Appetite suppression based on selective inhibition of NPY receptors


AIM: The aim of this review is to critically assess available evidence that blockade of the actions of NPY at one of the five NPY receptor subtypes represents an attractive new drug discovery target for the development of an appetite suppressant drug.

RESULTS: Blockade of the central actions of NPY using anti-NPY antibodies, antisense oligodeoxynucleotides against NPY and NPY receptor antagonists results in a decrease in food intake in energy-deprived animals. These results appear to show that endogenous NPY plays a role in the control of appetite. The fact that NPY receptors exist as at least five different subtypes raises the possibility that the actions of endogenous NPY on food intake can be adequately dissociated from other effects of the peptide. Current drug discovery has produced a number of highly selective NPY receptor antagonists which have been used to establish the NPY Y1 receptor subtype as the most critical in regulating short-term food intake. However, additional studies are now needed to more clearly define the relative contribution of NPY acting through the NPY Y2 and NPY Y5 receptors in the complex sequence of physiological and behavioral events that underlie the long-term control of appetite.

CONCLUSIONS: Blockade of the NPY receptor may produce appetite-suppressing drugs. However, it is too early to state with certainty whether a single subtype selective drug used alone or a combination of NPY receptor selective antagonists used in combination will be necessary to adequately influence appetite regulation.


Neuropeptide Y (NPY) exerts a powerful stimulatory effect on food intake after injection either into the cerebral ventricles or into the hypothalamus of satiated rats.1,2,3 Perhaps more importantly, infusion of NPY into the brain promotes continuing hyperphagia and an increase in body weight, which is accompanied by hyperinsulinemia and insulin resistance. These observations suggest that heightened brain NPY levels may be a contributing factor to the initiation and maintenance of the obese/diabetic state.4,5

Evidence for a physiological role of NPY in the control of food intake and body weight has been obtained from several studies and the following examples are instructive. Firstly, a close relationship exists between food intake and NPY expression levels in the hypothalamus. For example, hypothalamic NPY levels are increased in the dark phase when rats consume the majority of their daily food intake.6,7 Secondly, hypothalamic NPY levels are increased in certain models of hyperphagia, such as after food deprivation and food restriction as well as in spontaneous and experimentally induced diabetes.8,9,10,11 Hypothalamic NPY levels are also increased in monogenetic models of obesity such as the ob/ob mouse and Zucker fa/fa rat, which are hyperphagic and obese.12,13 Finally, inhibition of the synthesis or blockade of the actions of NPY with antibodies, antisense oligodeoxynucleotides (ODN), non-selective receptor antagonists, or other approaches leads to lower food intake in both freely feeding and energy-deprived animals.14,15,16,17,18,19 Together, these observations have been taken to suggest that NPY plays a physiologically important role in the control of food intake. Moreover, blockade of the central actions of NPY also leads to a decrease in food intake and body weight in the genetically obese Zucker fa/fa rat, which suggests a role for endogenous NPY in the pathogenesis of this obesity syndrome.20,21

The above findings have encouraged the pharmaceutical industry to develop NPY receptor antagonists as potential appetite suppressant and anti-obesity drugs. However, since both NPY and NPY receptors are widely distributed within the brain, it is not surprising that NPY has also been shown to play a role in the expression of behaviors other than food intake (Figure 1). The recent finding that the actions of NPY are mediated through at least five different receptors raises the possibility that the effects of NPY on appetite may be mediated through a specific ‘feeding’ receptor.22 In this case, selective blockade of this receptor would reduce the risk of inhibiting other actions of NPY which could lead to undesirable side-effects.

Figure 1

The actions of NPY.

Since drug discovery in this area relies upon NPY playing a physiologically important role in the control of food intake, the first part of this review will critically assess the available evidence supporting this basic assumption. We shall then evaluate the possibility that selective appetite suppressants with few side-effects can be produced by targeting individual NPY receptor subtypes, and finally discuss some pitfalls that seem likely to complicate the development of NPY antagonists.

Neuropeptide Y and food intake

Mechanisms of food intake

Food intake is a deceptively easy parameter to measure, but this simplicity masks a behavior with very complex motivation. Two schools of thought have emerged concerning the control of food intake—the physiological and the behavioral.23 The physiological school proposes that food intake is controlled by a combination of chemical (eg plasma glucose), hormonal (eg leptin) and neural (eg vagal afferents from the liver and viscera) inputs that converge on the brain.24,25,26

Feeding is undoubtedly influenced by these physiological signals, but it can also be initiated in the absence of energy depletion by learned associative cues. This is an aspect of food intake that is often overlooked. These cues can be linked both to palatability and the rewarding properties of the food eaten.27 Environmental cues such as stress, the time of day, place and an assessment of future food supply are also important regulators of food intake.28,29 Thus, it appears that experience and learning as well as an anticipation of future energy needs continuously interact with peripheral signals to control food intake. Consequently, many interconnected brain areas are used by the animal to initiate and then control the complex multifaceted behavior that results in a change in food intake.30

Food intake is highly variable from meal to meal, leading to well-tolerated variations in daily energy balance.31 This rather loose control of daily food intake contrasts with the stable body composition that is usually maintained for long periods of time, suggesting that over the long-term food intake must be very tightly controlled.23,31 Understanding the relative importance of the individual physiological and behavioral phenomena involved in the control of both short-term and long-term food intake is important, both for identifying new drug discovery candidates, and for utilizing them in treatment regimes that will maximize their appetite suppressant properties.

