Neuropharmacology 63 (2012) 46e56

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Neuropharmacology
journal homepage: www.elsevier.com/locate/neuropharm

Invited review

The role of the gut/brain axis in modulating food intake

Amir H. Sam, Rachel C. Troke, Tricia M. Tan, Gavin A. Bewick*
Section of Investigative Medicine, Imperial College London, London, W12 0NN, UK

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

Article history: Peptide hormones released from the gastrointestinal tract communicate information about the current
Received 4 August 2011 state of energy balance to the brain. These hormones regulate appetite and energy expenditure via the
Received in revised form vagus nerve or by acting on key brain regions implicated in energy homeostasis such as the hypothal-
28 September 2011
amus and brainstem. This review gives an overview of the main gut hormones implicated in the regu-
Accepted 13 October 2011
lation of food intake. Research in this area has provided novel targets for the pharmacological treatment
of obesity.
Keywords:
This article is part of a Special Issue entitled ‘Central Control Food Intake’
Peptide YY (PYY)
Glucagon like peptide-1 (GLP-1)
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Oxyntomodulin
Cholecystokinin
Ghrelin
Obesity

1. Introduction an increased risk of both all cause, and cause-specific mortality

Hormones released from the gut and adipose tissue play an
important role in the regulation of food intake and energy expen-
diture. These hormones may exert their effects both via the vagus
nerve and by acting directly on areas of the brain implicated in the
control of energy homeostasis. Peripheral signals from the gut and
adipose tissue constitute feedback mechanisms allowing mainte-
nance of a steady body weight, despite daily variations in energy
expenditure and nutrient intake.
The role of peripheral hormones and the gut/brain axis in the
regulation of appetite has become an area of interest in recent
years, owing to the growing global obesity crisis. Obesity is
a major worldwide public health problem, with a significant
burden of morbidity and mortality, as well as having substantial
economic consequences. It is an important risk factor for type 2
diabetes, ischaemic heart disease, stroke and cancer, and carries
Abbreviations: AgRP, agouti related peptide; ARC, arcuate nucleus; a-MSH,
alpha-melanocyte stimulating hormone; AP, area postrema; CART, cocaine and
amphetamine regulated transcript; CCK, cholecystokinin; DPP-IV, dipeptidyl
peptidase-4; GLP-1, glucagon like peptide-1; GLP-2, glucagon like peptide-2; NPY,
neuropeptide Y; POMC, pro-opiomelanocortin; NT, neurotensin; NTS, nucleus
tractus solitarius; OEA, Oleoylethanolamine; OXM, oxyntomodulin; PP, pancreatic
polypeptide; PYY, peptide tyrosine tyrosine; PVN, paraventricular nucleus; RYGB,
roux-en-Y gastric bypass; SFO, sub fornical organ; VIP, vasoactive intestinal
polypeptide.
* Corresponding author. Tel.: þ44 2083833086; fax: þ44 2083838320.
E-mail address: g.bewick@imperial.ac.uk (G.A. Bewick).
(Prospective_Studies_Collaboration, 2009; Ringback Weitoft et al.,
2008; Zheng et al., 2011). Peripheral signals controlling satiety
may present potential targets for developing novel anti-obesity
therapies. The focus of this review is to provide a synopsis of the
gut-brain cross talk involved in the regulation of food intake.
2. Neuroendocrine control of appetite (Fig. 1)
The hypothalamus and the brainstem are the main central
nervous system regions responsible for the regulation of energy
homeostasis. These brain areas receive peripheral neural and
hormonal signals that relay information about acute nutritional
state and adiposity (Murphy and Bloom, 2006). Neural afferents and
hormonal signals from the periphery are integrated with higher
brain centre signals (e.g. relaying reward drive and mood) to regu-
late appetite and control energy expenditure (Schwartz et al., 2000).
The arcuate nucleus (ARC) of the hypothalamus is believed to
play a crucial role in the regulation of food intake and energy
homeostasis. The ARC contains two populations of neurons with
opposing effects on food intake (Chaudhri et al., 2008). Medially
located orexigenic neurons (i.e. those stimulating appetite) express
neuropeptide Y (NPY) and Agouti-related protein (AgRP) (Bewick
et al., 2005; Broberger et al., 1998; Hahn et al., 1998). Anorexi-
genic neurons (i.e. those inhibiting appetite) in the lateral ARC
express alpha-melanocyte stimulating hormone (alpha-MSH)
derived from pro-opiomelanocortin (POMC), and cocaine- and
amphetamine-regulated transcript (CART) (Elias et al., 1998).

0028-3908/$ e see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuropharm.2011.10.008
 A.H. Sam et al. / Neuropharmacology 63 (2012) 46e56 47

Fig. 1. Gut-brain axis: regulation of food intake. Nutrients created by the digestion of food are proposed to activate G protein coupled receptors on the luminal side of ene-
troendocrine cells e.g. the L-cell. This stimulates the release of gut hormones which may influence food intake at three sites: the vagus nerve, brainstem and hypothalamus. Within
the arcuate nucleus of the hypothalamus two neuronal populations are thought to be critical conduits through which peripheral signals are integrated to alter the drive to eat, the
orexigenic NPY/AgRP neurons and the anorexigenic POMC neurons. Further connections between hypothalamic nuclei and higher brain centres may exist which control the hedonic
aspects of food ingestion. ARC (arcuate nucleus), AgRP (agouti related peptide), GLP-1 (glucagon like peptide-1), NPY (neuropeptide Y), POMC (propiomelanocortin), PVN (para-
ventricular nucleus), PYY (peptide YY).

The ARC is adjacent to the median eminence, a ‘circum-
ventricular organ’ with fenestrated capillaries and hence an
incomplete bloodebrain barrier (Peruzzo et al., 2000). Circulating
hormones can therefore influence the activity of the arcuate nucleus
neurons directly, after passing across the median eminence. Gut
hormones, released from the gastrointestinal tract on a meal to meal
basis, signal short-term nutrient availability to the ARC. Other
circulating factors such as insulin and leptin (a circulating peptide
released from adipose tissue) relay information regarding long-term
energy stores (Porte et al., 2002).
