Neuropeptides

Neuropeptides 40 (2006) 375–401

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Role of neuropeptides in appetite regulation and obesity – A review

Sarika Arora *, Anubhuti
Department of Biochemistry, Lady Hardinge Medical College, Shaheed Bhagat Singh Marg, Connaught Place, New Delhi, Delhi 110 001, India

Received 1 March 2006; accepted 7 July 2006

Available online 28 August 2006

Abstract

Obesity represents the most prevalent nutritional problem worldwide which in the long run predisposes to development of dia-
betes mellitus, hypertension, endometrial carcinoma, osteoarthritis, gall stones and cardiovascular diseases. Despite significant
reductions in dietary fat consumption, the prevalence of obesity is on a rise and is taking on pandemic proportions. Obesity develops
when energy intake exceeds energy expenditure over time. Recently, a close evolutionary relationship between the peripheral and
hypothalamic neuropeptides has become apparent. The hypothalamus being the central feeding organ mediates regulation of
short-term and long-term dietary intake via synthesis of various orexigenic and anorectic neuropeptides. 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 have been characterized in rodent models The
peripheral neuropeptides such as cholecystokinin (CCK), ghrelin, peptide YY (PYY3-36), amylin, bombesin regulate important gas-
trointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of
nutrients and may play a part in regulating food intake. The pharmacological potential of several endogenous peripheral peptides
released prior to, during and/or after feeding are being explored. Long-term regulation is provided by the main circulating hormones
leptin and insulin. These systems implicated in hypothalamic appetite regulation provide potential targets for treatment of obesity
which could potentially pass into clinical development in the next 5 years. This review summarizes various effects and interrelation-
ship of these central and peripheral neuropeptides in metabolism, obesity and their potential role as targets for treatment of obesity.
Ó 2006 Elsevier Ltd. All rights reserved.

Keywords: Appetite regulation; Role of hypothalamus in appetite regulation; Neuropeptide Y (NPY); Leptin; Insulin; Gut peptides; Pro-opiome-
lanocortins (POMC); Agouti-related peptide (AGRP); Cocaine- and amphetamine-related transcript (CART); Amylin

1. Introduction endometrium, prostate, bowel cancers (Neary et al.,

2004).
Obesity is a serious medical condition whose preva- Obesity represents a state of excess storage of body
lence is increasing in developing countries also. This fat. Although very similar, the term overweight is defined
growing incidence represents a pandemic that needs as an excess body weight for height. The body mass index
urgent attention if the potential morbidity, mortality, (BMI), also known as the Quetelet index is a WHO
and economic tolls that will be left in its wake are to accepted index for classifying the degree of obesity. Stan-
be avoided. Obesity predisposes to increased risk of a dards defining overweight and obesity on the basis of
number of medical conditions including type II diabetes BMI were developed by the International Obesity Task
mellitus, hypertension, coronary heart disease, osteoar- Force of the World Health Organization (WHO Report,
thritis, respiratory problems and cancers of breast, 1998) and adopted by an expert committee of the NHLBI
(NHLBI guidelines, 1998). BMI = (weight [kg])/(height
*
Corresponding author. Tel.: +91 11 25506229. [m]2). Under this convention for adults, grade 1 over-
E-mail address: sarikaarora08@rediffmail.com (S. Arora). weight (commonly and simply called overweight) is a

0143-4179/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.npep.2006.07.001
376 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401

BMI of 25–29.9 kg/m2. Grade 2 overweight (commonly of the ‘circumventricular’ organs where the blood–
called obesity) is a BMI of 30–39.9 kg/m2. Grade 3 over- brain barrier is specially modified to allow entry of
weight (commonly called severe or morbid obesity) is a peripheral peptides and proteins including insulin and
BMI greater than or equal to 40 kg/m2. leptin, both of which are considered to be signals of
The laws of thermodynamics are applicable here also fat mass. (Friedman and Halaas, 1998; Schwartz
because if energy expenditure by the body is less than et al., 1992a,b). The ARC contains populations of
the consumption, it will be stored in the body in the form neurons that express neuropeptide Y (NPY),
of adipose tissue. Appetite regulation is important agouti-related peptide (AGRP) and the melanocortin
because it modulates the energy consumption side of precursor pro-opiomelanocortin (POMC). Thus arcu-
the equation. Appetite includes various aspects of eating ate nucleus is a privileged site which can sample the
patterns such as frequency and size of eating episodes peripheral circulation through semi-permeable capillar-
(gorging versus nibbling), choices of high fat or low fat ies in the underlying median – eminence and is the
foods, energy density of foods consumed, variety of foods ideal position to integrate hormonal signals for energy
accepted, palatability of diet and variability in day-to- homeostasis.
day intake. Feeding behavior is controlled by a series of The paraventricular nucleus (PVN) is adjacent to the
short-term hormonal, psychological and neural signals superior part of the third ventricle in the anterior hypo-
that derive from the gastrointestinal tract, such as chole- thalamus. The PVN is the main site of corticotropin
cystokinin whereas other signals may initiate meals, such releasing hormone (CRH) and thyrotropin releasing
as the recently discovered hormone, ghrelin. Other hor- hormone (TRH) secretion. Numerous neuronal path-
mones such as insulin and leptin, together with circulat- ways implicated in energy balance converge in PVN,
ing nutrients, indicate long-term energy stores. All these including major projections from NPY neurons of the
signals act at several central nervous system (CNS) sites ARC, Orexins, POMC derivative a-melanocyte stimu-
but the pathways converge on the hypothalamus, which lating hormone (a-MSH) and the appetite stimulating
contains a large number of peptides and other neuro- peptide galanin. Thus PVN plays a role in the integra-
transmitters that influence food intake (Table 1). As tion of nutritional signals with the thyroid and hypotha-
energy deficit is most likely to compromise survival, it lamic-pituitary axis (Neary et al., 2004).
is not surprising that the most powerful of these path- Ventromedial nucleus of hypothalamus (VMH) is
ways are those that increase food intake and decrease mainly acting as satiety centre. It has been identified
energy expenditure when stores are depleted. as a key target for leptin, which acts on the hypothala-
When energy stores are low, production of leptin mus to inhibit feeding, stimulate energy expenditure
from adipose tissue, and thus circulating leptin concen- and cause weight loss. Lesions of either ventromedial
trations fall, leading to increased production of hypo- hypothalamic nuclei or PVN produce syndromes of
thalamic neurotransmitters that strongly increase food hyperphagia and obesity (Satoh et al., 1997).
intake, such as neuropeptide Y (NPY), galanin and The dorsomedial hypothalamic nucleus (DMH), has
agouti-related protein (AGRP) and decreased levels of extensive connections with other medial hypothalamic
a-melanocyte-stimulating hormone (a-MSH), cocaine nuclei and the lateral hypothalamus and serves the func-
and amphetamine-regulated transcript (CART). The tion of integration and processing of information from
hypothalamus has been recognized as a central region these nuclei (Elmquist et al., 1998).
of feeding regulation (Wilding, 2002). The appetite con- The lateral hypothalamic area (LHA) is the classical
trol system of the brain normally establishes a weight ‘feeding centre’, also contains glucose-sensitive neurons
‘set-point’ and tries to maintain it even when food that are stimulated by hypoglycemia (by ascending path-
supplies vary a great deal. ways from brainstem) and it is crucial in mediating the
marked hyperphagia which is normally induced by hyp-
oglycaemia (Bernardis and Bellinger, 1996). The
2. Role of hypothalamus approximate locations of different hypothalamic nuclei
are shown in Fig. 1.
The role of hypothalamus in feeding control has been The brainstem. There are extensive reciprocal connec-
revealed by classical (but crude) experiments and some tions between the hypothalamus and brainstem, particu-
of the nuclei have been discretely referred to as ‘feeding’ larly the Nucleus of Tractus Solitarius (NTS) (Ter Horst
and ‘satiety’ centres. The main regions of hypothalamus et al., 1989; Ricardo and Koh, 1978; van der Kooy et al.,
involved in feeding and satiety are: 1984). The NTS has a high density of NPY-binding sites
Arcuate (ARC), acts as a feeding control center and (Harfstrand et al., 1986), including Y1 receptors (Glass
integrates hormonal signals for energy homeostasis et al., 2002) and Y5 receptors (Dumont et al., 1998).
(Funahashi et al., 2000). The Arcuate Nucleus encloses Extracellular NPY levels within the NTS fluctuate with
the third ventricle and lies immediately above the med- feeding (Yoshihara et al., 1996), and NPY neurons from
ian eminence. The ARC-median eminence area is one this region project forward to the PVN (Sawchenko
 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401 377

Table 1
Major neuropeptides involved in appetite regulation
Neuropeptides Orexigenic Anorexigenic agents
Central 1. Neuropeptide Y 1. Cocaine and amphetamine related transcript (CART)
2. Melanin concentrating hormone (MCH) 2. Melanocortins (POMC)
3. Orexins/hypocretins 3. Glucagon like peptide
4. Agouti-related peptide (AGRP) 4. Corticotropin releasing factor (CRF)
5. Galanin 5. Insulin
6. Endogenous opioids 6. Serotonin
7. Endocannabinoids 7. Neurotensin
Peripheral 1. Ghrelin 1. Peptide YY
2. Cholecystokinin (CCK)
3. Leptin
4. Amylin
5. Insulin
6. Glucagon-like peptides
7. Bombesin

