The Hypothalamus and Obesity

Current Drug Targets, 2005, 6, 225-240
225
The Hypothalamus and Obesity

Peter J. King*
Johnson & Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica N.V., Metabolic
Disorders, Turnhoutseweg 30, B-2340 Beerse, Belgium
Abstract: Obesity, a condition already at epidemic proportions in the developed world, is largely attributable to an
indulgent lifestyle. Biologically we feel hunger more acutely than feeling full-up (satiety). The discovery over a decade
ago of leptin, an adiposity signal, revolutionised our understanding of hypothalamic mechanisms underpinning the central
control of ingestive behaviour. The structure and function of many hypothalamic peptides (Neuropeptide Y (NPY),
Melanocortins, Agouti related peptide (AGRP), Cocaine and amphetamine regulated transcript (CART), Melanin
concentrating hormone (MCH), Orexins and endocannabinoids) have been characterised in rodent models. The
pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are
being explored. Short-term signal hormones including Cholecystokinin (CCK), Ghrelin, Peptide YY (PYY3-36) and
Glucagon-like peptide 1 (GLP-1) control meal size via pathways converging on the hypothalamus. Long-term regulation
is provided by the main circulating hormones leptin and insulin. These systems among others, implicated in hypothalamic
appetite regulation all provide potential drugable targets by which to treat obesity.
Key Words: Food intake, Obesity, Energy homeostasis, Hypothalamus, Anti-obesity drugs.
INTRODUCTION
Obesity across the major markets is at epidemic
proportions (the prevalent population across the USA,
Europe and Japanese markets reached 114 million in 2003)
and is forecast to grow approximately 20 % by 2013
(reaching 140 million) [1]. Paralleling such growth will be
the commercial opportunities this offers, with obesity
research set to rise from $500 million in 2003 to $2.3 billion
in 2013 [1]. It has been proposed that centrally acting antiobesity agents will make up approximately three quarters of
the future obesity market, despite the lingering safety concerns following withdrawal of dexfenfluramine (Adifax/
Redux) and fenfluramine due to unwanted cardiovascular
side effects [2, 3] in the late 1990s and sibutramines
temporary withdrawal from the Italian markets in 2002.
Even though there have been many scientific breakthroughs in the understanding of the regulation of food
intake and energy disposal throughout the last few decades,
new anti-obesity drugs have not reached the marketplace.
The current marketed drugs available for the treatment of
obesity are insufficient to cope with the expanding obesity
populations now seen in both western and developing
countries. Not only are they limited in number, but also in
their efficacy at producing sustained weight loss beyond 10
% (Table 1). This is partly due to the complex neuronal
circuitry in the central nervous system (CNS) and periphery
that regulate energy deposition and expenditure, and the
difficulty of extrapolating findings in experimental animals
(mostly rodents) to humans. This plus contributing genetic
and environmental factors, plus the need for potent and safe
*Address correspondence to this author at the Johnson & Johnson Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica
N.V., Metabolic Disorders, Turnhoutseweg 30, B-2340 Beerse, Belgium;
Tel: +32(0)14/60.31.06; Fax: +32(0)14/60.54.03;
E-mail: pking3@prdbe.jnj.com
1389-4501/05 $50.00+.00
pharmacological interventions, the discovery of novel

disease targets has been tardy and unfruitful. Despite these
hurdles, abdominal obesity clearly represents a major contributing factor and also initiator of the metabolic syndrome
(defined by the World Health Organization (WHO) as
insulin resistance plus two of the five additional criteria of
hypertension, high triglycerides, low HDL cholesterol, high
body mass index (BMI), and high urinary albumin excretion), treating obesity is a heavily pursued area for academic
and industrial researchers and several new chemical entities
are currently being investigated for their treatment of obesity
(Fig. 1). Many excellent reviews have recently been
published outlining the potential therapeutic targets for the
treatment of obesity [4-10].
This article will highlight some of the newer prospective
drugable targets for treating obesity, particularly pathways
converging on the hypothalamus or some of the many
peptides and neurotransmitters expressed in this small brain
region, that influence feeding and energy homeostasis.
REGULATION OF ENERGY BALANCE
Obesity results from an energy imbalance, where the
energy intake exceeds energy expenditure. The likelihood of
obesity varies considerably between individuals of any given
population, with certain individuals being able to consume
almost any food without putting on an ounce of weight so
to speak, in comparison to those who easily put on the
pounds. Such paradigms are paralleled in rodents with
distinct high and low weight gain subset populations emerging from a genetically uniform single population of rats fed a
highly palatable diet [11]. It is not clear whether this
difference is attributable to metabolic adaptations limiting
excessive weight gain, but effects of lifestyle can obviously
be ruled out in the case of such a rodent model, which most
closely resembles human obesity.
2005 Bentham Science Publishers Ltd.
226
Current Drug Targets, 2005, Vol. 6, No. 2
Table 1.
Peter J. King
Current Drug Therapies for the Treatment of Obesity
Agent
Company/Brand
Advantages
Disadvantages
Pancreatic lipase inhibitor
Orlistat
Roches Xenical
Trials show that 5-10 gk or 5-10 % body weight is lost over 6

months to 1 year. Up to 30 % of patients maintain their weight
loss over two years therapy. Patients have reduced serum lipid
levels and improvements in risk factors for developing
cardiovascular disease and diabetes
Gastoinstestinal side effects include fecal

incontinence, flatulence and oily
spotting. Malabsorption of lipid-soluble
vitamins can occur in some patients
taking orlistat.
Serotonin and norepinephrine reuptake inhibitors
Sibtramine
Abbotts Meridia &

Reductil
Trials show that 3-6 kg or 5-10 % of body weight is lost over 6

months to 1 year. Up to 30 % of patients maintain their weight
loss over two years therapy. A study demonstrated that obese
patients with concurrent binge-eating disorder exhibited
improved control of eating behaviour while taking sibutramine
Common side effects include elevation

in blood pressure, increased heart rate,
dry mouth, anorexia, insomnia and
nausea. Sibutramine is contraindicated in
patients taking antidepressants or who
have uncontrolled hypertension.
Noradrenergic anorectic agents