Gastrointestinal vagal afferents are activated by mechanore-
ceptors and chemoreceptors, and converge in the nucleus of the
tractus solitarius (NTS) of the brainstem. Neuronal projections from
the NTS, in turn, carry signals to the hypothalamus. Circulating
factors such as gut hormones may influence the NTS neurons
through the adjacent circumventricular organ, the ‘area postrema’
(AP). Ablation of both the AP and another circumventricular organ,
the sub fornical organ (SFO), has been shown to influence the action
of the gut hormone Peptide tyrosine tyrosine (PYY) (Baraboi et al.,
2010). Gut hormones also alter the activity of the ascending vagal
pathways from the gut to the brainstem (Jobst et al., 2004).
Hence, the hypothalamic ARC orexigenic and anorexigenic
neurons are influenced by numerous neural and hormonal inputs.
These ARC neurons in turn project to a number of extra-hypothalamic
and intra-hypothalamic regions, including in particular the hypo-
thalamic paraventricular nucleus (PVN), where some of the impor-
tant efferent pathways regulating energy expenditure arise.
3. Enteroendocrine cells of the gastrointestinal tract
There are at least 15 different types of enteroendocrine cells
diffusely distributed throughout the gastrointestinal epithelium
(Sjolund et al., 1983). These cells produce and release a variety of
hormones and signalling molecules, which together constitute the
largest endocrine organ in the body (Cheng and Leblond, 1974;
Sjolund et al., 1983). The enteroendocrine cells are derived from
multipotent stem cells, located towards the base of the intestinal
crypts. The different enteroendocrine cell subpopulations are
constantly re-established by the differentiation of enteroendocrine
cells arising from these stem cells. The majority of enteroendocrine
cells undergo terminal differentiation as they migrate up from the
crypts to the epithelial surface (Tsubouchi and Leblond, 1979).
Immunohistochemical studies have shown that enter-
oendocrine cells frequently express two or more products. PYY has
been shown to co-localise with glucagon-like peptide-1 (GLP-1),
neurotensin (NT), and cholecystokinin (CCK) in enteroendocrine
cells in the colon (Roth et al., 1992). Approximately 50% of CCK, and
NT cells co express PYY (Roth et al., 1992). Substance P/serotonin
cells are commonly found in the same crypts as PYY/GLP-1/CCK/NT
cells and most of the substance P cells also contain serotonin.
However, co-expression of substance P/serotonin in the same cells
as PYY/GLP-1/CCK/NT is only rarely observed (Roth et al., 1992).
This suggests the existence of two separate branches of enter-
oendocrine L-cell differentiation, with one branch resulting in cells
producing substance P and serotonin, and the other resulting in
GLP-1, PYY, NT, and CCK-producing cells (Roth et al., 1992).
Chemosensing of gut luminal contents by the enteroendocrine
GI cells plays a critical role in the control of functions such as
digestion, pancreatic secretion, food intake, and metabolic regula-
tion. Evidence that endocrine cells can directly sense luminal
contents has been demonstrated in PYY and GLP-1 expressing L
cells. It has been shown that both human and rodent intestinal L
cells express receptors previously identified in the oral epithelium
for detecting sweet (T1R2 and T1R3) and bitter sensation (T2R), as
well as amino acids (T1R1 and T1R3) (Jang et al., 2007; Rozengurt
et al., 2006). The gustducin G protein associated with these taste
receptors has also been identified in L cells of the gut (Jang et al.,
2007; Rozengurt et al., 2006). The activation of these receptors
leads to an increase in intracellular calcium levels and release of
gastrointestinal peptides from enteroendocrine cells (Rozengurt
et al., 2006). The presence of the sweet taste receptor subunit
T1R3 and gustducin may also underlie a luminal glucose sensing
mechanism, since activation of these receptors mediates the post-
prandial release of GLP-1 from intestinal L cells (Jang et al., 2007).
Fatty acids derived from digestion of dietary fats appear to be
sensed via separate mechanisms. The short-chain fatty acid
receptors GPR43 and GPR41 are expressed in PYY-containing
enteroendocrine L cells (Karaki et al., 2006; Tazoe et al., 2009).
Short-chain fatty acids have been shown to increase PYY secretion
in rats when delivered directly into the colon (Cherbut et al., 1998;
48 A.H. Sam et al. / Neuropharmacology 63 (2012) 46e56
Fu-Cheng et al., 1995). GPR119 is another G protein coupled
receptor found in intestinal endocrine cells as well as pancreatic
beta cells (Chu et al., 2008, 2007). Administration of oleoyletha-
nolamide (OEA), an endogenous long chain fatty acid derivative,
and other GPR119 agonists increases GLP-1 secretion, both in vitro
and in vivo in rodents (Chu et al., 2008; Lauffer et al., 2009).
The enteroendocrine L cells therefore have the capacity to
integrate complex nutrient sensing in the gut and to respond
appropriately by releasing gut hormones. In addition to chemical
stimulation, the endocrine cells of the gut also respond to neural
and physical stimulation of the cell by releasing peptide containing
granules at the basolateral side of the cell. These peptides can have
an endocrine role, a local paracrine role, and/or activate receptors
present on nerves innervating the GI mucosa (Cummings and
Overduin, 2007).
4. Gut hormones regulating food intake
The gastrointestinal tract releases more than 20 different
regulatory peptide hormones that influence a number of physio-
logical processes. Gut hormones act on tissues such as exocrine
glands, smooth muscle and the peripheral nervous system (Murphy
and Bloom, 2006). The release of gut hormones such as PYY, GLP-1,
and oxyntomodulin (OXM) is stimulated by distension of the
stomach and interactions between nutrients and the luminal wall
of the intestine (Adrian et al., 1985; Le Quellec et al., 1992).