et al., 1985). There is also evidence for a melanocortin Five G-protein coupled NPY receptors have been
system in the NTS, separate from that of the ARC identified – Y1, Y2, Y4, Y5 and Y6 that mediate their
(Kawai et al., 1984). Also satiety signals following a actions in hypothalamus either by decreasing adenylate
meal are carried by afferent fibers of the vagus nerve cyclase and consequently decreasing cAMP levels and
to the brain stem (Williams et al., 2001). increasing intracellular calcium (Gehlert, 2004; Wahles-
The brainstem plays a role in individual meal size, tedt and Reis, 1993). These NPY receptors are found
increasing it with a decrease in the frequency of meals with individual distribution patterns in many hypotha-
as in experiments by Grill and Smith (1988). lamic neurons including neuroendocrine motorneurons,
magnocellular neurosecretory neurons and numerous
neurons connecting the hypothalamus with the limbic
3. Orexigenic neuropeptides secreted by hypothalamus and the autonomic nervous systems (Fetissov et al.,
2004). Y5 receptors have been implicated as important
3.1. Neuropeptide Y receptors that mediate the feeding effects of NPY
(Marsh et al., 1998; Pedrazzini et al., 1998). The Y5
Neuropeptide Y (NPY) contains 36 amino acid resi- receptor is expressed at relatively high levels in the
dues, including a tyrosine at each end (hence ‘Y’, the LHA, close to the site where NPY acts most potently
code for Tyrosine) (Williams et al., 2000). NPY is one to stimulate feeding (Williams et al., 2000). NPY recep-
of the most abundant peptides of the hypothalamus tor density in this area is decreased during starvation,
(Allen et al., 1983) and one of the most potent orexigenic which may be explained by down regulation of these
factors (Edwards et al., 1999; Kalra and Kalra, 2004). It receptors following local availability of NPY. NPY
has been functionally implicated in feeding behavior, release is known to be enhanced during food deprivation
cardiovascular regulation, control of neuroendocrine (Kalra et al., 1991).
axes, affective disorders, seizures, and memory retention NPY and other orexigenic peptides like AgrP, GABA
(Pedrazzini, 2004). The ARC is the major site of expres- and adrenergic transmitters, initiate appetitive drive
sion for NPY within neurons in the hypothalamus that directly through Y1, Y5, GABAA and a-1 receptors,
project to PVN, DMH, LHA, and other hypothalamic co-expressed in the magnocellular neurosecretory neu-
sites. Although NPY can produce diverse effects on rons and ARC neurons and by simultaneous repression
behavior and other functions, its most noticeable effect of anorexigenic melanocortin signaling in the ARC
is the stimulation of feeding after central administration (Kalra and Kalra, 2004). NPY synthesis in the ARC
(Inui, 2000). When administered intracerebroventricu- and its release into the PVN, the most abundant projec-
larly (ICV) in rats, it produces a powerful and prolonged tion, are regulated by afferent signals such as leptin,
increase in food intake (Clark et al., 1984). When insulin (both inhibitory), and glucocorticoids (stimula-
administered chronically, NPY produces hyperphagia, tory). The NPY neurons are potential hypothalamic tar-
decreased thermogenesis and obesity (Stanley et al., gets for leptin and as discussed later, inhibition of the
1986). NPY gene expression in the hypothalamus is synthesis (probably release) of NPY seems to partly
found to be increased compared to controls in many dif- explain the ability of leptin to induce hypophagia and
ferent rodent models of altered feeding (Williams et al., weight loss. Insulin receptors are expressed in the medi-
1989 and Wilding et al., 1993). obasal hypothalamus, and median eminence, and insulin
378 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401

Fig. 1. Diagram (not to scale) showing interrelationship between various appetite regulatory neuropeptides and their major sites of origin and action.
The upper part of the diagram shows the relative location of the hypothalamic nuclei involved in appetite regulation as seen in the coronal section of
the hypothalamus. The lower depicts the peripheral organs and their secreted neuropeptides. The solid lines indicate a stimulatory effect and dotted
line indicates an inhibitory effect of peripheral neuropeptide on the hypothalamic nuclei/neuropeptides. Various experimental studies have shown
that the lesions in the medial part of the hypothalamus are associated with hyperphagia whereas the lesions in the lateral part of hypothalamus lead
to loss of appetite. Abbreviations: PVN – Paraventricular nucleus: LHA – Lateral Hypothalamic Area: DMH – Dorsomedial hypothalamus: VMH:
Ventromedial Hypothalamus: ARC – Arcuate Nucleus: NTS – Nucleus of Tractus Solitarius: ?? – Unknown origin of neuropeptide Bombesin.
Abbreviations for neuropeptides are similar to those used repeatedly in the text.

has been shown to inhibit NPY synthesis and secretion orexigenic ghrelin from stomach determine the daily
in the PVN: however, it is not clear whether insulin meal pattern (Kalra and Kalra, 2004).
receptors are actually carried by the NPY neurons or NPY synthesis and secretion are all up-regulated in
by the neurons that impinge on them (Schwartz et al., models of energy deficiency or increased metabolic
1992a,b and Kalra et al., 1991). Circadian and ultradian demand such as starvation, insulin-dependent diabetes
pattern of NPY secretion and corresponding reciprocal mellitus, lactation and physical exercise. (Inui, 2000).
circadian and ultradian rhythmicities of peripheral neu- The NPY neurons that are activated by fasting are the
ropeptides like anorexigenic leptin from adipocytes and neurons that express the long form of the leptin receptor
 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401 379

(Baskin et al., 1999). A primary physiological role of the Non-peptide antagonists for MCH-1R prevented the
ARC NPY neurons may thus be to restore normal high-fat diet-induced obesity, and possess anti-anxiety
energy balance and body fat stores under conditions of and antidepressant effect (Hervieu, 2006). These finding
energy deficit, the signals of which are falling leptin indicate the involvement of MCH in the development of
and/or insulin occurring in these conditions. obesity, memory and emotion. MCH receptor antago-
By contrast, dietary obesity induced by voluntary nist might be useful for the treatment of obese syndrome
over-eating of highly palatable diet is not accompanied including psychological disorder-related obesity (Katsu-
by obvious increases in the activity of ARC NPY neu- ura and Inui, 2003; Xu et al., 2006; McBriar et al., 2006;
rons. Indeed there is some evidence that their activity Kowalski et al., 2006).
may be inhibited thus attempting to restrain overeating
palatable food (Widdowson et al., 1997). 3.3. Orexins

3.2. Melanin-concentrating hormone The orexins are a class of neuropeptides that were
earlier described as hypocretins (Sakurai et al., 1998;
Melanin-concentrating hormone (MCH) is an orexi- De Lecea et al., 1998). Orexin A and orexin B are 33-
genic cyclic 19 amino acid neuropeptide. It is cleaved and 28-amino acid peptides, respectively, sharing 46%
from its precursorprepro-MCH (ppMCH) along with identity. Both peptides are coded by the same gene
several other neuropeptides whose roles are not fully located on chromosome 17q21 (Sakurai et al., 1999),
defined. (Lieberman et al., 2006). The cell bodies of and are localized in neurons in the dorsal and lateral
MCH-containing neurons are mainly present in the lat- hypothalamic areas and perifornical hypothalamus
eral hypothalamus and zona incerta that are recognized (Sakurai, 2003; Dyer et al., 1999; Sakurai et al., 1998).
as the feeding center of mammalian brain (Inui, 2000). The orexins activate two closely related and highly con-
MCH was initially discovered in chum salmon pituitar- served G-protein coupled receptors termed orexin-1 and
ies as a regulator of skin color change (Nahon, 1994; orexin-2 receptor (OX1R and OX2R, respectively).
Vaughan et al., 1995). MCH signals in the brain While orexin-A has equal affinity for both the receptors
through two types of G protein-coupled receptors, but orexin-B has 10 times higher affinity for OX2R (Sak-
namely MCH-1R and MCH-2R (Maulon-Feraille urai et al., 1998; Smart et al., 1999; Smart et al., 2000).
et al., 2002). MCH-2R shares 32% amino-acid sequence Whereas OX1R is expressed widely in the hypothalamus
homology with MCH-1 and has higher affinity for including ARC, VMH and SCN, OX2R is found mainly
MCH than MCH-1 (Rodriguez et al., 2001). These in PVN. Activation of these receptors in hypothalamic
receptors are widely distributed in the brain areas, espe- cells leads to a marked increase in intracellular Ca2+ lev-
cially in the hippocampus, amygdala and cerebral cor- els, a post-synaptic effect mediated via stimulation of a
tex. MCH-1R is expressed in both normal (fetal and Gq G-protein and protein kinase C (van den Pol et al.,
adult) human pituitary tissues and in GH cell adeno- 1998). In the peripheral tissues OX1R is expressed
mas, suggesting that MCH may regulate pituitary GH mainly in the brown adipose tissue and OX2R is
secretion (Lieberman et al., 2006). The melanin-concen- expressed in adrenal medulla (Rodgers et al., 2002).
trating hormone system is thought to play a role in Crucial evidence indicates that orexin-A increases
arousal in correlation with specific goal oriented behav- food intake by delaying the onset of a behaviorally nor-
iors such as feeding or reproduction (Cvetkovic et al., mal satiety sequence. Selective orexin-1 receptor antago-
2003). Several lines of investigation suggest that the nist (e.g. SB-334867) suppresses food intake and
hypothalamic MCH regulates body weight in mam- advances the onset of a normal satiety sequence (Rodgers
mals. Obese mice lacking functional leptin overexpress et al., 2002). Orexin neurons project throughout the cen-
the MCH message in the fed or fasted state. Acute tral nervous system (CNS) to nuclei known to be impor-
Intracerebroventricular injection of MCH increases tant in the control of feeding, sleep-wakefulness,
energy intake in rats and decreases energy expenditure. neuroendocrine homeostasis, and autonomic regulation
On the other hand, the MCH- or MCH-1R-deficient (Willie et al., 2001). Central administration of orexins is
mice showed the resistance to high-fat diet induced also associated with increased EEG arousal and wakeful-
obesity (Ludwig et al., 2001). Moreover, MCH-trans- ness, locomotor activity, grooming, sympathetic activity,
genic mice exhibit obese syndromes when fed on high- metabolic rate and stimulated feeding in a dose-related
fat diet. Furthermore, MCH produces anxiety and fashion and pain thresholds (Sakurai et al., 1998; Rod-
increases the hippocampal synaptic efficacy, resulting gers et al., 2002). The orexin system is selectively acti-
in the enhancement of learning and memory processes vated by signals that indicate severe nutritional deficit,
(Katsuura and Inui, 2003). Independent of its effect hence it would be highly adaptive for a hungry animal
on adiposity, transgenic over-expression of MCH not only to seek sustenance but also to remain fully alert
results in glucose intolerance and insulin resistance to dangers in the environment (Rodgers et al., 2002).
(Pereira-da-Silva et al., 2005). orexin mRNA expression is up-regulated by fasting and
380 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401

