in CaSR-null cells [7].
The role of CCK in mediating the effects of
ingested carbohydrate remains uncertain. The sweet
taste receptors, T1R2/T1R3, are poorly expressed by
I-cells, although there is strong expression in other
entero-endocrine cells, notably the L-cells that
secrete glucagon-like peptide (GLP)-1 and peptide
tyrosine tyrosine (PYY). Consistent with this, the
T1R2/T1R3 inhibitor lactisole reduced glucose-
stimulated GLP-1 and PYY secretion in humans,
but had no effect on CCK release [9]. Even so, the
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Cholecystokinin Dockray
inhibition of gastric emptying by several hexoses
was reduced by a CCK-1 receptor antagonist,
suggesting a role for CCK in carbohydrate regulation
of gastric motility, perhaps by providing a back-
ground tone of vagal afferent stimulation [10].
NEURAL ACTIONS OF CHOLECYSTOKININ
There has been recent progress in elucidating the
actions of CCK both on the human brain and on
vagal, brain stem and hypothalamic neurons in
experimental animals.
Human central nervous system responses to
cholecystokinin
Elucidation of the mechanisms underlying central
nervous system (CNS) responses to circulating CCK
has been the subject of intense interest. Studies over
many years have contributed to the idea that CCK
released from the small intestine acts directly on
vagal afferent neurons that terminate in the nucleus
tractus solitarius (NTS) and activate ascending path-
ways that control ingestive behaviour. The matrix of
human CNS responses to endogenous CCK has now
been characterized by functional magnetic resonance
imaging (fMRI) following intragastric administration
of dodecanoate with or without the CCK-1 receptor
&&
antagonist, dexloxiglumide [11 ]. In response to a
relatively low dose of dodecanoate, there was acti-
vation of the brainstem and hypothalamus, and also
of the motor cortex; the responses were virtually
abolished by dexloxiglumide, indicating the import-
ance of CCK as a mediator of human CNS responses to
ingested fatty acids.
Vagal responses
The CCK-1 receptor mediates the action of CCK in
stimulating the discharge of vagal afferent neurons
and increasing intracellular calcium concentrations.
Vagal afferent neurons serving both the stomach
and small intestine are activated by CCK, but their
relative roles have been unclear. Recordings of
different populations of vagal afferent and efferent
nerve fibres serving the proximal and distal parts of
the rat stomach and small intestine support the idea
that CCK acts initially on intestinal afferent fibres,
probably via a paracrine mechanism, to inhibit an
excitatory vagal efferent pathway to the distal
stomach; subsequently, there is stimulation of gas-
tric vagal afferents, corresponding to a hormonal
effect, that is coupled to stimulation of an inhibitory
vagal efferent pathway to the proximal stomach
&&
[12 ]. Reflex control of gastric emptying by CCK
activation of vagovagal reflexes may, therefore,
www.co-endocrinology.com 9
 Growth and development
reflect sequential paracrine and then hormonal
activation of different afferent pathways that are
coupled to vagal efferent pathways controlling dis-
tal and proximal gastric motility, respectively.
Nodose ganglion neurons that express CCK-1
receptors also express several ion channels of the
transient receptor potential (TRP) class including
TRPV1–5. Ruthenium red which is an inhibitor of
this family of ion channels blocked CCK-induced
depolarization and increased intracellular calcium
in cultured rat nodose ganglion neurons, but a
specific TRPV1 inhibitor (SB366791) had little effect,
suggesting that TRPV2–5 might be important in
mediating the effects of CCK on nodose neurons
[13]. Several actions of CCK on rat vagal afferent
neurons are potentiated by leptin, and it seems
possible that interactions between Src and PI-3
kinase downstream of the CCK-1 receptor, and
STAT3 phosphorylation downstream of leptin
receptor targeted by leptin, act to regulate neuronal
excitation through closure of Kþ channels [14].