Phentemine
GlaxoSmithKlines Fastin,
UCBs lonamin, generics
Mazindol
Wyeth-Ayersts Mazanor,
Novartiss Sanorex
Trials demonstrate a weight loss of 0.5 kg/week or less than 5

% of body weight lost over two months of therapy
Side effects include overstimulation of

the CNS, restlessness, dizzness,
insomnia, euphoria, dysphoria, tremor
and headache. Drugs in this class are
approved for short-term use only.
Adapted from Metabolic Disorders Study # 11, Obesity, August 2004 with permission from Decision Resources, Inc., Waltham, MA [1].
Naturally occurring mutations, as well as ablative lesions,

have shown that the brain regulates both aspects of energy
balance and that abnormalities in energy expenditure contributes to obesity. Indeed, early evidence pointing towards a
model for hypothalamic control of energy balance came
from specific brain lesion experiments, either through physical or chemical destruction of neurones. In particular lesions
of the ventromedial hypothalamic nucleus (VMH), resulted
in obesity, whilst lesions of the lateral hypothalamic area
(LHA) lead to anorexia and weight loss [12]. From this first
conception, it is now understood that sensory information
from the upper gastrointestinal (GI) tract, abdominal viscera
and taste information from the oral cavity [13] are all
integrated in the nucleus of the tractus solitarius (NTS), an
area in the caudal brainstem. Satiety-inducing signals,
initiated by mechanical or chemical stimulation of the
stomach and small intestine, neural-inputs related to energy
metabolism in the liver [14] and humoral signals also
converge on the NTS via ascending vagal fibres from the
spinal cord [15]. Afferent fibres then carry the signals to the
hypothalamus and other forebrain regions (Fig. 2).
PERIPHERAL SIGNALS AFFECTING REGULATION
OF METABOLISM
Leptin
For much of the past two or so decades, the attention of
obesity and diabetes research has been directed towards
leptin. However, this circulating hormone is neither the most
potent nor the most physiologically important regulator of
the hypothalamic neurones, or indeed of energy balance.
Leptin, the 146-amino acid residue product of the ob gene, is
synthesised mainly in white adipose tissue (WAT) [16] and

also in brown adipose tissue (BAT) [17], stomach, skeletal
muscle, the placenta and mammary tissues, albeit at much
lower levels [18]. It is now generally accepted that leptin acts
as a signal that indicates the size of the adipose tissue mass
to the CNS centres that regulate feeding behaviour [19].
Considerable support for the involvement of leptin in the
central regulation of feeding has been provided by studies
using three genetic models of obesity, ob/ob and db/db mice
and the fa/fa Zucker rat [20-22]. All of these models have
different single-gene mutations that consequently result in
severe obesity due to hyperphagia.
Leptin injected into the bloodstream of experimental
animals readily enters the mediobasal hypothalamus and
arcuate nucleus (ARC), where the blood-brain barrier is
specifically modified to allow the passage of large molecules
[23]. It is also the site where an extended functional variant
of the leptin receptor (Ob-Rb) encoded by the db gene [24] is
expressed on various ARC neuron populations [25-29].
Although leptin is a potent inhibitor of feeding, the
hyperphagia and obesity in both animals and humans seems
to go hand in hand with hyperleptinaemia related to oversecretion of this hormone (and also insulin) [30]. The
counter-regulatory effects of leptin (that in normal weight
mammals decreases food intake through the hypothalamus),
is evidently lacking in obese mammals, with such mechanisms being more apparent in individuals or animals that
are predisposed to weight gain and diabetes [31]. Impaired
transport of leptin into the CNS is hypothesized to be
responsible for the proposed for the leptin resistance [32].
This insensitivity or resistance to leptin may explain the
227
Fig. (1). Emerging neural and hormonal targets in development for the treatment of obesity. Adapted from Metabolic Disorders Study # 11,
Obesity, August 2004 with permission from Decision Resources, Inc., Waltham, MA.
228
Peter J. King
Fig. (2). Simplified schematic overview of the hypothalamic structures (based on rat data) involved in food intake regulation and energy
expenditure. Coronal section showing the relative positions of the arcuate (ARC), ventromedial (VMH), dorsomedial (DMH), paraventricular
(PVN) nuclei and lateral hypothalamic area (LHA) with respect to each other through the brain. Circuits allowing communications between
these neuronal populations are indicated.
disappointing trials of peripherally administered recombinant

leptin or leptin analogues [31, 33, 34]. Despite these frustrating results other agonists of leptin are being developed.
Cambridge Biotechnology is investigating a series of leptin
mimetics, including CBT-001452 for the treatment of
obesity. Preclinical data showed centrally administered CBT001452 reduced food intake and body weight with effects
being evident in lean rats when administering the compound
either i.p. or p.o. This reduced food intake was not seen in
the Zucker fa/fa rats, proof that CBT-001452 works via the
leptin receptor1. Abbott Laboratories in collaboration with
Millenmium Pharmaceuticals Inc. (recently terminated)
developed antisense oligonucleotides against the product of
gene 46a (involved in the leptin breakdown) that cause a
reduction in 24 h food intake in ob/ob mice to a greater
extent than leptin treatment [35].
Insulin
Insulin has similar central catabolic effects to leptin on
energy homeostasis, in that it inhibits feeding, stimulates
____________________________
1
Manuef, Y.; Higginbottom, M.; Pritchard, M.; Ashford, M.; Lione, L.; Ho, M.; Payne,
K.; Littlefield, S.; Peck, E.; Chapman, E.; Horton, J.; Guyen, V-A.; Simpson, I.;
Stygall, J.; Tyzack, C.; Sedgwick, T. and Richardson, P. (2004) Diabetes, 53, Abs 64LB.
thermogenesis and induces weight loss. Insulin injected