insulin-induced hypoglycemia. C-fos expression in AGRP is expressed only in the ARC of the hypothal-
orexin neurons, an indicator of neuronal activation, is amus in the brain, and all of the AGRP-producing
positively correlated with wakefulness and negatively neurons co-secrete NPY and project to various hypotha-
correlated with rapid eye movement (REM) and non- lamic (such as PVN and DMH) and extra hypothalamic
REM sleep states (Willie et al., 2001). sites (Broberger et al., 1998a; Broberger et al., 1998b;
These data suggest that orexin-1 receptors mediate Haskell-Luevano et al., 1999; Hahn et al., 1998; Gold-
the episodic signalling of satiety and appear to bridge stone et al., 2002). Leptin inhibits the release of AGRP
the transition from eating to resting in the feeding–sleep (Hoggard et al., 2004b). Like NPY, expression of
cycle (Rodgers et al., 2002). Furthermore, it is likely that AGRP is up-regulated in leptin deficiency due to fasting
orexin-mediated food intake results partly from stimula- or mutation (Wilson et al., 1999; Hahn et al., 1998).
tion of feeding pathways in the hypothalamus such as AGRP is a potent and selective antagonist of MC-3
those involving the NPY pathway. Recent electrophysi- and MC-4 receptors (Yang et al., 1999), the melanocor-
ological studies have shown that orexin neurons are reg- tin receptors implicated in control of energy balance.
ulated by metabolic cues, including leptin, glucose, and The inhibition of melanocortin receptors may thus lead
ghrelin. The close relationship between orexin-A fibers to the obese phenotype that is associated with hyperpha-
and the surface of the cerebral ventricular system sug- gia, decreased thermogenesis, and increased caloric effi-
gests that orexin-A may be released directly into the ciency (Miltenberger et al., 1997; Fan et al., 1997). In
cerebrospinal fluid, where it could interact with other contrast to potent but short-lived effects of NPY, central
appetite-regulating factors (e.g. leptin and insulin) or administration of AGRP in rodents leads to increase in
perhaps have a neurohormonal role via volume trans- food uptake for upto 1 week (Rossi et al., 1998). Recent
mission (Zoli et al., 1998). Thus, orexin neurons have studies suggest that at least part of the long-term actions
the requisite anatomical connections and interactions of AGRP may be independent of competitive antago-
with hypothalamic feeding pathways, and regulation nism of MC3/4R and may involve additional mecha-
by circadian and nutritional factors to suggest that they nisms such as prolonged downstream signaling
may be an important cellular and molecular link in the changes initiated by MC3/4R antagonism, inverse agon-
integration of sleep and energy homeostasis (Sakurai, ism of MC3/4R, or interaction with an unknown recep-
2003). tor (Hagan et al., 2000). Chronic administration of
Orexin may also play a role as a peripheral hormone AGRP in rodents has been shown to cause sustained
involved in energy homeostasis. Orexin neurons, hyperphagia and leads to obesity (Small et al., 2001).
expressing both orexin and leptin receptors, have been Alterations in AGRP expression have been observed
identified in the gastrointestinal tract, and appear to in chronic conditions of positive or negative energy bal-
be activated during starvation (Kirchgessner and Liu, ance. Studies by Huang et al. (2003) have reported that
1999). Orexin is also expressed in the endocrine cells in 22 weeks of high-fat diet significantly reduced hypotha-
the gastric mucosa, intestine and pancreas (Kirchgessner lamic arcuate nucleus AGRP mRNA expression and
and Liu, 1999) and peripheral administration increases increased MC4R expression. Similarly, Tritos et al.
blood insulin levels (Nowak et al., 2000). (1998a) reported a suppressed AGRP mRNA expression
in obese mice with brown adipose tissue deficiency.
3.4. Agouti-related peptide
3.5. Galanin
AGRP is 132-amino acid peptide that has generated
intense interest because of evidence of its role in the reg- Galanin is a neuropeptide which is not a member of
ulation of feeding and body weight (Wilson et al., 1999). any known family of neuropeptides, despite repeated
AGRP has sequence similarity to the product of the efforts to discover related peptides. It is a 29 amino acid
Agouti coat color gene in mice, a paracrine-signaling C-terminally amidated (30 amino acid, non-amidated in
molecule produced normally in the skin that inhibits humans), highly conserved but unique neuroendocrine
the effect of a-melanocyte stimulating hormone, on peptide originally isolated from intestine. The first 14
MC-1 receptor (Leibel et al., 1997). Agouti is constitu- aa are fully conserved in almost all species. The first
tively expressed throughout the body of yellow Agouti 16 N-terminal amino acids appear to contain galaninag-
(Ay) mice, and this ectopic Agouti expression gives rise onist activity on increasing food consumption (Crawley
to pleiotropic effects including yellow coat color, obesity et al., 1990). Galanin is found in the brain and the gut. It
insulin resistance, hyperglycemia, and increased body modulates a variety of physiological processes including
length. Mice homozygous for null mutations of Agouti cognition/memory, sensory/pain processing, neuro-
do not display abnormalities of weight regulation (Wil- transmitter/hormone secretion, and feeding behavior
son et al., 1999). Humans also have an agouti gene that (Leibowitz et al., 1998; Leibowitz, 1995). Its actions
is normally expressed in adipose tissue (Mynatt et al., are mediated via Gi-protein-coupled receptors and ion
1997). channels, through inhibition of gastric neuropeptides
 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401 381

via potassium channels (Zhenjun et al., 2004). In many phin from prodynorphin, stimulates feeding after central
respects, these inhibitory actions of galanin are similar administration (Baile et al., 1986; Kalra et al., 1999; Mor-
to c-aminobutyric acid (GABA) and neuropeptide Y ley, 1987). POMC neurons are localized in the ARC and
(NPY). Galanin coexists with GABA, noradrenaline, innervate the PVN, VMH, and other areas of the hypo-
5-hydroxytryptamine (5-HT), and NPY in several thalamus, where microinjection of b-endorphin and opi-
regions of the brain. Evidence suggests that hypotha- ate agonists that bind to the l-opioid receptors stimulate
lamic galanin (GAL) has a variety of functions related feeding (Kalra et al., 1999; Baile et al., 1986). Dynorphin-
to energy and nutrient balance, body weight regulation, producing neurons are also found in various regions of
reproduction,water balance, and neuroendocrine regula- the hypothalamus, including the ARC and PVN. The
tion (Leibowitz, 1998). Many galanin-positive fibers as opioid receptor antagonists, especially the l- and j-
well as galanin-positive neurons have been demon- antagonists decreased feeding in animals and humans
strated in the dorsal vagal complex, suggesting that gal- (Morley, 1987). Antagonists such as naloxone and nal-
anin produces its effects by involving vagal neurons. The trexone decreased body weight during chronic adminis-
nucleus of the solitary tract is the major source of the tration, and were more potent in decreasing food
galanin terminals in the dorsal vagal complex (Zhenjun intake and weight gain in obese than in lean rodents
et al., 2004). (Baile et al., 1986). b-Endorphin reduces sympathetic
Acute central administration of galanin has been nerve activity thus having a potential role in thermogen-
reported to increase fat consumption. One of the studies esis (Egawa et al., 1993). Although the opioid-evoked
has shown that repeated central infusions of galanin feeding is modest, b-endorphin in particular may repre-
stimulates daytime intake of both diets, they failed to sent an important interconnected orexigenic signal
increase total daily energy intake or body weight in (Kalra et al., 1999). b-endorphin may be situated down-
the rat (Smith et al., 1994). stream from NPY, galanin, and GABA because all three
Studies of the newly discovered galanin family pep- molecules stimulate b-endorphin release in the hypothal-
tide, ‘galanin-like peptide’ (GALP), highlight the likely amus, and opioid antagonists such as naloxone inhibit
role of galanin peptides and receptors in the physiolog- feeding stimulated by any one of the three (Kalra et al.,
ical coupling of body weight, adiposity and reproductive 1999; Morley, 1987; Kalra, 1997). Opioid peptides may
function (Gundlach, 2002). GALP shows sequence provide the palatability and rewarding aspects of feeding
homology to galanin and binds to galanin receptors rather than those for energy needs (Levine and Billing-
in vitro (Krasnow et al., 2003). GALP is produced by ton, 1997).
a discrete population of neurons within the basomedial
arcuate nucleus (and median eminence) that send projec- 3.7. Endocannabinoids
tions to the anterior paraventricular nucleus and that
make close contacts with leutinizing hormone-releasing Over past centuries, Cannabis sativa (D9-tetrahydro-
hormone (LHRH) neurons in basal forebrain. Further- cannabinol) has been used extensively for both medici-
more, GALP neurons express leptin receptors and nal and recreational uses (Vickers and Kennett, 2005).
respond to leptin treatment by increasing their expres- Cannabis also has many pleasurable effects in elevating
sion of GALP mRNA. Centrally administered GALP mood and diminishing stress. There is historical support
activates LHRH-immunoreactive neurons and increases for the role of marijuana (i.e. exogenous cannabinoids)
plasma LH levels. These findings suggest a direct stimu- in the regulation of appetite. The search for the endog-
latory action of endogenous GALP on gonadotropin enous receptor for the psychoactive component of Can-
secretion via actions within the hypothalamus/basal nabis sativa has led to the discovery of physiological
forebrain, with leptin actions linking this system to body endocannabinoids (anandamide, 2-arachidonoylglycerol
adipose levels (Gundlach, 2002). (2-AG), noladin ether, NADA, and virodhamine) and
physiological ‘‘cannabinoid’’ signaling system that acts
3.6. Endogenous opioids on at least 2 receptors: CB1 and CB2 (Fride et al.,
2005; Vickers and Kennett, 2005; Wenger and Moldrich,
The opioid system is composed of three families of 2002).
biologically active peptides, b-endorphin, dynorphin, These receptors are located not only in pleasure cen-
and enkephalins,and their receptors, l-opioid receptor, ters of the central nervous system, but also in many
j-opioid receptor, and d-opioid receptor, respectively organs associated with feeding and energy regulation,
(Levine and Billington, 1989; Levine and Billington, such as the hypothalamus and the gastrointestinal tract
1997; Kalra et al., 1999; Kieffer, 1999). Opioid peptides (Wenger and Moldrich, 2002). In a number of species,
mediate the hunger component in the control of food including human beings, the administration of exoge-
intake (Baile et al., 1986). Opioid peptides may potentiate nous and endogenous cannabinoids leads to robust
fat as well as protein ingestion (Leibowitz, 1992). b- increases in food intake and can promote body weight
Endorphin, derived from precursor POMC, and dynor- gain. These effects are believed to be mediated through
382 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401