Cholecystokinin actions on brain stem
neurons
Recordings of miniature excitatory postsynaptic
currents in neurons of the centralis division of the
rat NTS indicate a glutaminergic input from vagal
afferent neurons. About 30% of neurons respond to
CCK and all of these also respond to the vanilloid
agonist capsaicin. Both responses are substantially
reduced by chemical lesioning of small diameter
afferent fibres using perivagal capsaicin [15] com-
patible with work over many years, indicating that
CCK inhibition of food intake and gastric emptying
is mediated by capsaicin-sensitive vagal afferent
neurons. Injection of N-methyl D-aspartate (NMDA)
receptor antagonists (MK-801, D-CPPene) into the
fourth ventricle, or directly into the NTS, inhibited
the effect of CCK on food intake, indicating a role
for brainstem NMDA receptors in mediating the
responses to intraperitoneal CCK [16].
Hypothalamic responses to peripheral
cholecystokinin
Peripheral administration of CCK (intraperitoneally)
stimulates neurons in the paraventricular nucleus
(PVN) of the hypothalamus. The PVN neurons acti-
vated by CCK express cocaine and amphetamine
regulated transcript (CART) and phosphor-mamma-
lian target of rapamycin [17,18]. When given alone,
CCK does not increase fos labelling in the arcuate
nucleus; however CARTp intracerebroventricularlly
stimulates fos labelling in the arcuate and CCK (intra-
peritoneally) augments this response [19]. Curiously,
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leptin is reported to suppress fos labelling in PVN,
and also supra optic nucleus, in response to CCK
(intraperitoneally), whereas there is no difference
in NTS labelling [20]; thus, although leptin and
CCK may interact positively at the level of vagal
afferent neurons, there may also be other – possibly
direct – actions of leptin on hypothalamic neurons
that modulate the response to CCK.
Cholecystokinin and vagal afferent plasticity
The vagal afferent neurons expressing CCK-1 recep-
tors exhibit plasticity in their neurochemical pheno-
type depending on nutrient status. Both acute and
chronic changes have been described. In the rat,
acute withdrawal of food over a period of 6 h or longer
induces expression in nodose ganglion neurons of
the neuropeptide transmitter melanin concentrating
hormone and of CB1 receptors (both associated
with orexigenic signalling), whereas there is reduced
expression of the putative satiety neuropeptide
CARTp and of a population of Y2 receptors [3,21].
Both exogenous and endogenous CCK reversed these
changes through mechanisms dependent on CCK-1
receptor activation. Recent work suggests co-operat-
ive interactions between CCK and leptin to control
transmitter and receptor expression in these neurons.
Thus, expression of CART is mediated by a CCK–
leptin interaction involving the transcription factor
& &
early growth response (EGR)-1 [22 ,23 ]. In unstimu-
lated vagal afferent neurons, EGR-1 is localized to the
cytosol but in response to CCK there is nuclear trans-
location which is strongly potentiated by leptin,
although leptin alone has no effect. Interestingly,
however, leptin strongly stimulates EGR-1 expres-
sion, whereas CCK has little or no effect on EGR-1
expression. It seems, then, that leptin determines the
magnitude of CCK stimulation of CART expression
by controlling EGR-1 abundance. There remains
some controversy over whether or not the gastric
orexigenic hormone, ghrelin, inhibits CCK stimu-
lation of vagal afferent discharge [24,25]; neverthe-
less, there is clear evidence that in rat nodose
ganglion neurons, ghrelin inhibits leptin stimulation
of EGR-1 expression at least in part by preventing
STAT3 relocation to the nucleus and it also inhibits
CCK stimulation of CART expression by preventing
&
nuclear relocation of EGR-1 [23 ].