Gut hormones are believed to contribute to the short-term feel-
ings of satiety and hunger (Badman and Flier, 2005). These peptides
may reduce food intake by decreasing hypothalamic orexigenic sig-
nalling, and increasing anorectic signalling (Batterham et al., 2002;
Jobst et al., 2004). Another effect of these peptides is to mediate
inhibitory feedback mechanisms on intestinal transit, contributing to
prolonged gastric distension, and increased satiety between meals
(Lin et al., 1996; Wen et al., 1995). These combined CNS effects and
‘intestinal brake’ mechanisms, mediated by gut peptides such as CCK,
PYY, GLP-1 and OXM, facilitate the control of food intake and post-
prandial transit through the gastrointestinal tract.
5. Peptide tyrosine tyrosine (PYY)
PYY, like NPY and Pancreatic Polypeptide (PP), belongs to the ‘PP-
fold’ family of proteins. These peptides are 36-amino acids in length
and share a common tertiary structural motif known as the PP-fold.
C-terminal amidation of these proteins is a necessary requirement
for biological activity. PYY exists endogenously in two forms: PYY1e36
and PYY3e36 (Grandt et al., 1994). The enzymatic cleavage of secreted
PYY1e36 at the amino terminal by the cell surface enzyme dipeptidyl
peptidase IV (DPP-IV) gives rise to PYY3e36 (Medeiros and Turner,
1994), the predominant form of circulating PYY immunoreactivity.
Low levels of PYY are detected in enteroendocrine cells in the
stomach, and levels increase distally along the small and large
intestine, reaching their highest levels in cells in the colon and
rectum (Adrian et al., 1985). Endogenous circulating concentrations
of PYY are lowest in the fasting state, and rise post-prandially as
PYY is released from enteroendocrine L cells lining the distal GI
tract in proportion to caloric intake (Adrian et al., 1985) Plasma
levels of PYY rise within 30 min of a meal, and in humans, circu-
lating levels plateau at 1e2 h post-prandially, remaining elevated
for up to 6 h (Batterham et al., 2003a). Protein rich meals cause the
greatest increase in PYY levels compared to other macronutrients
(Batterham et al., 2006; Pedersen-Bjergaard et al., 1996).
Peripheral administration of PYY3e36 reduces food intake and
weight gain in rodents (Batterham et al., 2002; Challis et al., 2003;
Chelikani et al., 2005; Vrang et al., 2006), and although there was
initial controversy regarding the effects of PYY3e36 on food intake
(Tschop et al., 2004), many groups have subsequently validated its
anorectic effects (Chelikani et al., 2005; Vrang et al., 2006).
Demonstration of the anorectic effect of PYY in rodents is depen-
dent upon the full acclimatization of the animals to the handling
and injection procedures, and is lost in the presence of even mild
stressors (Abbott et al., 2006; Halatchev et al., 2004). This is because
stress can reduce baseline food intake, making it difficult for
anorectic agents to further suppress appetite. Intravenous admin-
istration of PYY inhibits food intake in humans and it is equally
effective in normal and obese subjects (Batterham et al., 2003a).
The anorectic effects of PYY3e36 appear to be mediated centrally
via the ARC, as peripheral administration of PYY3e36 has been
shown to increase c-fos expression in this hypothalamic nucleus
(Batterham et al., 2002). As discussed previously, the ARC contains
two neuronal populations, orexigenic NPY/AgRP, and anorexigenic
POMC/CART neurons. There is conflicting data regarding the effects
of PYY3e36 on these neurons. Peripheral administration of PYY3e36
has been reported to decrease expression and release of NPY whilst
activating POMC neurons (Batterham et al., 2002). However, other
investigators have reported that PYY3e36 inhibits POMC neurons
via postsynaptic Y2R (Ghamari-Langroudi et al., 2005). Moreover,
POMC knockout mice maintain their acute anorectic response to
peripherally administered PYY3e36, suggesting that POMC is not
critical to the inhibitory effects of PYY3e36 on feeding. PYY1e36 and
PYY3e36 exert their effects through the neuropeptide Y family of
receptors (Larhammar, 1996). PYY1e36 binds with similar affinity to
all of the Y receptors, however PYY3e36 is a selective high affinity
agonist at the Y2 receptor subtype (Y2R) (Grandt et al., 1992). The
Y2R is thought to be the receptor responsible for mediating the
reduction of food intake by PYY. It is an auto-inhibitory pre-
synaptic receptor found on NPY neurons within the ARC (Broberger
et al., 1997), and deficiency of the Y2R abolishes the anorectic effects
of PYY (Batterham et al., 2002). Furthermore, the anorectic effects
of PYY3e36 are attenuated by Y2R antagonists (Abbott et al., 2005b).
PYY3e36 is therefore thought to reduce food intake through acti-
vation of the Y2R.
A vagal brainstem mediated pathway may also be involved in
the actions of circulating PYY3e36. PYY is present in myenteric
nervous plexus neurons innervating the gastrointestinal tract and
the Y2R receptor has been identified on the vagus nerve (Koda et al.,
2005). The effects of peripheral administration of PYY3e36 on both
food intake (Abbott et al., 2005a; Koda et al., 2005), and on the
activation of ARC feeding neurons, are abolished following bilateral
sub-diaphragmatic total truncal vagotomy or transectioning of the
brainstemehypothalamic pathway in rodents (Abbott et al., 2005a),
supporting a role for the vagus in appetite regulation.
PYY has been shown to have an effect on intestinal motility. Close
intra-arterial administration of PYY in cats causes an inhibition of
jejunal and colonic motility (Lundberg et al., 1982). PYY also delays
gastric emptying, decreases pancreatic secretions, and increases
absorption of fluids and electrolytes from the ileum in humans
(Savage et al., 1987; Symersky et al., 2005). It is possible that some of
the anorectic effects of PYY may be mediated by the gastric disten-
sion resulting from delayed gastric emptying.