centrally inhibits feeding and stimulates thermogenesis [36],
while injection of neutralizing antibodies targeted against
insulin specifically into the VMH stimulates feeding [37,
38]. Contrary systemic injection of insulin at pharmacological levels increases body weight in patients [39]. Generally
circulating insulin levels parallel body fat mass and, like
leptin, is a plausible hormonal signal of adiposity, with
plasma insulin concentrations being decreased in all states of
energy deficiency, such as starvation, insulin-deficient
diabetes (IDDM), lactation and physical exercise, which is
consistent with data showing insulin to act centrally and
directly to inhibit both hypothalamic neuropeptide Y (NPY)and galanin producing neurones under normal feeding
conditions [40, 41]
Despite wide distribution throughout the brain, insulin
receptors are especially rich in the ARC and paraventricular
nucleus (PVN) [42], with circulating insulin entering the
median eminence (ME) and ARC through specialized
regions of the blood brain barrier. Confirming insulins role
in the regulation of food intake and body weight, selective
knockout of insulin receptors in the brain leads to hyperphagia and obesity [38]. The use of small molecule insulin
mimetics, have previously been shown to stop the progress
of obesity in diet-induced obese mice by reducing food
intake and body weight gain, together with lessening adipo-
sity and insulin resistance [43], suggesting their potential use

in the treatment of obesity.
Cholecystokinin (CCK)
The gut peptide, CCK, was one of the first satiety factors
to be discovered. CCK is released upon nutrient stimulation
of neuroendocrine secreting cells lining the intestinal lumen
[44]. It dose-dependently decreases meal size in rodents [45]
without affecting body weight. CCKs proposed pathway of
action via afferent vagal fibres to the NTS, may account for
the observation that CCK can decrease hypothalamic and
hippocampal NPY levels in the rodent brain without
affecting levels elsewhere in the brain [46, 47]. This result
suggests a negative relationship between NPY and CCKpeptides, which is not surprising given their opposite roles in
the control of feeding.
The physiological effects of CCK are mediated through
two G-protein coupled receptor (GPCR)s, CCK1 (formerly
CCK-A) and CCK2 (formerly gastrin/CCK-B). Several
studies have confirmed that exogenous CCK acts via
peripheral CCK1 to elicit satiety in cats and rodents [48-52].
However, the receptor site of action for endogenous CCK in
the periphery remains unclear. Dourish and colleagues [53]
demonstrated that endogenous CCK acts predominantly at
central CCK2 expressed in the VMH and PVN to promote
satiety. Several reports state that antagonism of CCK1
increases food intake in contrast to CCK2 antagonism [51,
52, 54, 55]. Meal termination induced by satiety signals can
be demonstrated when all neuronal connections between the
forebrain and hindbrain are severed [56] implying that the
brain areas involved are independent of hypothalamic
influence. Both leptin [57] and insulin [58] enhance the
satiating effects of CCK. Evidence shows that leptin potentiates activation of NTS neurones by CCK [59, 60], thus
demonstrating that signals involved in energy homeostasis
modulate the response of NTS neurones to input related to
satiety. Indeed melanocortin (MC) 4 receptors [61], leptin
receptors [62, 63], NPY receptors [64] and pro-opiomelanocortin (POMC) neurones are present in the NTS [65]. More
recently, Fan and colleagues have demonstrated brainstem
POMC neurones to be activated by CCK and feeding
induced satiety, and that activation of the MC4-receptor is
required for CCK induced suppression of feeding [66].
Human studies [67, 68] demonstrated that CCK-8 (an
octapeptide form of CCK released from the small intestine
after eating) reduced food intake in normal subjects by
altering the size of individual meals, but that repeated
administration did not alter body weight [69]. In the late
1990s GSK reported on orally active CCK1 selective benzodiazepine derivatives (GI-181771), which was followed three
years later by Sanofi-Sythelabo publishing on SR 146131, a
thiazole derivative, a potent, selective and orally active
CCK1 agonist that entered phase II clinical trials for obesity.
However, out of these two promising drugs only GI-181771
has progressed into advanced clinical trials, according to
Current Drugs IDdb3, accessed Aug 2004.
Ghrelin
Ghrelin, a recently discovered 28 amino acid gastric
peptide [70-72] with orexigenic and adipogenic properties, is
229
the only known endogenous ligand identified for the growth