CHOLECYSTOKININ AND GUT–BRAIN
SIGNALLING IN OBESITY
The satiety effect of CCK is attenuated in obesity; this
is accompanied by decreased activation of NTS
neurons (compatible with decreased stimulation
by vagal afferent neurons) [4]. There may also be
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attenuated splanchnic sympathetic nerve discharge
with implications for vasomotor control [26]. The
mechanisms have been uncertain, but direct studies
of vagal afferent neuron responses to CCK have now
shown in obese mice (high-fat diet for 8–10 weeks,
60% calories as fat) that there is reduced stimulation
of jejunal afferent fibres by CCK and 5-hydroxytryp-
tamine, reduced mechanosensitivity of low-
threshold jejunal afferent fibres, reduced excitability
of nodose ganglion neurons including those projec-
ting to the small intestine and decreased numbers of
nodose neurons showing increased intracellular
&&
calcium in response to CCK [27 ]. Insensitivity of
vagal afferent neurons to CCK would, therefore,
appear to account for the reduced satiety effect of
CCK in obesity. Resistance to leptin also develops in
vagal afferent neurons in obesity, and interestingly
this occurs earlier than in CNS neurons [28]. The
relationship between loss of responsiveness to CCK
and to leptin in obesity remains to be elucidated.
However, in CCK-1 receptor-null mice placed on a
high-fat diet, a short fast leads to decreased time to the
first meal on reintroduction of food and this increased
drive to eat is mediated by ghrelin; moreover, a ghre-
lin receptor antagonist, D-(Lys3)-growth hormone
releasing peptide-6 increased expression of CART in
vagal afferent neurons of CCK-1-null mice on a high-
fat diet (but not wild-type mice). The data suggest that
the combination of a high-fat diet and loss of CCK-1
receptors leads to increased ghrelin stimulation of
food intake in part by suppressing the expression of
a putative satiety peptide (CART) in vagal afferent
neurons [29].
Mice null for CCK appear to be resistant to diet-
induced obesity. Thus, CCK/ mice on a high-fat
diet for 10 weeks exhibit reduced gain in body
weight compared with wild type and reduced adi-
posity [30]. Although food intake was similar, the
phenotype may reflect lower energy extraction, as
there were defects in fat absorption. However,
energy expenditure was also higher in the CCK/
mice and there was greater oxidation of carbo-
hydrates on the high-fat diet, suggesting CCK is
involved in metabolic regulation, as well as lipid
absorption, in response to high-fat diets.
ENTEROINSULAR AXIS
The role of CCK as an insulin-releasing hormone,
that is, incretin, has generally been considered to be
of minor significance compared with other intesti-
nal hormones such as GLP-1 and glucose-dependent
insulin releasing peptide. However, in the islets of
obese mice (ob/ob on a C57Bl/6 background), there
is upregulation of CCK gene expression. Moreover,
in CCK/ mice bred onto an ob/ob background,
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Cholecystokinin Dockray
there is decreased islet cell size and b-cell mass,
suggesting a role for CCK in maintaining islet mass
[31]. Interestingly, mice null for both glucagon
and GLP-1 receptors (Gcgr//Glp1r/) exhibit
increased expression of CCK-1 receptors in islets,
and increased sensitivity to CCK for insulin release
[32]. Together, these studies indicate that CCK
either hormonally or as a paracrine/autocrine factor
might play a role in mediating compensatory mech-
anisms within the islets of Langerhans.
CONCLUSION
The release of CCK by intestinal I-cells in response to
fatty acids and amino acids involves two G-protein-
coupled receptors: GPR40 and CaSR, respectively.
Local release of CCK acts in a paracrine manner to
stimulate vagal afferent neurons, and subsequently
rising concentrations in the blood are associated with
hormonal stimulation of vagal afferent fibres to the
stomach. The stimulation of vagal afferent neurons is
associated with acute inhibition of food intake and
gastric emptying and, over a period of a few hours,
with changes in receptor and neuropeptide trans-
mitter expression in these neurons. Ghrelin inhibits,
and leptin potentiates, many of these effects. The
human CNS responses to ingestion of lipid are largely
mediated by release of CCK. In obesity, vagal afferent
neurons exhibit resistance to the effect of CCK, appa-
rently due to decreased electrical excitability.
Acknowledgements
The author’s work in this area has been supported by
grants from the Biotechnology and Biosciences Research
Council and the Wellcome Trust.
Conflicts of interests
There are no conflicts of interest.
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