activation of the CB1 receptor (Vickers and Kennett, paraventricular nucleus, dorsomedial nucleus, periforni-
2005). cal regions, lateral nucleus, and the arcuate nucleus. In
The endocannabinoids appear to regulate energy bal- the paraventricular nucleus, CART mRNA is colocal-
ance and food intake at four functional levels within the ized with vasopressin and corticotropin-releasing fac-
brain and periphery: (i) limbic system (for hedonic eval- tor-containing neurons (Li et al., 2002). CART
uation of foods), (ii) hypothalamus and hindbrain (inte- neurons are also associated with reinforcement and
grative functions), (iii) intestinal system, and (iv) adipose reward, sensory processing (Koylu et al., 1998), stress
tissue. At each of these levels, the endocannabinoid sys- and endocrine regulation (Kristensen et al., 1998), and
tem interacts with a number of other neuropeptides feeding (Elmquist et al., 1999).
involved in appetite and weight regulation, including lep- There is evidence that CART and leptin pathways are
tin, ghrelin, and the melanocortins (Fride et al., 2005). linked (Niimi, 2001). ICV administration of CART (42–
Functional relationships between cannabinoids and 89), (particularly in 4th ventricle) results in neuronal
leptin have been demonstrated (Di Marzo et al., 2001), activation in the paraventricular nucleus (PVN), rich
and that endocannabinoid synthesis may be regulated in corticotrophin-releasing factor (CRH) and thyrotro-
by leptin. Thus, leptin administration, which exerts an phin-releasing factor (TRH) and thus, reduces normal
anorectic action, suppresses hypothalamic endocannab- and fast-induced feeding in rats (Zheng et al., 2002;
inoid levels in normal rats, while genetically obese, Stanley et al., 2001; Larsen et al., 2000; Lambert et al.,
chronically hyperphagic rats and mice express elevated, 1998). The CART peptides are colocalized with leptin
leptin-reversible, hypothalamic anandamide or 2-AG receptors in hypothalamic neurons, both fa/fa rats and
levels (Di Marzo et al., 2001). These findings provide ob/ob mice have reduced levels of CART mRNA in
evidence for the role of the hypothalamic endocannabi- the arcuate nucleus, and administration of leptin to
noid system in food intake and appetite regulation ob/ob mice increased CART mRNA (Larsen et al.,
(Wenger and Moldrich, 2002). 2000; Kristensen et al., 1998; Elias et al., 1998). Fasting
Experiments with selective CB1 receptor antagonists or diabetes attenuates CART mRNA expression in the
(e.g. Rimonabant, SR141716) have demonstrated reduc- hypothalamus, demonstrating that CART mRNA regu-
tions in food intake and body weight with repeated com- lation is related to the fuel availability and peripheral
pound administration. These reductions in body weight hormonal status (Li et al., 2002). Administration of
appear to be greater in obese animals and may be the CART antiserum increases nighttime feeding (Lambert
result of a dual effect on both food intake and metabolic et al., 1998). There is a decrease in arcuate nucleus
processes (Vickers and Kennett, 2005). CART mRNA following food deprivation. Interest-
ingly, CART administration blocks the NPY-induced
feeding in fasted and normal rats (Larsen et al., 2000).
4. Anorectic neuropeptides secreted by hypothalamus
4.2. Melanocortins
4.1. Cocaine and amphetamine regulated transcript
(CART) The melanocortins are bioactive peptides derived
from the precursor molecule pro-opiomelanocortin
CART is a relatively new neuropeptide which (POMC) via tissue-specific post-translational cleavage.
appears to be a powerful physiological anorexic signal. The POMC gene is expressed at physiologically signifi-
The high conservation of CART across species suggests cant levels in a number of mammalian tissues including
that it has an important role in mammalian physiology anterior and intermediate pituitary, skin, the immune
(Murphy, 2005). The gene for CART peptides has system and hypothalamic neurons (Bertagna, 1994; Cas-
now been characterized in both humans and mice tro and Morrison, 1997; Smith and Blalock, 1981). The
(Adams et al., 1999; Douglass and Daoud, 1996) along repertoire of products derived from POMC by any tissue
with several CART peptides produced through post- is determined by the specificities of the endoproteases
translational modifications (Kuhar and Yoho, 1999). (convertases) expressed in the tissue (Bloomquist et al.,
Human and rat CART mRNA share 92% sequence 1991; Zhou et al., 1993). Thus, anterior pituitary
identity. In the rat, a long and a short splice variant of expresses prohormone convertase1 (PC1) and cleaves
the CART peptide are produced, whereas humans only POMC to ACTH which acts via MC2 receptor to stimu-
produce the short form: CART (1–89) (Larsen et al., late adrenal steroidogenesis. The intermediate lobe in
2000). Cocaine- and amphetamine-regulated transcript lower animals expresses prohormone convertase 2
mRNA were identified on the basis of their increase fol- (PC2)and cleaves ACTH to yield a-MSH which is
lowing cocaine or amphetamine treatment in rats (Dou- involved in the control of coat/skin color. The physiolog-
glass et al., 1995). ical roles of the various melanocortin peptides have been
The CART peptides are localized in specific areas of defined with varying degrees of certainty. Bioactive pep-
the hypothalamus including the periventricular nucleus, tides generated in hypothalamic neurons act as endoge-
 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401 383

nous ligands for the melanocortin-4 receptor (MC4R), a GLP-2 are both involved in a wide variety of peripheral
key molecule underlying appetite control and energy functions, such as glucose homeostasis, gastric empty-
homeostasis (Pritchard et al., 2002). The MC3 and ing, intestinal growth, insulin secretion as well as the
MC4 receptors are biologically unique in that there is regulation of food intake (Small and Bloom, 2004;
an endogenous antagonist (AGRP) in addition to endog- Tang-Christensen et al., 2001). After a meal, GLP-1
enous agonist (the melanocortins) (Neary, 2004). and GLP-2 are secreted in parallel in the circulation.
Central ICV administration of a-MSH inhibits feed- Intravenous (IV) GLP-1 has an inhibitory effect on gas-
ing and reduces body weight. The stimulatory effect of tric emptying, hunger and food intake in man (Schmidt
AGRP is inhibited by a-MSH (Rossi et al., 1998). Thus et al., 2003). GLP-1 containing nerve fibres and the
a-MSH and Ag RP neurons act as a dynamic system GLP-1 receptor are found predominantly in hypotha-
in vivo. Mice over expressing AGRP as well as MC4- lamic midline nuclei. GLP-1 given centrally to naive rats
R knockout mice are hyperphagic and obese and are results in a marked induction of c-Fos protein in the
insensitive to a-MSH (Graham et al., 1997; Huszar supraoptic nucleus, paraventricular nucleus of the hypo-
et al., 1997). POMC is co-expressed in arcuate neurons thalamus (PVN) and central nucleus of the amygdala,
with CART, and these neurons are directly stimulated but only a moderate increase in the arcuate nucleus.
by leptin (Cowley et al., 2001). The pattern of c-Fos activation is compatible with the
Functional mutations of the MC4 receptor are also a appetite suppressing effects of GLP-1. This anorectic
cause of monogenic obesity and are much more common effect of GLP-1 appears to be mediated by the PVN,
than leptin deficiency, being found in up to 4% adults as direct injections of GLP-1 into this nucleus cause
with severe childhood-onset type obesity. The minority anorexia without concomitant taste aversion, suggesting
with homozygous mutations tend to be more severely a specific action upon neuronal circuits involved in the
obese (Farooqi et al., 2000). In POMC deficiency, obes- regulation of feeding. Recent experiments have also
ity reflects the lack of POMC-derived peptides as ligands shown that GLP-1 is implicated in mediating signals
at the MC4 and MC3 receptors, (expressed in the hypo- from the gastrointestinal tract pertaining to discomfort
thalamic leptin-melanocortin pathway) Hypocortisolism and malaise. The distribution of the co-localized pep-
and alteration of pigmentation are caused by the lack of tide, GLP-2, displays a perfect overlap with GLP-1 in
POMC-derived peptides at the adrenal MC2 receptor the CNS with the highest concentration in the diffuse
and the skin MC1 receptor, respectively (Krude et al., ventral part of the dorsomedial nucleus (DMH) (Kinzig
2003). The symptoms of severe early onset obesity, adre- et al., 2002; Tang-Christensen et al., 2001). In rodents,
nal insufficiency, and red hair define the proopiomelano- central administration of GLP-2 increases satiety similar
cortin (POMC) deficiency syndrome. to GLP-1 (Schmidt et al., 2003). In contrast to the
Recently, the focus has shifted to role of peripheral widely distributed GLP-1 receptor mRNA, GLP-2
receptors of circulating melanocortins in body weight receptor mRNA is exclusively expressed in the compact
regulation. The presence of MC 4 receptors in rat adipo- part of the DMH. Interestingly, the compact part of
cytes supports the involvement of this receptor subtype DMH is also the only nucleus responding to central
in this interaction. Leptin administered to ob/ob mice administration of GLP-2 with a significant increase in
in turn increases the release of a-MSH into the circula- the number of c-Fos positive cells. When injected into
tion suggesting a possible feedback loop between the the lateral ventricle, GLP-2 has a marked inhibitory
sites of a-MSH release and the release of leptin from effect on feeding. The effect of GLP-2 on feeding is both
the adipose tissue. However, physiological significance behaviorally and pharmacologically specific (Tang-
of this putative feedback probably depends upon the Christensen et al., 2001).
underlying state of energy balance, since in the fasting Repeated administration of GLP-1 reduced food
state there is a parallel decrease in plasma leptin and intake and body weight without an apparent tachyphy-
plasma a-MSH (Hoggard et al., 2004a). laxis in response (Meeran et al., 1999). The GLP-1-
receptor antagonist, exendin 9-39, stimulated feeding
4.3. Glucagon-like peptides in satiated animals, and daily administration of exendin
9-39 augmented food intake and body weight gain. The
Preproglucagon gene expression is limited to a-cells anorectic effects of GLP-1 may be mediated through
in the pancreas, L cells in the gut, and neurons in the NPY signaling because GLP-1 inhibited and exendin
brain stem nucleus of the solitary tract (NTS). Whereas 9-39 augmented NPY-induced feeding, respectively
posttranslational processing of proglucagon in the pan- (Turton et al., 1996; Kalra et al., 1999). The GLP-1
creas leads to the formation of glucagon and the major receptor antagonist also blocked the leptin-induced
proglucagon fragment, proteolytic cleavage in the L cells inhibition of food intake and body weight, indicating
of the gut and in the NTS yields the peptides glicentin, that the GLP-1 pathway may be one of the targets
oxyntomodulin, glucagon-like peptide (GLP)-1,and for the anorectic effects of leptin (Goldstone et al.,
GLP-2 (Vrang et al., 2003). GLP-1 (7–36 amide) and 1997).
384 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401