Interestingly, it has recently been shown that acute effects of
gastrointestinal bypass surgery on body weight are lost in PyyKO
mice (Chandarana et al., 2011), and that wild-type mice losing weight
after gastrointestinal bypass surgery exhibit increased colonic Pyy
expression and circulating fasting PYY levels (Chandarana et al.,
2011). This suggests that PYY plays a key role in mediating the early
weight loss that occurs following gastrointestinal bypass surgery.
The effects of PYY3e36 on satiety and central control of appetite
are clear. Most are mediated via anorectic neuronal populations in
the ARC, but vagal/brainstem-mediated pathways and peripheral
effects of PYY on gastric emptying and intestinal motility may also
 A.H. Sam et al. / Neuropharmacology 63 (2012) 46e56
play a part. High plasma concentrations of PYY result in nausea, but
the importance of PYY3e36 at physiological levels in the regulation
of energy intake make it a prime focus for new obesity therapies,
targeted either at PYY itself, or against the Y2 receptor.
6. Glucagon-like peptide-1 (GLP-1)
GLP-1 is a 30 amino acid peptide resulting from cleavage of the
preproglucagon precursor molecule (Dhanvantari et al., 1996). The
two bioactive forms of GLP-1, GLP-17e37 and GLP-17e36 amide, are
released into the circulation from L cells of the gastrointestinal tract
in response to an oral glucose load (Herrmann et al., 1995). Physi-
ologically, GLP-1 is an important incretin, stimulating glucose-
dependent insulin release (MacDonald et al., 2002). In addition to
its incretin effect, GLP-1 also inhibits the secretion of glucagon,
thereby inhibiting endogenous glucose production (Willms et al.,
1996). The net effect is to reduce blood glucose following a meal.
GLP-1 also delays gastric emptying (Schirra et al., 2006), and
increases satiety (Punjabi et al., 2011).
Like PYY, GLP-1 has been shown to act centrally in hypothalamic
nuclei known to be implicated in the control of appetite including
the ARC, PVN and supraoptic nucleus (Shughrue et al., 1996). Both
acute peripheral and central administration of GLP-1 reduce food
intake in rats (Tang-Christensen et al., 2001; Turton et al., 1996) and
chronic administration of GLP-1 reduces weight gain (Meeran et al.,
1999). The intravenous administration of GLP-1 to normal and
obese humans decreases food intake in a dose dependent manner
(Verdich et al., 2001) as well as reducing gastric emptying (Naslund
et al., 1999; Nauck et al., 1997). These effects are thought to be
mediated through vagal and brainstem pathways since peripheral
administration of GLP-1 activates neurons within the brainstem in
rats (Imeryuz et al., 1997). Furthermore, this increase in neuronal
activity, and the anorectic effects of GLP-1, are abolished following
vagotomy in rodents (Abbott et al., 2005a; Imeryuz et al., 1997),
reinforcing the argument for vagal involvement. More recently,
techniques such as functional magnetic resonance imaging (fMRI)
have confirmed a change in signal intensity within neuronal pop-
ulations in the VMH and the PVN following peripheral adminis-
tration of GLP-1 (Parkinson et al., 2009). This adds further weight to
the evidence that appetite and feeding are regulated by GLP-1 via
these hypothalamic and brainstem areas.
GLP-1 is rapidly degraded in the circulation by the enzyme DPP-
IV, making native GLP-1 unsuitable for therapeutic use. Longer
acting GLP-1 mimetics have been developed as new treatments for
type 2 diabetes (Joy et al., 2005). Exendin-4 is a naturally occurring
GLP-1 mimetic isolated from the venom of Heloderma suspectum,
a lizard native to several southwestern American states (Eng et al.,
1992). A truncated form of this peptide, exendin 9e39, acts as
a competitive antagonist at the GLP-1 receptor. Acute intra-
cerebroventricular administration of exendin 9e39 increases food
intake, and chronic administration increases body weight in rats
(Meeran et al., 1999; Turton et al., 1996). Endogenous peripheral
GLP-1 may physiologically reduce appetite and food intake after
a meal. However, GLP-1 receptor knockout mice do not have altered
food intake or body weight (Drucker, 2006). This may be because
developmental changes compensate for the lack of GLP-1 signal-
ling, or may reflect that GLP-1 has a more important physiological
role in controlling blood glucose than in regulating food intake.
The discovery of exendin-4 has led to the development of
a synthetic version, exenatide. Exenatide has a much longer in vivo
half-life than GLP-1 and is the first incretin mimetic approved for
the treatment of type 2 diabetes (Drucker and Nauck, 2006). Exe-
natide is effective at stimulating insulin release, suppressing
glucagon and lowering blood glucose. Clinical trials have demon-
strated that exenatide is useful for the treatment of type 2 diabetes
49
mellitus. Exenatide has also been shown to reduce body weight in
treated diabetics in phase III clinical trials (Buse et al., 2004;
DeFronzo et al., 2005; Kendall et al., 2005). The weight loss asso-
ciated with exenatide is considered a significant advantage as many
anti-diabetic treatments are commonly associated with weight
gain. Nausea is a relatively common side effect of the treatment.
However, it does not seem to be intrinsically linked to the effects on
appetite (Murphy and Bloom, 2006). Whilst GLP-1 has been
developed as a treatment for diabetes due to its incretin properties,
the observed effects of GLP-1 on satiety and weight loss are
a valuable secondary effect. Indeed recent data suggests liraglutide
maybe useful for the treatment of obesity, causing sustained weight
loss over 2 years but with a 50% rate of nausea and vomiting in the
3.0 mg/day group in the first year (Astrup et al., 2011).