hormone secretagogue receptor (GHSR)-1 to date [73, 74]. A
unique feature of ghrelin is that specific post-translational
modification of serine-3 to be n-octanoylated is fundamental
for its bioactivity. [75-77]. Ghrelin is primarily expressed (as
mRNA) in the stomach [70, 78, 79], with concentrations
decreasing distally along the intestinal tract (antrum >
duodenum > ileum > colon). Ghrelin expression is also
observed in the pancreas, kidney, liver, hypothalamus
(mainly ARC), pituitary gland, immune cells (B and T cells,
neutrophils) and placenta [70, 80-83].
Despite the robust effect on growth hormone (GH) secretion and stimulation of feeding/weight gain upon repeated
administration [84, 85], ghrelins lesser physiological activities in rodents include enhancing gastric motility, gastric
acid secretion, gastric and insulin release [86, 87]. The
orexigenic activity of exogenous ghrelin, is thought to be
mediated, at least in part, by brain NPY and agouti-related
protein (AGRP) [88, 98] as administration of either neutralizing antibodies or antagonists to these neuropeptides abolishes ghrelins augmentation of feeding in animals [90, 91].
In humans, as in rodents, Ghrelin 1) stimulates GH secretion
and increases food intake and appetite [92, 93]; 2) secretion
levels are increased in states of negative energy balance,
such as fasting and 3) levels rise between meals and fall
rapidly after eating [85, 94-96]. While obese human subjects
have much reduced ghrelin levels [85], the post-prandial
suppression of ghrelin after a meal appears to be absent [97]
that may contribute to the development of obesity. Indeed,
significantly increased ghrelin levels are present in morbidly
obese patients with Prader-Willi syndrome and may be a
factor to their extreme hyperphagia [94, 98]
Despite ghrelin knockout only exhibiting a preference for
fat utilization [99, 100], the selective knockout of the GHSR1 in the ARC nucleus of transgenic animals show a leaner
phenotype that is characterised by reduced epididymal and
mesenteric fat masses in addition to decreased food intake
and body weight [101]. Taken together with the limited
availability of ghrelin antagonists, such as [D-Lys3]GHRP-6
that reduces ghrelin-stimulated food intake in mice [102],
and administration (i.c.v.) of polyclonal anti-ghrelin antibodies decreases food intake in both fasted and normal dark
phase feeding rats [89], emphasize a role of ghrelin in feeding. Two recently published papers highlight new interest in
ghrelin. Helmling and colleagues described the use stable
RNA-based compounds, named spiegelmers (spiegel
meaning mirror in German) to bind active n-octanoyl ghrelin
with nanomolar affinities, inhibiting ghrelin mediated GHSR
activation in-vitro and growth hormone release in-vivo when
administered i.v. in rats [88]. The second discloses novel
analogs to human ghrelin with enhanced stability, increased
affinity for the GHSR, and ability to stimulate weight gain
[103]. This second paper also corroborates previous research
indicating that another receptor other than the GHSR
mediates the feeding activity of ghrelin [91, 104-107].
All these observations point to the presence of a
regulatory axis between the gastrointestinal system and the
hypothalamus-pituitary unit, with ghrelin as the intermediary
and makes antagonising the ghrelin GHSR system in the
CNS, a viable pharmacological approach to reduce food
intake, and ultimately reduced body weight.
230
Peptide YY (PYY3-36)
Professor Bloom and colleagues first described Peptide
YY3-36s (PYY3-36) effect on satiety and eating behaviour
[108]. Belonging to the same family as NPY, PYY3-36 is
released postprandially by the endocrine L-cells in the distal
ileum and colon in proportion to the nutrient content ingested
from a meal [109, 110]. Believed to act through the NPY-Y2
autoreceptors, PYY3-36 reduces the activities of NPY containing neurones, which in turn removes the tonic inhibitory tone
normally suppressing the anorexigenic POMC neurones, thus
overall inhibiting food intake [108, 111]. Like CCK, PYY3-36
transiently inhibits food intake, with its actions only lasting
3-4 hours post injection [108, 112, 113], though many have
found these results hard to reproducibly replicate [114, 115].
Unlike CCK, PYY3-36 does not cause its inhibition on food
intake via neuronal activation in the brainstem, but directly
in hypothalamic neurones that express POMC [112], in
particular those neurones in the ARC [108]. In a one study
[108] PYY 3-36 given i.p. was able to suppress fasted-induced
feeding in rats and mice via the NPY-Y2 receptors.
Even though it has been shown that fasting and postprandial levels of PYY3-36 are significantly lower in obese
subjects [116], variants in the genes encoding for PYY and
the NPY-Y2 receptor are not commonly found in humans
with severe early-onset obesity [117]. Despite this, PYY3-36
is a credible target for human obesity, as it has also been
shown to inhibit appetite and energy intake acutely in both
rodent and humans [35, 108, 116]. Indeed, there is considerable interest in the role of this gut hormone for suppression
of appetite, according to information in Current Drugs
IDdb3 (accessed Aug 2004). Amylin Pharmaceuticals Inc., is
currently developing the human gut PYY3-36 for the potential
treatment of obesity and diabetes. In January 2004, they
submitted patents on PYY3-36 for the treatment of obesity
with clinical trials planned. Nastech Pharmaceutical Co. Inc.,
has reported positive results from phase I studies with a nasal
PYY spray, showing that a mean reduction in food intake for
all doses of PYY was 8.2 % in the 9 of 11 responders, 5 of
which had greater than a 24 % reduction in food intake. PYY
was also well tolerated with the moderate side effects
(nausea, headache and dizziness) being resolved without
treatment. Merck are now set to co-develop PYY3-36 drug
with Nastech, with Merck assuming primary responsibility
for clinical and non-clinical studies and regulatory affairs,
with Nastech responsible for manufacturing.
BRAIN SIGNALS AFFECTING REGULATION OF
METABOLISM
Neuropeptide Y (NPY)
NPY, a 36 amino acid neurotransmitter [118] is one of
the most abundant and widely distributed neurotransmitters
in the mammalian brain [119] and is an important regulatory
peptide in both the central and peripheral nervous system
[120, 121]. Anatomical mapping of the sites involved in
NPY-mediated changes in energy homeostasis has localized
the effects to the PVN, dorsomedial hypothalamic nuclei
(DMH), ARC and (LHA), with short projections that terminate within the ARC itself [122], suggesting that NPY released within the ARC acts as a short negative feedback loop
Peter J. King
involving NPY autoreceptors. Indeed this inhibition is the