4.4. Corticotropin releasing factor (CRF) and related been made that food deprivation and obesity can blunt
peptides the expression of the CRH type 2[a] receptor in the ven-
tromedial hypothalamic nucleus and can induce the
Corticotropin releasing factor (CRF) is a 41-amino expression of the CRH-binding protein (a CRH-inacti-
acid mammalian neurohormone that is best known as vating protein) in brain areas involved in the anorectic
the major physiological regulator of pituitary ACTH and thermogenic actions of CRH (Richard Denis, 1999).
secretion. In addition, it stimulates complimentary Two identified endogenous ligands for CRF-2 recep-
stress-related endocrine,autonomic, and behavioral tors indicated in mediation of anorexic and vascular
responses (Vale et al., 1981; Owens and Nemeroff, responses in the stress are human Stresscopin (SCP)
1991; Turnbull and Rivier, 1997). There is considerable and Stresscopin-related peptide (SRP). These are able
evidence indicating that CRF is an endogenous anorec- to suppress food intake, delay gastric emptying and
tic and thermogenic agent (Richard Denis, 1999). CRF decrease heat-induced edema. The gene of SCP and
secretion modulates food intake in the absence of stress SRP are expressed in central and diverse peripheral tis-
by exerting an inhibitory tone on appetite (Crespi et al., sues. Because CRF-2 is believed to be important in the
2004). CRF mediates its actions through interaction regulation of the recovery phase of the stress response,
with two distinct receptor subtypes, CRF-1 and CRF- SCP and SRP might be important in protecting the
2, which have been cloned and characterized (Chalmers organism from damage incurred by prolonged or exces-
et al., 1996; Turnbull and Rivier, 1997). CRF-2 receptor sive exposure to stress. Urocortin is a 40-amino acid
is primarily involved in the feeding-suppressive and ther- peptide that is a potent activator of CRF-2 rather than
mogenic response to CRF and CRF-related peptides CRF-1receptors (Vaughan et al., 1995; Spina et al.,
(Martinez et al., 1998; Smagin et al., 1998). 1996). Urocortin reduces food intake and promotes
Both CRF and NPY may exert local site-specific weight loss at doses that do not activate the stress
effects on feeding behavior within the PVN relative to response (Spina et al., 1996; Asakawa et al., 1999).
the extra hypothalamic site that constitutes a sensitive Unlike CRF and Urocortin, SCP and SRP have mini-
substrate for non-appetite behavioral actions of these mal effects on ACTH release and the resultant elevations
peptides (Heinrichs et al., 1998). In addition to coordi- in glucocorticoids (Hsu and Hsueh, 2001).
nation of anorectic and thermogenic effects, CRF is also Almost all obesities depend on the presence of adre-
sensitive to the action of peripheral peptides signaling nal glucocorticoids and an over activity of type II corti-
the brain about the fluctuations in energy reserves espe- costeroid receptors (York and Hansen, 1998).
cially leptin. Leptin has been reported to reduce CRF Glucocorticoids also stimulate food intake by inhibiting
expression in the PVN of leptin-deficient obese rodents CRF while facilitating NPY actions (Crespi et al., 2004).
thus, inhibiting the hyperactivity of the hypothalamic- All types of hyperphagia and obesity syndromes are
pituitary adrenal axis and the resultant energy deposi- reversed or prevented by adrenalectomy and can be
tion. Leptin has also been reported to increase the readily restored by steroid replacement (Tempel and
expression of the CRH type 2[a] in the ventromedial Leibowitz, 1994) providing further evidence in support
hypothalamic nucleus, a key structure in the control of of the role of CRH system in control of feeding.
insulin secretion and in the regulation of energy balance
(Richard Denis, 1999). Injection of CRF into the brain, 4.5. Serotonin
specifically into the PVN of the hypothalamus, decreases
spontaneous feeding or fasting-induced feeding (Levine Serotonin (5-HT) originates from the midbrain dorsal
and Billington, 1989; Morley, 1987; Schwartz et al., raphe nucleus and projects to the hypothalamus, includ-
1995; Heinrichs et al., 1998). Chronic administration ing the PVN and the VMH. It is an important modula-
of CRF causes sustained anorexia and progressive body tor of many developmental, behavioral, and
weight loss (Schwartz et al., 1995). CRF decreases feed- physiological processes, including sleep, appetite, tem-
ing stimulated by GABA agonists, norepinephrine, perature regulation, pain perception, and motor activity
dynorphin, and NPY (Levine et al., 1983). Conversely, (Vanhoutte et al., 1993).
pharmacological blockade of CRF receptors with antag- The pivotal role of 5-HT in the control of appetite
onists or antisense oligonucleotides, immunoneutraliza- was formally proposed nearly 30 years ago. In particular
tion, or immunotoxin targeting of CRF in the endogenous hypothalamic 5-HT has been implicated in
hypothalamus enhances basal and NPY-stimulating the processes of within meal satiation and the end state
feeding, suggesting that CRF may tonically restrain of post meal satiety. Of the numerous 5-HT receptor
the actions of orexigenic signals (Heinrichs et al., 1991; subtypes currently identified, 5-HT1B and 5-HT2C recep-
Hulsey et al., 1995). Finally, the CRH system appears tors are believed to mediate the 5-HT induced satiety
to demonstrate plasticity in obesity and in response to (Halford et al., 2005). Functional interrelationships
food deprivation that is consistent with its action on between serotonin and CRF, CCK, or NPY were also
food intake and thermogenesis. The observations have suggested, which were thought to be through 5-HT2A,
 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401 385

5-HT2C, or 5-HT2A(2C) receptors (Samanin and Garat- phatidyl inositol (PI) turnover (Erwin and Radcliffe,
tini, 1996; Curzon et al., 1997). Serotonin and its ago- 1993; Hermans et al., 1994), intracellular Ca2+ influx
nists inhibit food intake when administered either (Slusher et al., 1994; Trudeau, 2000), phospholipase C
peripherally or centrally in freely feeding or food- (Hermans et al., 1992; Chabry et al., 1994), and Na+,
deprived animals (Leibowitz, 1989; Heinrichs et al., K+-ATPase activity (Lopez Ordieres and Rodriguez de
1998). Stimulants of this monoamine reduce weight gain Lores Arnaiz, 2000).
and increase energy expenditure in both animals and Neurotensin is produced in the ARC, PVN, and
humans by action on medial hypothalamus, specifically DMH of the hypothalamus and its microinjection into
PVN, VMH and suprachiasmatic nuclei (Leibowitz, the PVN decreases food intake (Stanley et al., 1983;
1989). 5-HT drugs such as d-fenfluramine, selective sero- Alexander et al., 1989; Kalra et al., 1999). Evidence from
toninergic reuptake inhibitor (SSRIs) and 5-HT2C recep- in vivo studies in rats indicate that NT may modulate the
tor agonists have all been shown to significantly central effects of leptin on feeding behavior (Cui et al.,
attenuate rodent body weight gain, an effect strongly 2005). NT neurons appear to play an anorectic role
associated with marked hypophagia. D-Fenfluramine, downstream of leptin. Evidence of this is seen in leptin-
sibutramine, fluoxetine and the 5-HT2C receptor agonist deficient ob/ob mice (Wilding et al., 1993) or leptin-insen-
[1-(3-chlorophenyl) piperazine] (mCPP) have also all sitive fa/fa rats (Beck et al., 1998), in which hypothalamic
been shown to reduce caloric intake by modifying appe- NT expression is decreased and food intake is reduced.
tite in both lean and obese humans. Specifically, 5-HT In contrast, intracerebroventricular injection of leptin
drugs reduce appetite prior to and after the consump- into the PVN significantly stimulates NT synthesis in
tion of fixed caloric loads, and reduce premeal appetite association with reduced food intake (Beck et al., 1998;
and caloric intake at ad libitum meals. Clinically signif- Sahu, 1998). Furthermore, immunoneutralization with
icant weight loss over a year or more can be produced by an NT antibody or an NT receptor antagonist com-
both D-fenfluramine and sibutramine treatment, but pletely reverses the effects of a leptin-induced decrease
apparently not by the SSRI fluoxetine. Treatment with in food intake (Sahu et al., 2001). These results suggest
the preferential 5-HT2C receptor agonist mCPP and that leptin action may be mediated, at least in part, by
the serotonin precursor 5-HTP has also been shown to NT. Neurotensin has also been shown to inhibit the orex-
produce weight loss in the obese (Halford et al., 2005). igenic effect of MCH, but not that of NPY, after i.c.v.
coadministration (Tritos et al., 1998b).
4.6. Neurotensin ICV injections of NT-antiserum or NTR antagonists
(SR 48692) were shown to completely block the action
Neurotensin (NT) is a 13-amino acid peptide, first of leptin on food-deprivation induced feeding. Also
isolated in 1973 from bovine hypothalamus by Carr- intraperitoneal injection of NTR antagonists were
away and Leeman. In 1988, the rat NT gene was isolated shown to affect the satiating effects of leptin on food-
and sequenced (Kislauskis et al., 1988). The gene deprivation induced feeding (Sahu et al., 2001).
encodes a 170-amino acid precursor protein containing
both the tridecapeptide NT and a closely related hexa-
peptide, neuromedin N (NN). The four amino acids at 5. Role of peripheral neuropeptides
the carboxy terminal of NT and NN are identical, and
amino acids 8–13 of NT are essential for biologic activ- Numerous peripheral signals from the GI Tract and
ity (Lambert et al., 1995). the liver are involved in short-term regulation of feeding
There are currently three characterized receptors for and energy homeostasis. Afferent signals from stretch
NT in the CNS: a receptor with low affinity for NT receptors and chemoreceptors travel via vagus nerve
(NTRL or NT2) that also binds the histamine H1 receptor fibers to the higher control centers. These receptors signal
antagonist levocabastine (Chalon et al., 1996; Mazella the presence and the energy-density of food in the gastro-
et al., 1996; Vita et al., 1998), a high affinity receptor intestinal tract and contribute to satiety in the immediate
(NTRH or NT1) (Tanaka et al., 1990; Vita et al., 1993), post-parandial period (Mei, 1985). Also changes in circu-
and a third NT receptor (NTR; NT3) that is located intra- lating glucose concentrations appear to elicit meal initia-
cellularly (Mazella et al., 1998; Zsürger et al., 1994). There tion and termination by regulating activity of specific
is strong homology and identity between NT1 and NT2 hypothalamic neurons that respond to glucose. However,
across species (Cusack et al., 1995). Both NT1 and NT2 the energy density of food and short-term hormonal sig-
are G-protein coupled receptors with the typical 7-trans- nals by themselves are insufficient to produce sustained
membrane configuration. Second messenger system asso- changes in energy balance and body adiposity. Rather,
ciated with the NTRs in vivo are unclear, However these signals interact with long-term regulators (i.e. insu-
in vitro the NT system has alternately been shown to reg- lin, leptin and possibly orexigenic gastric peptide and
ulate cyclic AMP (Yamada et al., 1993; Slusher et al., ghrelin) to maintain energy homeostasis (Blundell and
1994), cyclic GMP (Gilbert and Richelson, 1984), phos- Halford, 1994).
386 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401