7. Oxyntomodulin (OXM)
OXM, like GLP-1, is also a product of the preproglucagon
precursor molecule. It is a 37 amino acid peptide released post-
prandially from L cells in proportion to caloric intake (Le Quellec
et al., 1992). OXM delays gastric emptying and reduces gastric
acid secretion (Schjoldager et al., 1989), and has been shown
acutely to decrease food intake and in the longer term to decrease
weight gain in rodents (Dakin et al., 2001, 2004). In addition,
chronic administration of OXM causes rats to lose more weight than
pair-fed controls, suggesting an increase in energy expenditure
(Dakin et al., 2002). OXM also reduces food intake in normal weight
human volunteers when administered intravenously or subcuta-
neously (Cohen et al., 2003). Given preprandially to obese subjects
it reduces both food intake and body weight (Wynne et al., 2005).
As in rats, there is evidence that OXM may also increase energy
expenditure in humans (Wynne et al., 2006).
Although OXM has some agonist activity at the glucagon receptor,
there is evidence that its anorectic effect is predominantly mediated
via the GLP-1 receptor (Baggio et al., 2004; Dakin et al., 2001). The
anorectic effects of OXM are abolished in GLP-1 receptor knockout
mice (Baggio et al., 2004) and in the presence of the GLP-1 receptor
antagonist exendin 9e39 (Dakin et al., 2004), suggesting that OXM
acts via the GLP-1 receptor. OXM has a roughly 50-fold lower affinity
for the GLP-1 receptor than GLP-1 itself, but despite this, it reduces
food intake with similar potency (Dakin et al., 2001). Furthermore,
although the administration of exendin 9e39 directly into the ARC
blocks the anorectic effects of OXM, it does not block those of GLP-1
(Dakin et al., 2004). Therefore, it is possible that OXM may act via an
as yet unidentified receptor or a specific subpopulation of the GLP-1
receptor. Studies using manganese-enhanced magnetic resonance
imaging MRI (MEMRI) have shown that intraperitoneal administra-
tion of OXM causes a reduced rate of signal enhancement, reflecting
a reduction in neuronal activity, in the ARC, PVN, and supraoptic
nucleus. This pattern of activation was distinct from that of GLP-1
under the same conditions (Chaudhri et al., 2006), implying that
these two hormones act via different hypothalamic pathways.
8. Cholecystokinin (CCK)
CCK is released post-prandially from the small intestine
(Murphy and Bloom, 2006), and has also been shown to co-localise
with PYY in L cells (Roth et al., 1992). Two types of CCK receptor
have been identified in the CNS and peripheral tissues. CCK1
receptors are present in peripheral tissues such as the pancreas,
gallbladder, and on vagal afferent nerve fibres innervating the gut
(Moran and Kinzig, 2004). Furthermore, CCK1 receptors have been
identified in areas within the CNS involved in the regulation of food
intake such as the NTS, AP, and dorsomedial hypothalamus (Moran
et al., 1986). The CCK2 receptor has a different distribution, and is
50 A.H. Sam et al. / Neuropharmacology 63 (2012) 46e56
found in the cortex, hypothalamus, vagal afferents and gastric
mucosa (Moran et al., 1986), once again encompassing several areas
known to be involved in appetite regulation.
CCK is released post-prandially in response to saturated fat, long
chain fatty acids, amino acids and small peptides that would nor-
mally result from protein digestion (Liddle et al., 1985; Rehfeld
et al., 2003). CCK release and signalling via the CCK1 receptors in
response to these long chain fatty acids mediates stimulation of
PYY release and inhibition of ghrelin (an orexigenic gut hormone)
in human subjects (Degen et al., 2007). Both of these hormones
would then further act to suppress appetite and inhibit food intake.
Post-prandial secretion of CCK also triggers the release of pancre-
atic enzymes, and of bile salts from the gallbladder, into the
duodenum, promoting protein and fat digestion (Liddle et al., 1985;
Rehfeld et al., 2003). In addition, CCK regulates other gastrointes-
tinal functions including gastric emptying (Fried et al., 1991).
The effects of CCK on appetite are well documented. Peripheral
administration of CCK in rodents results in a dose dependant
reduction in food intake, decreasing both meal size and duration
(Antin et al., 1975). CCK administration is also associated with an
increase in post-prandial satiety behaviours such as increased
grooming and decreased locomotor activity (Antin et al., 1975). The
Otsuka Long-Evans Tokushima Fatty rat was bred to produce
a polygenic model of diabetes. These rats lack the CCK1 receptor,
are hyperphagic and obese, suggesting that CCK has a physiological
role in the regulation of food intake (Bi and Moran, 2002). However,
CCK1 receptor knockout mice do not differ significantly in body
weight from wild types (Kopin et al., 1999). This discrepancy has
been suggested to be due to a number of reasons. The most likely
explanation is the potential for the OLETF phenotype to be driven
by other, as yet unidentified, genetic mutations in addition to the
loss of CCK1. These data suggest that CCK may play a role in acute
rather than long-term energy homeostasis. It has been reported
that endogenous circulating concentrations of CCK cannot activate
vagal circuits, suggesting that the actions of CCK on food intake
might be paracrine or neurocrine rather than endocrine (Moran,
2000). In humans, intravenous administration of physiological
doses of CCK reduces food intake and increases the perception of
fullness (Lieverse et al., 1995). Unfortunately, the therapeutic
potential of CCK as a treatment for obesity is limited by nausea and
tachyphylaxis of the anorectic effects associated with chronic
administration (Covasa et al., 2001).
9. Pancreatic polypeptide (PP)
PP is an amidated 36-amino acid peptide and belongs the ‘PP-
fold’ family of peptides. It is released post-prandially under vagal
control by pancreatic islet PP cells (Adrian et al., 1976; Larsson et al.,
1975; Schwartz et al., 1978). PP is comparable to other anorectic
intestinal peptides such as PYY, being secreted in proportion to
caloric intake. Circulating levels rise after meals and remain
elevated for up to 6 h post-prandially (Adrian et al., 1976).