focus of PYY3-36 effects on feeding as discussed previously.
The effects of NPY on feeding are robust and elicited by
nanomolar doses injected into the lateral ventricles or hypothalamic structures (PVN or LHA) [123, 124], by increasing
both carbohydrate consumption [125, 126] and the size and
duration of the first meal, rather than by affecting meal
number [127]. Chronic administration of NPY into the PVN,
with the resulting 3-10 fold increase in hyperphagia demonstrates that NPY is capable of overriding powerful short- and
long-term mechanisms of satiety and body weight regulation
[128]. Such effects of NPY are also attributed to NPYs
insulin secretatogue actions, as insulin receptors located in
the hypothalamus [25, 129] are in near proximity to those
containing NPY, and anti-thermogenic properties, which are
mediated through the autonomic nervous system.
Inappropriate and unrepressed over-activity of the ARC
NPY neurones leads to obesity, as seen in rodent models of
obesity that is due to interruption of the leptin signaling
system, which is expected in view of leptins inhibitory effect
on the NPY neurones. Also, obesity develops through the
combination of decreased BAT activity, thermogenesis and
hyperphagia. Raised NPY mRNA levels are present in all of
these models, with increased NPY levels in the ARC, PVN
and DMH and enhanced NPY secretion in the PVN in fatty
Zucker rat [130]. Moreover, down-regulation of NPY
receptors, specifically of non-NPY-Y1 receptors (putatively
NPY-Y5 receptors) sites in the perifornical LHA, was shown
in the fatty Zucker rat [131]. All these observations strengthen
the hypothesis that overactivity of the ARC-PVN projection
plays a role in the hyperphagia and reduced energy expenditure that leads to obesity in these models. By contrast,
dietary-induced obesity leads to a fall in hypothalamic NPY
mRNA levels and an up-regulation of the non-NPY-Y1
receptors in the LHA [132]. This suggests that the hypothalamic NPY-ergic activity, particularly of the ARC-PVN
neurones, does not drive the hyperphagia associated with
exposure to a palatable diet [132], indeed these same
neurones appear to be inhibited, perhaps in an attempt to
limit hyperphagia and weight gain.
It is proposed that multiple NPY receptor subtypes
located in the brain, are involved in the regulation of food
intake (six characterised and cloned to date), with the notion
that NPY- Y1 receptors mediate the stimulatory effect of NPY
on carbohydrate intake and meal size, while NPY-Y2
receptors have the opposite effect of suppressing carbohydrate intake [125, 127], with much recent attention coming
from PYY3-36. Nonetheless, much attention has focused on
the NPY- Y5 receptor subtype as being the feeding receptor
[133]. However, the fact that the initial highly selective
antagonists developed as anti-obesity drugs did not have
major effects on normal feeding or body weight in rats [134],
and anecdotal evidence from Phase-2a trials with human
NPY-Y5 receptor antagonists not being successful, have
fueled the debate as to the involvement of each of NPYs
receptors in the regulation of food intake
Melanocortins & Agouti Related Protein (AGRP)
The melanocortin (MC) system has come under intense
academic and pharmaceutical scrutiny for its potential role
in several physiological processes including pigmentation,

sexual function, inflammation, cardiac function, memory and
other neuronal processes and critically, energy homeostasis.
The latter being highlighted as there are several reports
linking alterations in POMC or MC4-receptor genes with
obesity in humans [135-137]. For a more detailed role of the
melanocortin system in obesity and the current peptide, nonpeptide small molecule ligands under development the reader
is referred to the recent review [138] and references therein.
MC4-R and, to a lesser extent, MC3-R are the key
receptor sub-types implicated for pivotal roles in the control
of food intake. MC-receptors are activated by one of several
peptides derived from the POMC pituitary precursor (including ATCH, -, -, -melanocortin stimulating hormone
(MSH), -endorphin [139, 140]. Agouti and AGRP are
competitive antagonists at the MC4-R and their unique
endogenous existence confers an extra level of control on the
system. Evidence for this came from early studies on the
mutant yellow obese agouti (Ay/a) mouse. In this model
expression of agouti (a 131 amino acid peptide) in the fair
follicles antagonises the action of -MSH at the MC-1
receptor switching production of eumelanin (brown-black)
induced by -MSH, to phaeomelanin (yellow-red), resulting
in the yellow fur pigmentation that is characteristic in such
mice [141, 142]. The obesity in the agouti mouse is a
consequence of agoutis ectopic expression antagonising the
hypothalamic MC-3 and MC-4 receptors in the brain [142],
to which -MSH binds to with high affinity [143, 144].
Furthermore, injection of either -MSH, or its stable
analogue MTII (i.c.v.), inhibits normal feeding, with the
extent of -MSHs inhibition of feeding being extended to
four mice models of hyperphagia, including fasted obesity
prone C57BL/6J, ob/ob, (Ay/a) mice and NPY-induced
hyperphagic mice [145]. By contrast, the selective MC-4
peptide receptor antagonists, HS024, HS028 and SHU9119,
increased feeding in both normal and satiated rodents [145147]. Huszar and colleagues (1997) observed that null mice
for the MC4-R are hyperphagic and exhibit an obese
phenotype [142].
A vast number of agonistic compounds have been
screened but to date none have been clinically evaluated.
MC4-R antagonists block anorexia in rodents induced by
central administration of both endogenous agonist ligand, MSH and other synthetic peptide agonists [148]. Chiron have
reported on more encouraging potent and selective nonpeptidic molecules [149], with GSK under license from
Chiron Corp2, Proctor & Gamble Co. [150-152], Amgen Inc.
[153], Novartis, Neurocrine Biosciences Inc., Millennium
Pharmaceuticals Inc, Eli Lily & Co [154], and their subsidiary company Novasite Pharmaceuticals Inc., Merck & Co
Inc., and the University of California [155], to highlight just
a few are all investigating MC receptor ligands for the potential treatment of obesity, cachexia and erectile dysfunction.
Clearly the ability to separate anti-obesity activity from
spontaneous erectile activity will be a significant factor in
determining whether any MC4-R agonist, peptide or not, will
be developed as a weight loss agent. With the high level of
____________________________
2
Chiron Corp (2003) Press Release., Chiron and GSK to codevelop MC-4R
231
validation for the involvement of the MC4-R in energy

homeostasis, it is to be expected that selective small molecule MC4-R agonists will eventually be clinically evaluated
for the treatment of obesity.
Cocaine
(CART)
and
Amphetamine
Regulated
Transcript
In 1998, the peptide cocaine- and amphetamine-regulated