6. Orexigenic peripheral peptides However, other factors besides body composition

may impact ghrelin levels since significant decrease in
6.1. Ghrelin plasma ghrelin levels are observed in anorexic patients
even before the changes in the body mass index appear.
Ghrelin is a 28-amino acid peptide that was isolated Also, healthy lean subjects have higher ghrelin levels
from rat stomach (Kojima et al., 1999). It is mainly pro- (Tolle et al., 2003) and patients with bulimia nervosa
duced in endocrine cells of the human gastric mucosa, have higher ghrelin levels than weight-matched controls
but it was also found in several other tissues, e.g., in (Tanaka et al., 2002). It is apparent that ghrelin plays an
the pituitary, the hypothalamus and the pancreas, lung, important role in both acute and long-term control of
immune cells, placenta, ovary, testis, kidney and in dif- energy balance and is also influenced by behavioral
ferent tumors including pituitary adenoma, neuroendo- parameters (Tanaka et al., 2003). Thus, ghrelin may be
crine tumors, thyroid carcinomas, endocrine tumors of regarded as a thrifty gene product that evolved to help
the pancreas and lung (Hagemann et al., 2003; Hubina animals consume and store fat well, thereby increasing
et al., 2005). It is a ‘‘saginary’’ hormone, from the Latin, their chances of survival during times of famine (Cum-
saginare, which means, ‘‘to fatten’’. It is only known cir- mings et al., 2005).
culating appetite stimulant (Cummings et al., 2005). The
functional receptor belongs to the family of the 7-trans-
membrane G-protein receptors, which are predomi- 7. Anorectic peripheral peptides
nantly detected in the pituitary and at lower levels in
hypothalamic nuclei, the stomach, heart, lungs, kidneys, 7.1. Peptide YY
gut, the adipose and many other tissues. According to
the widespread distribution of the peptide and its recep- Peptide YY (PYY) is a 36 amino acid peptide belong-
tor, ghrelin has multiple biological effects: it stimulates ing to PP-fold peptide family [NPY, PYY and PP]. All
the release of growth hormone in the pituitary (due to these peptides share sequence homology and are rich
its action on Growth hormone secretagogue receptor in tyrosine residues (Conlon, 2002). Produced by the
(GHS-R)) and induces a rise in the serum concentration intestinal L-cells, the highest tissue concentrations of
of ACTH, cortisol, aldosterone, catecholamines and PYY are found in distal segments of the gastrointestinal
prolactin (Hagemann et al., 2003; Kojima et al., 1999; tract, although it is present throughout the gut (Ekblad
Arvat et al., 2001). The high levels of ghrelin expressed and Sundler, 2002). Circulating PYY exists in two major
in stomach (Kojima et al., 1999) led to the recognition forms: PYY1–36 and PYY3–36. PYY3–36, the peripherally
of its central role in the regulation of appetite, body adi- active anorectic signal, is created by cleavage of the N-
posity and energy balance (Tschop et al., 2000). Ghrelin terminal Tyr-Pro residues by dipeptidyl peptidase IV
causes an increase of food intake and body weight by (DPP-IV) (Eberlein et al., 1989). PYY3–36 is a major
stimulating the production of neuropeptide Y (NPY) form of PYY in both the gut mucosal endocrine cells
and agouti-related protein (AGP) in the arcuate nucleus and the circulation.
and antagonizes the leptin-induced inhibition of food Like NPY, PYY also acts on Y receptors. PYY3–36
intake (Greenman et al., 2004). It further leads to ele- shows high affinity for Y2 and some affinity for Y1
vated concentrations of plasma glucose (Hagemann and Y5 receptors (Larhammar, 1996). Following food
et al., 2003). ICV and peripheral administration of ghre- intake PYY is released into the circulation and peak
lin to rodents caused a dose-dependent increase in food plasma levels appear postprandially after 1–2 h (Adrian
intake and body weight coupled to a reduction in fat uti- et al., 1985a). PYY concentrations are proportional to
lization (Tschop et al., 2000). Ghrelin levels in GH-defi- meal energy content, so that higher levels are seen after
cient adults are similar to those in healthy subjects and fat-intake as compared to carbohydrates and proteins
do not change with GH replacement (Janssen et al., (Lin and Chey, 2003). Administration of PYY causes a
2001). Ghrelin administration to GH-deficient dwarf delay in gastric emptying, a delay in secretions from
rats, however, resulted in effective food intake and the pancreas and stomach, and increases the absorption
increased body weight (Tschop et al., 2000). On the of fluids and electrolytes from the ileum after a meal
other hand, ghrelin treatment failed to induce adiposity (Hoentjen et al., 2001; Adrian et al., 1985b). Peripheral
in hypophysectomised rats (Tschop et al., 2002). administration of PYY3–36 to rodents has been shown to
In humans, ghrelin levels increase during fasting and inhibit food intake, reduce weight gain (Batterham
decrease following feeding (Ariyasu et al., 2001). This et al., 2002; Challis et al., 2003) and improve glycaemic
pre-parandial rise in ghrelin levels may serve as a signal control in rodent models of diabetes (Pittner et al.,
for meal initiation (Cummings et al., 2001). Ghrelin lev- 2004). The binding of PYY3–36 to the Y2 receptor leads
els are decreased in obese subjects (123) and are mark- to an inhibition of the NPY neurones and a possible
edly raised in patients with anorexia nervosa (Ariyasu reciprocal stimulation of the pro-opiomelanocortin
et al., 2001). neurones. Thus, PYY3–36 appears to control food intake
 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401 387

by providing a powerful feedback on the hypothalamic memory and anxiety, as well as satiety (Schick et al.,
circuits. The effect on food intake has been demon- 1994; Crawley and Corwin, 1994). Cholecystokinin plays
strated at physiological concentrations and, therefore, an important role in several physiological functions like
PYY3–36 may be important in the everyday regulation stimulation of pancreatic secretion, gall bladder contrac-
of food intake (Roux and Bloom, 2005). tion, intestinal motility, memory enhancement and inhi-
The effect on appetite may be dependent on a minimi- bition of gastric motility (Morley, 1982; Morgan, 2004;
zation of environmental stress, which in itself can result Morgan, 2000; Moran and Schwartz, 1994).
in a decrease in food intake (Halatchev et al., 2004). It is also demonstrated that endogenous CCK has an
Acute stress has been shown to activate the NPY system important role in the control of meal size and several
(Conrad and McEwen, 2000; Makino et al., 2000), studies have uncovered the pathways by which CCK
which may render the system insensitive to the inhibi- mediate these effects (Konturek et al., 2003). Cholecys-
tory effect of PYY3–36, resulting in masking of the ano- tokinin mediates these physiological effects by its endo-
rectic effect of the peptide. crine actions in the intestines and by its paracrine and
Single 90-min intravenous infusion of PYY3–36 to neurocrine actions in other parts of the body especially
normal-weight human subjects also has potent effects the brain. Cholecystokinin acts by binding to the CCK
on appetite, resulting in a 30% reduction in food intake receptors (CCKr). There are two types of CCKr (CCKA
(Renshaw and Batterham, 2005; Batterham et al., 2002, and CCKB) that are characterized molecularly and
2003). The reduction in calories is accompanied by a pharmacologically (Morgan, 2000). CCKA receptors
reduction in subjective hunger without an alteration in bind to CCK-8 and CCK-33 with a sulphated tyrosine
gastric emptying. This effect persists for up to 12 h after moiety. CCK-B receptors in contrast have a high affinity
the infusion is terminated, despite circulating PYY3–36 to desulphated CCK (Morgan, 2000). The CCK recep-
returning to basal levels (Batterham et al., 2002). Thus, tors are G-protein coupled receptors consisting of seven
PYY3–36 may be physiologically important as a post- transmembrane domains. It has been demonstrated that
prandial satiety signal. the satiety actions of CCK are mediated by CCK-A
Obese human subjects have a relatively low circulat- receptors and not CCK-B (Morgan, 2000; Kopin
ing PYY and a relative deficiency of post-prandial secre- et al., 1999). CCK-A receptors are found in the afferent
tion (Renshaw and Batterham, 2005; Batterham et al., vagal neurons and on the circular muscle cells of the
2003), although these subjects retain sensitivity to pyloric sphincter. CCK-A receptors are reported to exist
exogenous administration. Obese patients treated by in two functional states, a low affinity state and a high
jejunoileal bypass surgery (Naslund et al., 1997) or affinity state. CCK contracts the pyloric sphincter and
vertical-banded gastroplasty (Alvarez et al., 2002) have activates the gastric and duodenal vagal neurons. Activ-
elevated PYY levels, which may contribute to their ity of CCK at both these sites is reported to be mediated
appetite loss. Thus long-term administration of PYY3–36 by the low affinity state of the receptor (Morgan, 2004,
could be an effective obesity therapy. After chronic 2000). The actions of CCK mediated by the low affinity
peripheral administration of PYY3–36, rodents demon- sites suggest that the actions of CCK in mediating the
strated reduced weight gain (Batterham et al., 2002). satiety signal is not an endocrine action but a neurocrine
Potential therapeutic manipulations based on the or paracrine because plasma concentrations of CCK can
PYY system include development of Y2 agonists, exog- activate only the high affinity receptors (Morgan, 2000).
enously administration of PYY or increased endogenous It is suggested that CCK has a direct effect on the food
release from the gastrointestinal tract (Renshaw and intake through the activation of CCK-A receptors
Batterham, 2005). located on the vagal afferent neurons (Morgan, 2000).
Administration of CCK, to both humans and ani-
7.2. Cholecystokinin mals, has long been known to inhibit food intake by
reducing meal size and duration (Gibbs et al., 1973;
Cholecystokinin (CCK) is an important endogenous Kissileff et al., 1981), an effect which is enhanced by gas-
peptide found in the gastrointestinal tract and the brain. tric distension (Kissileff et al., 2003). Although CCK
It is present in multiple bioactive forms, including CCK- exerts its effect on food intake rapidly, its duration of
58, CCK-33 and CCK-8, all derived from the same gene action is brief. It has a half-life of only 1–2 min, and it
product (Reeve et al., 1994). CCK is rapidly released is not effective at reducing meal size if the peptide is
locally and into the circulation in response to nutrients, administered more than 15 min before a meal (Gibbs
and remains elevated for up to 5 h (Liddle et al., 1985). et al., 1973). Recently, it was demonstrated that exoge-
Mapping of CCK-sensitive brain sites in the rat revealed nous CCK-8 rapidly mobilizes gastric leptin with a con-
that active sites lie not only in the LH, but also in the comitant increase in plasmaleptin concentrations (Bado
medial pons and lateral medulla in the vicinity of the et al., 1998). Evidence was provided for a synergistic
NTS, where vagal afferent fibers terminate, being interaction between leptin and CCK leading to short-
involved in diverse processes such as reward behavior, term reduction in food intake (Barrachina et al., 1997).
388 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401