The functions of PP in regulating gallbladder motility and
pancreatic secretions have previously been well characterized
(Adrian et al., 1979, 1976; Greenberg et al., 1979). PP has been
shown to augment basal insulin and glucagon release in rats and
this is thought to be via a direct paracrine effect on the pancreatic
beta and alpha cells respectively (Szecowka et al., 1983). Intraper-
itoneal injection of PP acutely reduces food intake in fasted mice
(Asakawa et al., 2003), an effect that remains apparent for 24 h after
injection. Furthermore, chronic administration of PP over 6 days in
ob/ob mice significantly reduces body weight gain and improves
glucose profile (Asakawa et al., 2003). Pancreatic polypeptide-over-
expressing mice with supraphysiological PP concentrations have
reduced food intake and gain less weight (Ueno et al., 1999).
Intravenous infusion of PP at doses that achieve normal post-
prandial plasma concentrations reduces appetite in lean humans
and inhibition of food intake persists for 24 h after infusion
(Batterham et al., 2003b). PP has also been shown to reduce food
intake at lower infusion rates (Jesudason et al., 2007). Furthermore,
pancreatic polypeptide has been shown to reduce food intake in
patients with obesity secondary to PradereWilli syndrome
(Berntson et al., 1993).
PP has also been implicated in energy homeostasis, with exog-
enous administration of PP causing an increase in oxygen
consumption (Asakawa et al., 2003), thus implying that part of the
effect of PP on body weight may be due to increased energy
expenditure. It has also been shown to increase spontaneous
locomotor activity in mice (Liu et al., 2008).
PP binds to all the members of the Y receptor family, but has the
highest affinity for the Y4 receptor subtype (Michel et al., 1998). The
effects of PP are likely to be mediated by both the hypothalamus
and brainstem (Asakawa et al., 2003). The Y4 receptor mRNA has
been shown to be present in the appetite-regulating areas of the
brainstem notably the AP and in the ARC (Larsen and Kristensen,
1997; Parker and Herzog, 1999). Functional imaging with MEMRI
following peripheral administration of PP has also suggested
a central mode of action, demonstrating a significant reduction in
signal intensity in the ARC, VMH and PVN of fasted mice. This
reduction in signal intensity implies a reduction in activity of
neurons in these areas central to the control of appetite. The
decrease in signal intensity correlated with a reduction in food
intake (Hankir et al., 2011). It has also been suggested that inhibi-
tion of food intake by PP may be secondary to an effect on gastric
emptying, and therefore increased gastric distension. However,
while some investigators have reported an inhibition of gastric
emptying, others have failed to show this (Adrian et al., 1981;
Batterham et al., 2003b; Schmidt et al., 2005). Furthermore, the
anorectic effects of PP in humans appear to be independent of
changes in gastric motility (Batterham et al., 2003b). These data
have lead to a concerted effort to develop long acting PP analogues,
which have completed Phase I trials (Tan et al., 2011).
10. Glucagon
Glucagon is a 29 amino acid peptide secreted from the a-cells of
the pancreatic islets of Langerhans. It is a further product of pre-
proglucagon cleavage alongside OXM and GLP-1. Glucagon is
released into the portal vein in fasted states and also in response to
exercise, and acts on the liver to promote hepatic glycogenolysis
and gluconeogenesis and maintain glycaemic balance (Stevenson
et al., 1987; Striffler et al., 1981; Studer et al., 1984; Wasserman
et al., 1989).
Glucagon mediates its effects via the glucagon receptor, a 7-
transmembrane G protein coupled receptor which has a wide
tissue distribution. It is expressed in the gut, adrenal glands, brain,
heart, pancreas, spleen and in adipocytes, but is predominantly
found in the liver and kidney (Svoboda et al., 1994).
As a potential treatment for obesity, glucagon has been shown to
increase energy expenditure in rats, and also in humans during
insulin deficiency (Davidson et al., 1960; Nair, 1987). It also signif-
icantly reduces food intake, with a subjective reduction of appetite
in man (Schulman et al., 1957). Infusion of glucagon into the portal
vein but not the inferior vena cava causes a reduction in meal size in
rats (Geary et al., 1993; Le Sauter et al., 1991).
Glucagon presents an interesting prospect in the treatment of
obesity due to its effect on increasing energy expenditure, and
increasing satiety. It has been demonstrated that the potential
unfavourable effect on glucose tolerance due to glucagon’s actions
on hepatic glycogenolysis and gluconeogenesis is effectively
 A.H. Sam et al. / Neuropharmacology 63 (2012) 46e56
counteracted by dual agonism at the glucagon and GLP-1 receptors
(Day et al., 2009; Pocai et al., 2009). The data from these studies
demonstrated highly effective weight loss in diet-induced obese
mice whilst avoiding the hyperglycaemia that might be expected
from agonism at the glucagon receptor.
11. Ghrelin
Ghrelin is a 28-amino acid acylated peptide secreted from the
stomach. It was originally identified as an endogenous ligand for
the ‘growth hormone secretagogue’ receptor (GHS-R) and is
a growth-hormone-releasing peptide (Kojima et al., 1999).
Ghrelin is the only orexigenic gut hormone (Bewick et al., 2009),
causing an increase in food intake and weight gain in rodents
following both peripheral and central administration (Lawrence
et al., 2002; Tschop et al., 2000; Wren et al., 2000). Intravenous
administration of ghrelin has also been shown to stimulate gastric
acid secretion and motility in rats (Masuda et al., 2000). In normal
subjects, ghrelin levels are highest in the fasted state (Toshinai
et al., 2001), and levels are chronically higher in people with
weight loss due to anorexia nervosa or dietary reduction (Ariyasu
et al., 2001; Cummings et al., 2002; Shiiya et al., 2002). In
contrast to other gut hormones, plasma ghrelin levels decrease
after meals (Ariyasu et al., 2001; Tschop et al., 2001) and are low in
obese subjects (Shiiya et al., 2002). Ghrelin concentrations are also
reduced after gastric bypass surgery, and this may contribute to
weight loss in such patients (Cummings et al., 2002).