transcript (CART) was added to the list of neuropeptides
identified for affecting feeding behaviour (Fig. 3). CART
mRNA was initially identified using a PCR differential
display technique whose levels in the brain were specifically
induced by psychomotor stimulants, cocaine and amphetamine [156]. In the brain regions sensitive to the actions of
the psycho-stimulants, such as the striatum, CART was
shown to be induced 4 - 5 fold [157]. Further investigation
revealed that CART mRNA was found enriched in the
hypothalamus [158], with low levels also present in the eye,
adrenal and pituitary, with no other signals detected
elsewhere in the rat [157, 159, 160].
Food restriction decreased CART levels in the ARC
[161, 162] and obese animals were shown to have minimal
or no expression of CART, fueling speculation that CART is
involved in the regulation of feeding behaviour.
Considerable evidence now exists to suggest that CART is
an endogenous satiety factor modulating the actions of NPY
and leptin. Studies showed that administration of recombinant CART (i.c.v.) inhibited both normal and starvationinduced feeding [162-164] and completely inhibited NPYinduced feeding in rodents [162], whereas central infusion of
anti-CART antibodies resulted in higher food consumption
[162-164]. Furthermore, peripheral administration of leptin
in obese animals induced the expression of CART in the
ARC [162].
Unfortunately, the CART peptide fragments, CART (82103) and CART (55-102), have been shown to only
transiently decrease the feeding response induced by NPY,
with central intra-hypothalamic administration of CART
shown to actually increase feeding [165]. In addition, CART
knockout mice only become obese when fed a high-calorie
diet [166]. However, CART, and in particular its putative
receptor (not yet identified) represent another possible
therapeutic target to control food intake and obesity, with the
hypothesis that a proportional reduction in NPY and an
increase in CART, control the leptin-mediated suppression
of food intake [164].
Melanin Concenrtating Hormone (MCH)
A role for MCH in feeding was initially demonstrated by
studies showing that its expression is higher in the
hypothalamus of both ob/ob and fasted mice and that acute
i.c.v. injection of MCH to rats and mice stimulate feeding
[167-171]. MCH is a cyclic neuropeptide with rat, mouse
and human sharing a high degree of homology with salmon
MCH, from which MCH was initially isolated [172-174]. In
rodents and humans prepro MCH is expressed predominantly
with the LH and zona incerta of the CNS [175, 176].
These MCH expressing neurones project widely
throughout the CNS (including pituitary) suggesting MCH to
be involved in many neuronal functions [177], including
232
Peter J. King
Fig. (3). Neural and hormonal mediators of hunger and satiety. Adapted from Metabolic Disorders Study # 11, Obesity, August 2004 with
permission from Decision Resources, Inc., Waltham, MA.
regulating the release of lutenising hormone [178, 179] and

adrenocorticotropic factor (ACTH) [180, 181]. In the rat and
human approximately 70 -% of the MCH neurones in the LH
and nearly 95 % in the ZI co-express the anorexigenic peptide CART [182, 183], whereas in the rat, such populations
of neurones are also in close proximity to orexin cells in the
LHA [184]. Two MCH receptors (both GPCRs) have been
identified. The MCH-1R (as known as SLC-1 or GPCR 24)
[185, 186] is found in rodents and higher mammalian species
[187] and is distributed widely throughout the brain
including the nucleus accumbens, VMH, DMH and ARC of
the hypothalamus [185, 188, 189], a pattern consistent with
the terminal fields of MCH neurones. The second, MCH-2R
has only a 37 % homology with MCH-1R [190, 191], but
unlike MCH-1R it is not expressed in rodents but is present
in ferrets, dogs, rhesus monkeys and humans [187, 192]. Due
to MCH-2Rs lower and more restricted expression, plus its
differing species-species expression pattern it is currently
unclear as to its role in food intake and energy expenditure.
The most intensively study role for MCH is in the regulation of feeding behaviour and energy homeostasis. MCHexpressing neurones in the LH receive afferent projections
from NPY/AGRP and POMC expressing neurones in the
ARC that respond to circulating leptin and insulin. Specifically, fibres for NPY and AGRP, and the anorexigenic
peptide -MSH innervate MCH neurones, with this innervation most intense in the perifornical area [193]. Chronic
central infusions of MCH to mice on a high fat diet produce
persistent hyperphagia together with increased adiposity,
hyperinsulinaemia and hyperleptinaemia [194, 195] whereas
i.c.v. administration of a potent MCH-1R agonist to rats
produced similar effects [196]. Intriguingly, no sustained
hyperphagia is produced following repeated injections [197].
Transgenic mice overexpressing MCH are hyperphagic,
obese and insulin-resistant [198]. Conversely, MCH knockout mice have a lean phenotype characterised by hypophagia and increased energy expenditure [199]. Interestingly,
mice lacking both MCH and leptin, despite consuming
similar amounts of food, are leaner compared to ob/ob mice
due to their increased energy expenditure and improved
glucose tolerance [200]. This hypermetabolic phenotype was
also observed in the MCH-1R null mice, despite being
hyperphagic, they are lean and have decreased leptin and
insulin levels that are similar to the MCH deficient mice
[197, 201]. Such hyperphagia is not explained by alterations
in the expression of NPY, AGRP, orexin or CART and
POMC, nor in the tone of endogenous orexigenic signals as
evidenced by a normal response to exogenously administered
NPY or AGRP [197, 201].
The promising pharmacology of the MCH-1R has made
this an attractive target for the development of smallmolecule antagonists by several companies. A recent review
details the advances in MCH-1R antagonists [202]. Highlighting just a few of the in-vivo effects, Merck have described the activity of a peptide MCH-1R antagonist [196],
while Takeda [203] and Synaptic [204] have small molecular
weight antagonists. All reverse the orexigenic effects of
MCH-1R agonists in rats. Arena Pharmaceuticals Inc., have
also reported an orally bioavailable MCH receptor modulator
able to reduce body weight equivalent to that of sibutramine3.
On a cautionary note, increased heart rate has been observed
233
in MCH-1R null mice, and as with NPY receptors, the wide