It was further suggested that CCK can contribute to (Mercer et al., 1996; Guan et al., 1997; Håkansson
the long-term control of feeding and body weight when et al., 1998). After binding to its receptors in hypothal-
central leptin levels are elevated (Matson and Ritter, amus, leptin stimulates a specific signaling cascade that
1999). Intraperitoneal administration of CCK-8 failed results in the inhibition of several orexigenic peptides,
to decrease food intake in mice lacking CCK-A recep- while stimulating several anorectic peptides. The orexi-
tors, whereas CCK-8 decreased food intake by up to genic neuropeptides downregulated by leptin are NPY,
90% in both wild-type and CCK-B receptor-deficient MCH, orexins and AGRP. The anorectic neuropep-
mice. However, CCK-A receptor-deficient mice showed tides that are up-regulated by leptin are a-MSH which
normal day- and night-food intake and body weight that acts on MC4 receptor, CART and CRH (Jequier,
is comparable to the corresponding age- and sex- 2002). Obese db/db mice, which have a mutation in
matched wild-type controls (Kopin et al., 1999). the intracellular portion of Ob-Rb are unable to per-
form JAK-STAT signal transduction (Lee et al., 1996;
7.3. Leptin Meister, 2000).
Circulating leptin is transported across the blood–
Leptin (also termed OB protein), a product of leptin brain barrier via a saturable process (Banks et al.,
gene (Lep(ob) was discovered in 1994 by Friedman and 1996). Regulation of transport may be an important
colleagues (Zhang et al., 1994). It is a protein of molec- modulator of the effects of leptin on food intake. Starva-
ular weight 18,000, containing a signal sequence which is tion reduces transport, whereas refeeding increases the
cleaved to produce the mature hormone of molecular transport of leptin across the blood–brain barrier (Kas-
weight 16,000 (Zhang et al., 1994). Initial studies sug- tin and Pan, 2000). The short forms of the receptor have
gested that leptin was only synthesized by the White adi- been proposed to have a role in the transport of leptin
pose tissue, but it is now recognized that the hormone is across the blood–brain barrier (El Haschimi et al.,
produced in several other sites like brown adipose tissue, 2000),whereas the secreted form is thought to bind to
stomach, placenta, mammary gland, ovarian follicles circulating leptin thus modulating its biological activity
and certain fetal organs such as heart and bone or car- (Ge et al., 2002).
tilage and perhaps even the brain (Trayhurn et al., Production of leptin correlates positively with adi-
1999; Trayhurn et al., 2001; Masuzaki et al., 1997). pose tissue mass (Maffei et al., 1995). Independent of
The ob gene is expressed in all adipose tissue depots the adiposity leptin levels are higher in women than in
but the subcutaneous adipose tissue expresses higher lev- men (Sinha and Caro, 1998). Leptin has a dual regula-
els of ob mRNA than omental fat (Hube et al., 1996; tion in human physiology. During the periods of weight
Montague et al., 1998). A mutation in the ob gene, maintenance, when energy intake and output are equal,
resulting in the absence of circulating leptin, leads to leptin levels reflect total body fat mass. However, in con-
the hyperphagic obese phenotype of the ob/ob mouse, ditions of negative (weight loss programs) and positive
which can be normalized by the administration of leptin (weight-gain programs) energy balances, the dynamic
(Campfield et al., 1995; Halaas et al., 1995; Pelleymoun- changes in plasma leptin concentration function as a
ter et al., 1995). Similarly, mutations resulting in the sensor of energy imbalance and influences the efferent
absence of leptin in humans cause severe obesity and energy regulation pathways (Sinha and Caro, 1998).
hypogonadism (Montague et al., 1997; Strobel et al., Rising levels of leptin signal the brain that excess energy
1998) which can be ameliorated with recombinant leptin is being stored, and this signal brings about adaptations
therapy in both children (Farooqi et al., 1999) and of decreased appetite and increased energy expenditure
adults (Licinio et al., 2004). that resist obesity. Transgenic overexpression of leptin
One or more isoforms of leptin (Ob-R) are found in in the liver by using the human serum amyloid P compo-
most tissues (Hoggard et al., 1997), including white adi- nent promoter has resulted in markedly decreased food
pose tissue, suggesting that the hormone may have an intake and body weight gain with the complete disap-
autocrine or paracrine function in adipose tissue. Lep- pearance of white adipose tissue and brown adipose tis-
tin receptors, of which there are several spice variants sue (Ogawa et al., 1999). Restriction of food intake, over
(Ob-Ra through Ob-Re) belong to the superfamily of a period of days, results in a suppression of leptin levels,
cytokine receptors, which use the JAK-STAT pathway which can be reversed by refeeding (Frederich et al.,
of signal transduction. The different splice forms of the 1995; Maffei et al., 1995) or administration of insulin
receptor can be divided into three classes: long, short (Saladin et al., 1995). Exogenous leptin replacement
and secreted (Tartaglia, 1997; Ge et al., 2002). The decreases fast-induced hyperphagia (Ahima et al.,
long-form Ob-Rb receptor differs from the other forms 1996), and chronic peripheral administration of leptin
of the receptor by having a long intracellular domain, to wild-type rodents result in reduced food intake, loss
which is necessary for the action of leptin on appetite of body weight and fat mass (Halaas et al., 1995).
(Lee et al., 1996). Ob-Rb is found mainly in the In human beings, there is a highly organized pattern
ARC, PVN, DMH and LHA of the hypothalamus of leptin secretion over a 24-h period. In general, the cir-
 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401 389

cadian pattern is characterized by basal levels between disulfide bridge between amino acids 2 and 7 (Wester-
0800 and 1200 h, rising progressively to peak between mark et al., 1986). In contrast to amylin, which is
2400 and 0400 h, and receding steadily to a nadir by only expressed by the b cell of the pancreas, CGRP
1200 h (Sinha et al., 1996). The nocturnal rise in leptin is expressed in many tissues, such as the brain, spinal
secretion is entrained to mealtime probably due to cord, thyroidal C cells and pancreatic islets, and is a
cumulative hyperinsulinemia of the entire day (Sinha potent vasodilator, involved in regulating blood flow
and Caro, 1998). Unlike in rodents, increases in leptin (Westermark et al., 1986). When amylin action is
secretion do not appear to be driven by meal patterns. blocked with a CGRP receptor antagonist, the anorec-
Leptin is secreted in a regular pulsatile fashion with an tic effects of CCK and bombesin are also attenuated
interpeak interval of about 44 min, and the circadian in rats (Morris and Nguyen, 2001).
rhythm is attributable solely to increased pulse height. Concerning amylin as a satiating hormone, it is well
This circadian pattern of leptin secretion is preserved established that amylin is released during meals, and
in obese patients and hyperleptinemia in these patients that exogenous amylin leads to a dose-related reduction
could be due to increased pulse height. This circadian in meal size. Amylin has a rapid onset and brief duration
and pulsatile pattern of fluctuation in blood leptin levels of action. The area postrema (AP) plays a predominant
implies that neural and neurohormonal components in role in peripheral amylin’s satiating effect, involving a
brain may regulate leptin secretion from adipocytes direct activation of AP neurons by blood-borne amylin.
(Sinha et al., 1996). About 5% of obese populations The nucleus of the solitary tract (NTS) relays this effect
can be regarded as ‘‘relatively’’ leptin deficient which to higher brain structures, the lateral parabrachial
could benefit from leptin therapy (Sinha and Caro, nucleus, and possibly the central nucleus of the amyg-
1998). dala and the bed nucleus of the stria terminalis (Lutz,
2005). Amylin’s anorectic effect may in part be due to
7.4. Amylin reduced expression of orexigenic neuropeptides in the
lateral hypothalamic area (Lutz, 2005).
Amylin consisting of 37 amino acids, also known as There is evidence that amylin may also exert its
islet amyloid polypeptide was identified in 1987 (Reda effects through serotonergic, histaminergic, and dopami-
et al., 2002). Amylin is a member of a family of struc- nergic systems. Amylin may induce anorexia through its
turally related peptides, which includes calcitonin effect on brain serotonin by increasing the transport of
gene-related peptide (CGRP) and calcitonin (CT). In the precursor tryptophan into the brain (Chance et al.,
mammals, amylin is co-released with insulin from pan- 1992) to inhibit feeding by serotonin action in the para-
creatic b-cells in response to food intake and has an ventricular nucleus. Serotoninin rats reduces the size
anorectic effect (Bhavsar et al., 1998). Amylin seems and duration of meals as well as the rate of eating,
to decrease food intake through both central and but does not affect the latency to feed or meal fre-
peripheral mechanisms and indirectly by slowing gas- quency, suggesting increased satiation rather than
tric emptying. The mean basal amylin concentration reduced hunger (Leibowitz and Shor-Posner, 1986).
is higher in obese than in lean human subjects. Amy- Amylin’s anorectic effect is through stimulating hista-
lin and CCK-8 have been reported to reduce food mine H1 receptors and not by enhancing endogenous
intake in rodents when given centrally as well as histamine release, as indicated by the anorectic effect
peripherally (Bhavsar et al., 1998). One mechanism being absent in mice lacking functional H1 receptors
by which amylin appears to reduce food intake is by (Mollet et al., 2001). Additionally, the anorectic effect
augmenting the actions of other peptides such as of amylin was attenuated in rats treated with dopamine
CCK, glucagon, and bombesin, all of which also D2 receptor antagonists (Pi-Sunyer et al., 1999; Lutz
increase amylin secretion. However, the CCK antago- et al., 2001).
nists failed attenuate amylin’s reduction of food In animal and human studies, it has been found that
intake, suggesting that amylin does not produce its amylin delays gastric emptying and decreases food
effect through the release of CCK (Morley et al., intake. Obese subjects exhibit hyperamylinemia, and
1994). Instead it appears to be the converse that the their elevated amylin levels may causedown-regulation
anorectic effects of CCK and bombesin depend partly of amylin receptors and lessen the impact of postpran-
on the presence of amylin or the calcitonin gene- dial amylin secretion on satiety and gastric emptying.
related peptide (CGRP) (Morris and Nguyen, 2001). Obese subjects often experience hyperglycemia and
Amylin is 50% homologous to the 37-amino-acid increased corticosteroid secretion (Leibowitz and
neuropeptide a- and b-CGRP (Lutz et al., 1997), all Shor-Posner, 1986), both of which enhance amylin
of these act on a family of related G protein-coupled secretion in response to a meal, which could lead to
receptors by modulating nitric oxide synthesis (Morley amylin resistance. Amylin administration to obese indi-
et al., 1995). Both CGRP and amylin peptides have viduals may have the potential to promote weight loss
nearly identical N- and C-terminal regions and the by delaying gastric emptying and inhibiting food
390 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401