Ghrelin and its receptor are both expressed in vagal afferents in
mice (Page et al., 2007), and blockade of the gastric vagal afferent
has been shown to abolish ghrelin-induced feeding, growth
hormone secretion, and activation of NPY-producing and growth-
hormone-releasing hormone producing neurons in rats (Date et al.,
2002). Central administration of ghrelin has been shown to
increase pancreatic exocrine secretion via the vagus in conscious
rats (Sato et al., 2003).
Ghrelin receptors are found in the ARC of the hypothalamus, and
c-fos expression is increased in the ARC after peripheral adminis-
tration of ghrelin (Hewson and Dickson, 2000). In rodents who had
undergone ablation of the ARC, administration of ghrelin did not
stimulate food intake (Tamura et al., 2002). When given centrally,
ghrelin also stimulates c-fos expression in other nuclei known to be
involved in appetite control including the PVN, dorsomedial
nucleus, and lateral hypothalamus as well as in the AP and NTS in
the brainstem (Lawrence et al., 2002). Hypothalamic levels of
orexigenic peptides NPY and AgRP mRNA were also increased after
chronic central administration of ghrelin (Kamegai et al., 2001).
Diet-induced obesity is associated with a blunting of ghrelin’s
orexigenic effect. There has therefore been recent interest in the
interaction between the ghrelin system and macronutrients. High
fat feeding has been shown to render NPY/AgRP neurones relatively
ghrelin resistant (Briggs et al., 2010), and diets high in fat have been
shown to directly inhibit the hyperphagic effect of ghrelin
(Gardiner et al., 2010; Perez-Tilve et al., 2011). These data have
significant implications for developing anti-obesity treatments
targeting the ghrelin system and suggest success of these
approaches could depend on the fat content of the diet the patient
consumes. More recently, ghrelin has been shown to engage
neurons in the ventral tegmental area of the brain and may provide
a link between the gut and neuronal control of stress-induced
eating of ‘comfort foods’ (Chuang et al., 2011).
12. Other gut peptides
A number of other gut-derived peptides have been shown to
reduce food intake. However, the physiological role of these
51
peptides in the regulation of food intake and energy homeostasis
remains unclear.
NT was first isolated from hypothalamic tissue, but is widely
distributed throughout the central nervous system. However, the
majority of NT is found within enteroendocrine cells of the GI tract
(Carraway and Leeman, 1976). NT regulates a number of digestive
processes, including gastrointestinal motility, and pancreatic and
biliary secretion (Kitabgi, 2006). It also has trophic effects on the
pancreas and small intestine (Feurle et al., 1987; Wood et al.,
1988a,b). Plasma levels of NT increase after a meal, with intra-
luminal fat being the most potent stimulus (Rosell and Rokaeus,
1979). Peripheral administration of neurotensin decreases food
intake and grooming behaviour in rats only at large doses (Sandoval
and Kulkosky, 1992). Therefore at physiological levels, neurotensin
is unlikely to play a major role in appetite regulation. Although
neurotensin acutely reduces food intake when administered cen-
trally in rats or peripherally in mice, chronic administration to mice
has no significant effect on food intake or body weight (Cooke et al.,
2009). The lack of chronic effects on body weight suggests that NT
is unlikely to be useful as a treatment for obesity.
Intracerebroventricular injection of glucagon-like peptide-2
(GLP-2) into rats inhibits food intake. In contrast, GLP-2 adminis-
tered peripherally does not inhibit food intake in rodents or
humans (Schmidt et al., 2003; Scott et al., 1998). GLP-2 appears to
play a more important physiological role as an intestinal growth
factor (Scott et al., 1998).
Amylin is a peptide co-secreted with insulin by pancreatic beta
cells. Injection of amylin or amylin agonist has been shown to
reduce food intake in a number of species, including humans
(Chance et al., 1993; Lutz et al., 1994; Ratner et al., 2005; Rushing
et al., 2000; Whitehouse et al., 2002). The amylin receptor
agonist pramlintide has been shown to cause weight loss in dia-
betic humans (Ratner et al., 2005; Whitehouse et al., 2002).
Vasoactive intestinal polypeptide (VIP) has been shown to
reduce appetite, in addition to its well-characterized effects on the
cardiovascular system and gastrointestinal motility and secretion.
Intracerebroventricular administration of VIP has been shown to
cause a potent short-lived decrease in food intake and an increase
in activity and energy expenditure in rats. Treatment of hypotha-
lamic explants with VIP stimulated the release of the anorexigenic
peptide a-MSH (Ghourab et al., 2011). These studies suggest
a possible endogenous role for VIP in the hypothalamic control of
energy homeostasis.
13. Gut hormones and the treatment of obesity
Lifestyle and dietary modification alone are inadequate for the
successful treatment of the majority of obese individuals. However,
despite an increasingly high demand for intervention, the field of
obesity therapeutics has limited options to offer these patients. The
history of obesity pharmacotherapy is littered with examples of
drugs withdrawn from the market due to adverse effects out-
weighing the beneficial effects of weight loss. Recent examples
include Sibutramine, a norepinephrine and serotonin reuptake
inhibitor, and Rimonabant, which is a cannabinoid-1 receptor
blocker. Sibutramine was withdrawn after it was found to increase
heart rate and blood pressure in some subjects, and was associated
with an increased risk of stroke and non-fatal myocardial infarction
in patients with pre-existing cardiovascular conditions (James et al.,
2010), whilst Rimonabant was withdrawn amidst concerns
regarding adverse psychiatric events (Christensen et al., 2007). The
only currently licensed product in the UK is Orlistat, a pancreatic
lipase inhibitor which prevents fat absorption and confers a modest
weight loss of 2.9 kg more than placebo over the course of a year
(Rucker et al., 2007).