distribution of MCH-1R in the CNS indicates the likelihood
of multiple roles for MCH-1R signaling [189].
Glucagon-Like Peptide 1 (GLP-1)
Extra hypothalamic targets may include the neurones of
the medulla that express the gut peptide, GLP-1, an alternative cleavage product of the preproglucagon gene. Preproglucagon mRNA and GLP-1 like immunoreactivity have
been shown in cell bodies of the nucleus of the solitary tract,
that project to the PVN, one of the main feeding control
centres in the hypothalamus [205]. Specific GLP-1 receptors
are also located in the PVN and amygdala [206] and GLP-1
has been shown to reduce food intake and body weight when
injected centrally in rats [207]. More recently both central
and peripheral administration of exendin-4 (a small peptide
agonist of GLP-1 that is isolated from salivary venom of the
Gila monster) reduced food intake in rats4.
GLP-1 is convincingly implicated as a short acting
endogenous, meal related satiety peptide [208], as it has been
shown to interact with other regulators of food intake, as it
completely inhibits the effects of NPY on food intake [209].
The role of leptin in GLP-1s actions is mixed. Even though
prolonged treatment in the diabetic db/db mice with exendin4 had no effect on body weight [210], contrary data has
shown that both lean and obese (fa/fa) Zucker rats have
reduced food intake and body weight after chronic treatment
with exendin-4 [211, 212]. GLP-1 has also been shown to
activate the hypothalamo-pituitary adrenocortical axis
through stimulation of CRH neurones, and this activation
may also be responsible for the inhibition of feeding behaviour [206].
However, the actions of GLP-1 on feeding are too short
[207] to play a central role in the long-term regulation of
feeding (possible due to the very short half-life of GLP-1 in
the circulation system) and are thought to mediate postprandial satiety. Despite this, GLP-1 angonism through
increased stability and biological activity, or inhibition of
dipeptidy peptidase IV (DPP IV) that rapidly inactivates
GLP-1 may prove promising therapies for the treatment of
obesity and also diabetes. Amylin and Eli Lily [213]
presented data at various meetings5 showing subjects treated
with Exendin-4 (Exenatide and Exenatide-LAR), as having
significant weight loss 6, with such data reflected in C57Bl/6J
mice fed a high fat diet7. Several competitors including Novo
Nordisks Liraglutide and again Amylin Pharmaceutical with
Pramlintide may offer effective prospects for anti-obesity
treatment.
____________________________
3
Bjenning, C.A.; Whelan, K.; Creehan, K.; Gonzalez, L.; Al-Shammal, H.; Thomsen,
W.J.; Tran, T.; Semple, G.; Funakoshi, T.; Nishiguchi, M.; Kanuma, K.; Sekiguchi, Y.
and Chaki, S. (2004) Soc. Neurosci. Abst., 34, (San Diego) Abs. 629.8.
4
Al-Barazanjika, K.A.; Buckingham, R.E.; Tadayyon, M. and Arch, J.R.S. (1998) Int.
J. Obesity, 22, suppl 23, S73.
5
64th ADA scientific meeting in Orlando, USA; 40th EASD Annual meeting in
Munich, Germany; SMis annual Diabetes meeting in London, UK.
6
Mack, C.M.; Wilson, J.K.; Young, A.A. and Parkes, D.G. (2004) Diabetes, 53, Abs
1717-P.
7
Moore, C.X.; Jodka, C.M.; Hoyt, J.A.; Young, A.A. and Sams-Dodd, F. (2003)
Diabetes, 52, suppl 6, Abs 1691-P.
234
Orexins/Hypocretins
Several hypothalamic neuropeptides function in the
central control of food intake, but until the discovery of
orexins (also known as hypocretins) only MCH was specifically produced in the LHA [214]. Even though central
administration of either peptide stimulates food intake 215,
216], orexins and MCH are not co-localised in the lateral
hypothalamus (LH) [187]. Orexin-A and orexin-B (33 & 28
amino-acids, respectively) are found to be abundant in the rat
hypothalamus, medulla-pons, and midbrain-thalamus, with
moderate expression found in the cerebral cortex, with their
mRNA being restricted to cell bodies present in the LH [187,
216]. However, levels of orexin-B were found to be much
greater than that of orexin-A in the LH, as well in a lesser
extent in other brain regions [217, 218]. Immunohistochemical mapping of orexins have demonstrated that orexincontaining fibres project to selective nuclei in the hypothalamus, central gray, dorsal raphe nucleus of the midbrain,
as well as the locus coeruleus of the medulla [219]. This
would explain the high orexin contents of the midbrainthalamus, medulla-pons and cortical mantle that receive
abundant projections from the LH [219]. After 48 hour
fasting, both orexin-A and -B exhibited a trend to increase in
the LH, with prepro-orexin mRNA being up-regulated 2.4
fold after [216]. There are contradictory data with respect to
either of the orexins involvement in feeding. Both orexin-A
and orexin-B equally and dose-dependently stimulated feeding in rats when injected in the cerebral ventricles [216].
However, single injections of orexin-A into the third
ventricle of C57BL/6J mice 3 hours into the light phase
increased metabolic rate but only slightly stimulated feeding
and orexin-B had no effect [220]. Despite the species
differences these data suggest that orexins are more likely to
be involved in control of energy metabolism rather than food
intake. Further to this notion, Cai and colleagues (1999)
observed an increase in hypothalamic prepro-orexin mRNA
only in rats fasted for 48 hours, or when rats were made
acutely hypoglycaemic but only in the absence of food.
Intriguingly, chronic 6-day food restriction, streptozotocininduced diabetes, hypoglycaemia in which rats were allowed
to feed, neuroglycopenia provoked by 2-deoxy-D-glucose,
and dietinduced obesity all failed to bring about changes in
orexin mRNA levels. Moreover, no obvious relationship of
orexin expression was observed with respect to insulin,
leptin or body fat mass observed [221].
The roles of the orexins remain unclear, but the above
data suggests that orexin peptides may be linked to nutritional status of the circadian cycle together with the state of
hunger rather than to satiety. Orexins also are strongly
involved in the sleep-wake patterns, being documented as
causing narcolepsy in animal models when its actions are
blocked, therefore, shedding doubt as to its direct effects on
feeding [222, 223].
Serotonin (5HT)
Although the brain 5-HT system has been known since
the 1970s to be intrinsically linked to feeding, it is only
recently that we have been able to define the receptor subtypes responsible for and understand 5HT-mediated hypophagia.
Peter J. King
It is believed that fourteen 5-HT receptor subtypes exist