intake, and overcoming resistance at the target tissues. Both the NPY and melanocortin systems are impor-
Preclinical data with amylin and clinical data with tant downstream targets for the effects of insulin on food
pramlintide (a human amylin analogue) support a role intake and body weight (Schwartz et al., 1992a,b; Benoit
for amylin in satiety. Pramlintide administration led to et al., 2002). i.c.v. administration of insulin during food
sustained weight loss when given for up to one year to deprivation in rats prevents the fasting-induced increase
type 1 and type 2 diabetic patients at doses resulting in in hypothalamic levels of both NPY in the PVN and
plasma concentrations close to those in non-diabetic NPY mRNA in the ARC (Schwartz et al., 1992b; Air
humans (Whitehouse et al., 1998, 2002; Ratner et al., et al., 2002). Insulin receptors have also been found on
2002). POMC neurons in the ARC (Benoit et al., 2002).
Administration of insulin into the third ventricle of fast-
7.5. Insulin ing rats increases POMC mRNA expression (Air et al.,
2002). The reduction of food intake caused by i.c.v.
Insulin is a major metabolic hormone produced by injection of insulin is also blocked by a POMC antago-
the pancreas and the first adiposity signal to be nist (Benoit et al., 2002). Furthermore, POMC mRNA is
described (Schwartz et al., 1992b). Levels of plasma reduced by 80% in rats with untreated diabetes, and this
insulin vary directly with changes in adiposity (Bagdade can be attenuated by peripheral insulin treatment which
et al., 1967) so that plasma insulin increases at times of partially reduces the hyperglycemia (Sipols et al., 1995).
positive energy balance and decreases at times of nega- Male mice with neuron-specific deletion of the insulin
tive energy balance (Woods et al., 1974). Visceral fat is receptor in the CNS are obese and dyslipidemic with
a key determinant of insulin sensitivity and hence increased peripheral levels of insulin (Bruning et al.,
plasma insulin levels (Porte et al., 2002). However, 2000). Reduction of insulin receptor proteins in the med-
unlike leptin, insulin secretion increases rapidly after a ial ARC, by administration of an antisense RNA direc-
meal, whereas leptin levels are relatively insensitive to ted against the insulin receptor precursor protein, results
meal ingestion (Polonsky et al., 1988). Insulin pene- in hyperphagia and increased fat mass (Obici et al.,
trates the blood–brain barrier via a saturable, recep- 2002).
tor-mediated process, at levels proportional to the Treatment of mice with orally available insulin
circulating insulin (Baura et al., 1993). Recent findings mimetics decreases the weight gain produced by a
suggest that little or no insulin is produced in the brain high-fat diet as well as adiposity and insulin resistance
itself (Woods et al., 2003; Banks, 2004). Once insulin (Air et al., 2002).
enters the brain, it acts as an anorexigenic signal
(Marks et al., 1990). 7.6. Bombesin
The insulin receptor is composed of an extracellular
b-subunit which binds insulin, and an intracellular b- Bombesin is a 14-aminoacid peptide originally puri-
subunit which transduces the signal and has intrinsic fied from the skin of the European amphibian Bombina
tyrosine kinase activity. There are several insulin recep- bombina (Spindel, 1986; Taché and Brown, 1982). The
tor substrates (IRSs) including IRS-1 and IRS-2, both known mammalian bombesin-like peptides are neurom-
identified in neurons (Baskin et al., 1994; Burks et al., edin B (NMB) and gastrin-releasing peptide (GRP).
2000). The phenotype of IRS-1-knockout mice does Bombesin and related peptides bind to G-protein cou-
not show differences in food intake or body weight pled receptors and mediate their actions through phos-
(Araki et al., 1994), but that of IRS-2-knockout mice pholipase C. These receptors are designated as BB1
is associated with an increase in food intake, increased (specific for NMB, NMB-R), BB2 (specific for GRP,
fat stores and infertility (Burks et al., 2000). IRS-2 GRP-R) (Battey et al., 1991). More recently, a third
mRNA is highly expressed in the ARC, suggesting that Bombesin receptor subtype 3 (BRS3) has been cloned
neuronal insulin may be coupled to IRS-2 (Burks whose endogenous ligands have not yet been success-
et al., 2000). There is also evidence to suggest that fully established (Ohki-Hamazaki et al., 2005). The
insulin and leptin, along with other cytokines, share GRP-receptors and neuromedin B-receptors are widely
common intracellular signalling pathways via IRS expressed in the CNS and gastrointestinal tract (Wada
and the enzyme phoshoinositide 3-kinase, resulting in et al., 1991 and Wada et al., 1992). The GRP-R is also
downstream signal transduction (Niswender et al., expressed in the hypothalamus such as in the PVN,
2001; Porte et al., 2002). Insulin receptors are widely and GRP is more potent than neuromedin B in inhibit-
distributed in the brain, with highest concentrations ing feeding.Although NMB-R is not highly expressed in
found in the olfactory bulbs and arcuate nucleus of these regions, it may participate in the control of food
hypothalamus. Other regions of hypothalamus express- intake in the caudal hindbrain (Ladenheim et al.,
ing Insulin receptors are DMH, PVN, and suprachias- 1997). Bombesin, induced by gastric distension, might
matic and periventricular regions (Corp et al., 1986; act as a messenger informing the nervous centres that
Marks et al., 1990). the subject is satiated (Rampal, 1986). Meal-related fluc-
 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401 391

tuations in the release of bombesin (GRP)-like peptides ple find it difficult to lose weight despite availability of
were reported in the PVN of rats (Plamondon and widely available choice of diets and exercise pro-
Merali, 1994). grammes, and even more difficult to maintain weight
In the CNS,these neuropeptides are thought to play a loss (Frandsen et al., 1998). Current second-line treat-
role in the regulation of feeding behavior, metabolism, ments available are medications and surgery.
and thermoregulation. Central administration of bom- Currently, the only obesity treatment in clinical use
besin and bombesin-related peptides elicit suppression that has shown significant long-term weight loss is gas-
of food intake (Merali et al., 1993). Central administra- trointestinal Roux-en-Y bypass surgery (Frandsen
tion of bombesin-receptor antagonists blocked the sati- et al., 1998; Mitchell et al., 2001). However, because of
ety effect of bombesin and also enhanced food intake its complications, this procedure is restricted to patients
insatiated rats (Merali et al., 1993; Flynn, 1993). Certain with morbid obesity. Post-surgical weight loss is not
hypothalamic and hindbrain structures, such as the caused by malabsorption, but is due to a loss of appetite
PVN and the nucleus tractus solitarius (NTS), are par- (Atkinson and Brent, 1982), which may be secondary to
ticularly sensitive to the feeding suppressant effects of elevated PYY and glucagon-like peripheral peptides like
bombesin (Flynn, 1992). Bombesin might mediate its oxyntomodulin, (Naslund et al., 1997; Sarson et al.,
feeding-suppressant effects through an interaction with 1981) and suppressed ghrelin levels (Cummings et al.,
CRF because CRF antagonists attenuated the satiety 2002). This suggests that therapies based on these hor-
effects of bombesin administered centrally or peripher- mones may be effective in the long term, without the
ally (Plamondon and Merali, 1997). Animal studies also need for surgical intervention.
suggested that at least some of the effects of bombesin- Therapies specifically targeted to homeostatic path-
like peptides on food intake are mediated through ways such as the gut-hypothalamic axis, anorexic and
endogenous cholecystokinin (CCK) release, although orexigenic hormone receptors within hypothalamus,
in humans, GRP can act independently to reduce food effectors of leptin and insulin signal transduction, and
intake (Gutzwller et al., 1994). Because the effects of sys- central and peripheral nutrient sensing pathways, are
temically administered bombesin are abolished by total possible. Effective weight loss and long-term mainte-
neural disconnection of the gut from the brain and are nance of weight loss will probably require multidrug
attenuated by central pretreatment of bombesin antise- therapy that targets these different regulatory elements
rum or antagonists, the satiety effects of bombesin (Korner and Aronne, 2004).
maybe neurally communicated to the brain where bom- Anti-obesity medicines in clinical use have been fen-
besin receptors participate (Plamondon and Merali, fluramine, D-fenfluramine and more recently sibutr-
1997). amine and orlistat. Only two drugs, sibutramine and
Studies on the gene knock-out mice showed that orlistat, are approved by the Food and Drug Adminis-
GRP-R deficient mice showed some increase in weight tration for long-term use (Hines, 2004).
gain (Wada et al., 1997; Hampton et al., 1998; Laden- Sibutramine, a serotonin and nor-adrenaline re-
heim et al., 2002; Maekawa et al., 2004). However, sim- uptake inhibitor, is recommended by the National Insti-
ilar changes were not seen with NMB-R deficient mice tute of Clinical Excellence (NICE) for the treatment of
indicating that for regulation of food intake GRP/ obesity in patients with a BMI of 30 kg/m2 or the pres-
GRP-R is more important as compared to NMB/ ence of an obesity-related disease and a BMI of over
NMB-R (Maekawa et al., 2004). BRS-3 deficient mice 27 kg/m2 (Korner and Aronne, 2004).
also demonstrated mild obesity due to reduced meta- Orlistat, an inhibitor of pancreatic and gastrointesti-
bolic rate, increased feeding efficiency, hyperphagia nal lipases, prevents the absorption of approximately
(Ohki-Hamazaki et al., 1997). BRS-3 deficient mice also 30% of dietary fat (Padwal et al., 2003). Orlistat reduces
demonstrated elevated circulating leptin levels and resis- low density lipoprotein and cholesterol levels indepen-
tance to exogenously administered leptin. However, dent of reductions in body weight, decreases the pro-
when leptin was applied intracerebroventricularly, gression to a diabetic state, and leads to better
food-intake was inhibited in wild-type mice but this glycemic control in patients with diabetes. Side effects
effect was attenuated in BRS-3 deficient mice (Maekawa due to the mode of action include oily spotting, liquid
et al., 2004). Orexigenic response to MCH, MCH levels stools, fecal urgency or incontinence, flatulence, and
and MCH mRNA expression was seen to enhanced in abdominal cramping. As orlistat may impair the absorp-
BRS-3 deficient mice (Maekawa et al., 2004). tion of fat-soluble vitamins, a multivitamin supplement
should be taken 2 h before or after the medication (Kor-
7.7. Treatment alternatives for obesity: Current and ner and Aronne, 2004).
future These drugs have all been effective at reducing and
controlling patients’ body weight, a clinical effect
Reducing energy intake and exercise is the first line directly related to their hypophagic action. Their
treatment for inducing weight loss. However, most peo- drawback has been their side effect profiles (primary
392 S. Arora, Anubhuti / Neuropeptides 40 (2006) 375–401

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