52 A.H. Sam et al. / Neuropharmacology 63 (2012) 46e56
The only obesity treatment that has been shown to confer long-
term, sustained weight loss and a decrease in overall mortality is
bariatric surgical intervention (Adams et al., 2007; Sjostrom et al.,
2007). Several surgical procedures are available to achieve weight
loss. Gastric banding restricts the amount of food that can be
comfortably ingested and increases the satiating effect of food
(Dixon et al., 2005). A more efficient reduction in appetite and
weight loss is seen with surgical procedures that involve gastro-
intestinal bypass, such as Roux-en-Y Gastric bypass (RYGB) (Adams
et al., 2007; Kenler et al., 1990; Sjostrom et al., 2007). Weight loss is
normally associated with reduced plasma levels of the adipocyte-
derived anorectic hormone leptin, causing increased hunger
(Chan et al., 2003). However, following RYGB, despite significant
reductions in body weight and leptin levels, appetite is markedly
reduced (Kenler et al., 1990).
A significant difference in the effects of different forms of bariatric
surgery on type 2 diabetes has been shown (Gan et al., 2007). RYGB
ameliorates coexistent type 2 diabetes mellitus before substantial
weight loss has occurred and more rapidly than gastric banding. The
differences between gastric banding and RYGB may be due to alter-
ations in the anorectic and incretin gut hormone profile that is seen
following RYGB, but not following gastric banding (Kellum et al.,
1990; le Roux et al., 2006). Experimental evidence suggests that
these anorectic gut hormones may mediate the effects of RYGB on
appetite and body weight (le Roux et al., 2006; le Roux et al., 2007).
Post-prandial PYY and GLP-1 levels begin to rise as early as 2 days
following gastric bypass in humans (le Roux et al., 2007), and
secretory products of enteroendocrine L cells, including PYY and GLP-
1 remain elevated two years after bypass surgery (le Roux et al., 2010).
Inhibiting gut hormone release with somatostatin analogue octreo-
tide increases the food intake after gastric bypass surgery but not
following gastric banding (le Roux et al., 2007), further suggesting
that these hormones play a critical role. Determining the mechanisms
behind this sustained reduction in appetite may identify pathways
that can be targeted by anti-obesity agents. To this end there has been
recent concerted effort to mimic the rise in gut hormones following
gut bypass by either the development of peptide based analogues or
by the design of small molecule drugs which target nutrient sensing
receptors on the enteroendocrine L-cell.
Long acting versions of PYY and OXM are being actively pursued
by the pharmaceutical industry, such as Pfizer’s OAP-189, we await
the dissemination of data from ongoing trials. Given that gut
hormones are co-released one logical approach would be the
development of combination therapies. Indeed data suggests that
co-administration of gut hormones can have additive effects on
food intake inhibition, for example PYY þ GLP-1 (Neary et al., 2005)
or PYY þ OXM (Field et al., 2010). Such combination approaches
may prove more effective than individual administration. Very
recently the development of chimeric agonists has emerged as
a novel form of combination therapy (Day et al., 2009). GLP-1/
glucagon co-agonists combine the appetite suppressive effects of
GLP-1 and glucagon with the energy expenditure promoting effects
of glucagon. Whilst at the same time GLP-1’s insulinotropic effects
inhibit the detrimental hyperglycaemic effects of glucagon. Mar-
cadia Ltd., now a subsidiary of Roche, first reported the beneficial
effects of this approach and their compound is now undergoing
clinical trials. In addition, Zealand Pharma is also developing
a similar compound, ZP-2929, in partnership with Boehringer
Mannheim. Time will tell if the promising pre-clinical data trans-
lates in to clinical benefit (Daugaard et al., 2010).
Considerable energy has also been directed toward the devel-
opment of gut hormone secretagogues. The most well charac-
terised class being agonists of GPR119. These compounds have been
shown to release both GLP-1 and PYY (Chu et al., 2008). Their anti-
diabetic effects are well defined; stimulation of GLP-1 and a direct
insulinotropic action (Chu et al., 2007). It is less clear if these
compounds will be effective as anti-obesity agents, but some
agonists have been shown to significantly reduce food intake, for
example PSN632408 (Overton et al., 2006). GPR119 is currently the
only target for which synthetic modulators stimulate both incretin
and insulin release. This highly beneficial profile has generated
great industry interest with at least 9 companies actively working
in this area. Initial clinical trials have been successful with respect
to the anti-diabetic indication (Jones et al., 2009; Shah and
Kowalski, 2010).
14. Conclusion
Obesity has emerged as a major global healthcare challenge. The
significant mortality and morbidity associated with obesity has
inspired a vast amount of research directed towards developing safe
and efficacious weight loss agents. The beneficial effects of centrally
acting weight loss agents have been negated by their potentially
hazardous effects on mood, reward, dependence and autonomic
tone. Gut hormones, as outlined in this article, play an important
role in the homeostatic control of food intake and offer an alterna-
tive to centrally acting drugs. In particular, recent data suggests that
mimicking the gut hormone profile observed following gastric
bypass may offer viable new treatments for obesity. This can be
accomplished either through the use of long acting peptide based
therapies, alone or in combination, or with gut hormone secreta-
gogues. We believe the most promising avenues for future exploi-
tation lie in the development of longer acting GLP-1 agonists,
combination therapies including GLP-1/glucagon co-agonists and
gut hormone secretagogues targeting L-cell nutrient receptors
(eg. GPR119 agonists) either as small molecules or as functional
foods. Thus, our emerging understanding of the physiological
systems in the gut which regulate food intake has identified novel
targets for the treatment of obesity and its related co-morbidities.
We believe that in time these approaches will develop clinically
useful compounds which will offer a real answer to the ever
growing burden of obesity.
Acknowledgements
The Section is funded by grants from the MRC, BBSRC, NIHR, an
Integrative Mammalian Biology (IMB) Capacity Building Award, an
FP7-HEALTH-2009-241592 EuroCHIP grant and is supported by the
NIHR Imperial Biomedical Research Centre Funding Scheme. Amir
H. Sam is funded by a Wellcome Trust Research Training Fellow-
ship. Tricia Tan is funded by Developmental Pathway Funding and
Developmental Clinical Schemes from the Medical Research
Council. Gavin A Bewick is funded by an EFSD Paul Langerhans
grant and by an NIHR career development fellowship.
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