and these are conveniently divided into 7 classes, 5HT1 to
5HT7. Of these, research into potential treatments for obesity
in terms of food intake has centred upon 5HT1A, 5HT1B,
5HT2A and 5HT2C with the latter currently the best candidate.
5HT1A is an autoreceptor that reduces 5HT release onto
post-synaptic 5HT receptors, activation of which, in rats,
results in hyperphagia [224, 225]. The precise role of 5HT1B
in the control of feeding is still up for discussion. Although
activation of 5HT1B receptors has been shown to attenuate
feeding in animal models [226-228] and transgenic 1B
receptor knockout mice gain more weight than their WT
littermates [229], these results are in no way universal [230].
Hypophagia associated with activation of 5-HT 2A receptors is
thought to be as a result of non-specific behavioural disruption, namely sedation and nausea [231].
More importantly, there is considerable evidence that 5HT2C specifically mediates hypophagia in both animals and
man, and appears to be a consequence of increased satiety.
Recent studies have concentrated on the 5-HT2C receptors.
The presence of 5-HT2C receptor mRNA in the choroid
plexus, various cortical areas, hippocampus, amygdala,
nucleus accumbens, substantia nigra and brainstem nuclei in
the rat, monkey and humans [232, 233] has been confirmed
by immunohistochemical analysis and in situ hybridization
experiments. Moreover, 5-HT2C receptor expression was
noted in the VMH in humans [234]. Immunohistochemical
studies, rather than autoradiographical studies of the rat brain
have reported 5-HT2C receptor expression in the ARC,
DMH, PVN and LH nuclei [235-237]. There is some evidence also to suggest a role for 5-HT2C receptor mediated
hypophagia in hypothalamic control of feeding. It has been
hypothesised that 5-HT 2C receptor activation of ARC POMC
neurones results in -MSH activation of MC3 and MC4
receptors to produce the hypophagic effect [238]. Support for
this came in another study that revealed that d-fenfluraminemediated hypophagia is prevented by prior treatment of
animals with the MC receptor antagonist, SHU9119 [238]. It
has also been reported that sibutramine indirectly causes
MC3/4 receptor down-regulation in certain hypothalamic
nuclei8 thereby adding further evidence for downstream activation of the ARC melanocortin system by 5-HT2C receptors.
Equally efficacious as both sibutramine and dexfenfluramine is AR-10A, an orally active 5-HT2C receptor agonist
presented by Arena Pharmaceuticals Inc., acute administration of which dose-dependently reduced food consumption in free-fed SD rats, an effect reversed by the 5-HT2C
antagonist, SB-242084, but not by a 5-HT2A antagonist,
according to information in Current Drugs IDdb3
(accessed August 2004).
There are a number of compounds which while not
specific act more selectively as 5-HT2C receptor agonists.
Agonists tri-fluoromethylphenylpiperazine (TFMPP) and mchlorophenylpiperazine (mCPP) [239-243], have been shown
to increase the latency to feed, reduce the size of the first
meal following treatment and slow the rate of feeding [226,
____________________________
8
King, P.J. and Berwaer, M. (2003) NAASO meeting, Ft Lauderdale, FL, USA.
Obesity Research, 11, Abs. 124-OR
227, 244]. A recent review by Bickerdike, 2003 [245]

describes in more details MK-212, Org 37684, Ro 60-0175,
PNU-22394 and VER 3323, all of which acutely attenuate
food intake by satiety processes in animal models [246-2529,
10
]. However, this does not mean that a prolonged drop in
food intake and/or loss of body weight results from chronic
treatment with these compounds. The possibility of receptor
desensitization in-vitro [253, 254] as well as in-vivo has been
well documented [255-259], even though chronic administration doesnt appear to promote tolerance in drug-induced
hypophagia [260, 261].
Cillary Neurotrophic Factor (CNTF)
An alternative approach to finding small molecule
agonists for the leptin receptor is to mimics leptins actions.
This approach has been adopted by Regeneron, using a
genetically engineered version of human CNTF (Axokine)
for the treatment of obesity (Fig. 1).
CNTF is a naturally occurring protein that functions as a
regulator of cell differentiation and survival, and is expressed
in hypothalamic regions of the brain that effect energy
balance. Although the mechanism by which CNTF administration leads to weight loss in humans and animals [262-264]
is still unclear, it is believed to work through leptin-like
independent mechanisms. CNTF receptors are present in the
ARC of the hypothalamus and upon activation, signal to
satiety centres in the brain [265]. Studies in ob/ob, db/db and
DIO mice showed that CNTF and CNTFAx15 (Axokine, a
second generation analog) can suppress food intake without
increasing NPY levels and causing muscle wasting [263265], indicating that CNTF acts, at least in part, downstream
of the leptin receptor, bypassing the leptin resistance. One
study showed that CNTF affects adipocyte signaling in
rodents and induces insulin action in vitro [266] suggesting
that the ability of CNTF to induce weight loss is not solely
mediated by the CNS.
However, due to the fact that approximately 70 % of
users in clinical trials formed neutralizing antibodies during
treatment, according to information in Current Drugs
IDdb3 (accessed August 2004), it will make this drugs
market more selective.
Keeping the brains feeding centres in mind, much

attention now focuses on the myriad of interacting systems
controlling both the short-term (meal-to-meal) and long-term
(energy balance equilibrium) signals that converge on the
hypothalamus, working in partnership to control feeding
behaviour, as depicted in Fig. (3). However, due to numerous
pathways involved in weight regulation, many of which still
remain to be fully explored, up and coming drug targets are
likely be effective for only certain patient groups.
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