Exogenous NPY and food intake

NPY enhances motivation and reward

The increase in food intake produced by administration of NPY into the brain could be due either to an increase in perceived hunger or to an enhancement of the motivating/rewarding properties of the food being eaten. Progress in this area is hampered by the difficulty in distinguishing a hungry animal from an animal that may be eating for some other reason. However, evidence has accumulated in recent years suggesting that both the motivation to eat and the subsequent rewarding properties of the food eaten may both play an important role in the action of exogenous NPY on food intake. Evidence supporting this hypothesis has come from a series of studies demonstrating that central administration of NPY directly enhances reward. For example, injection of NPY into the hypothalamus enhances the motivation to respond to rewarding stimuli.32,33 Furthermore, when presented with both palatable sweet food and regular chow, animals centrally injected with NPY choose the palatable food and will even tolerate an intense foot shock or other aversive stimuli to get it.34,35 The underlying increase in sweet intake in these experiments may be due to an associative learning effect of NPY-receptor stimulation to strengthen a gustatory preference for these foods.

Does exogenous NPY-stimulated food intake represent a true hunger state?

Whether NPY-induced eating represents a true hunger state has also been the focus of attention. For example, neither NPY nor peptide YY (PYY); (a close analog of NPY which acts on NPY receptors) when injected into the brain induces the same discriminative stimulus effects as food deprivation.36,37 That is, rats can readily perceive the distinction between stimulation of NPY receptors in the brain and food deprivation. Furthermore, injection of NPY into the brain produces generalized behavioral activation that enhances the appetitive phase (the period immediately before eating when the animal is actively looking for food) but does not change or may even decrease the consummatory phase (the period of biting, chewing and swallowing) of food intake.38,39,40 These are aspects of feeding different from deprivation-induced food intake and give reason to believe that exogenous NPY acts primarily to increase the motivation of animals to eat by mechanisms that are not the same as either food deprivation or other types of metabolic challenge.41 Indeed it has been suggested that the actions of exogenously administered NPY are more in keeping with pathophysiological states such as binge eating rather than normal food intake.42,43 Care should, however, be exercised in the interpretation of many of these studies, since NPY was injected intracerebroventricularly and the same behavioral changes may not be observed if NPY is injected in small doses directly into discrete areas of the hypothalamus. Examples of the major differences observed between food intake stimulated by exogenous NPY and food intake induced by food restriction are summarized in Table 1.

Table 1 Examples of differences between the effects of NPY and food deprivation on food intake

NPY and NPY receptor density in different brain areas in response to changes in energy balance

Evidence is accumulating to show that the content of NPY and NPY receptor density are changed in many brain areas in response to changes in food restriction and obesity. For example, energy deprivation produced either by fasting or by food deprivation has been shown to increase the NPY content of the hypothalamus (paraventricular nucleus, arcuate nucleus/median eminence), hippocampus and cortex and to decrease NPY levels in the striatum.44,45,46 In contrast, NPY levels are not altered in either the caudate nucleus or the nucleus accumbens.46 The increased NPY levels produced by energy deprivation are associated with decreased NPY Y5 and/or NPY Y2 receptor density in the hypothalamus (lateral (perifornical)), dorsal, ventromedial, hippocampus (CA3 region) thalamus (paraventricular and reuniens nuclei) and amygdala (centromedial nucleus).47,48 In ob/ob mice that have high brain NPY levels, similarly decreased receptor density has been shown in the hypothalamus, thalamus (midline group), cortex (cingulate, retrosplenal and granular) and hippocampus.49 In contrast, animals made obese by feeding a high-fat diet, in which hypothalamic NPY levels are low, increased NPY Y5 and/or NPY Y2 receptor density has been shown in the hypothalamus, amygdala and thalamus.47 Many of these brain areas are also influenced by other regulators of food intake such as GLP-1, MC-4 receptor agonists, AGRP, leptin, CART (cocaine and amphetamine related transcript) and the orexins.50,51,52,53 Together, these studies strongly suggest that food intake in response to changes in energy balance may involve the coordinated activity of NPY containing neurons and receptors in many brain regions, and not just those in the hypothalamus.

NPY injected into many brain areas alters food intake

NPY is commonly perceived to increase food intake only when injected into the hypothalamus, but it also exerts this effect at several extra-hypothalamic sites, including the frontal cortex, the hind brain and the hippocampus (Figure 2A).54,55,56,57,58 In the hippocampus, NPY increases the activity of acetylcholine-containing nerve terminals believed to be important in modulating reward and arousal,56 suggesting that stimulation of NPY receptors in this region may increase food intake by enhancing the perception of the rewarding properties of the food eaten.56

Figure 2

Sites of action of NPY on the brain to effect food intake. (A) NPY has been shown to stimulate food intake after injection into the cortex, hippocampus, hind brain as well as into the hypothalamus. (B) Injection of NPY into the ventricular system (black areas) ensures a wide distribution of the peptide within the brain (represented by the thick arrow). Injection of NPY into the hypothalamus may activate only certain other brain areas (represented by the thin arrows). The background figures are reprinted from Brain maps—structure of the rat brain, by LW Swanson (Elsevier: Amsterdam, 1998, 2nd edn), with permission from Elsevier Science.

Does NPY-induced hyperphagia mimic the actions of the endogenous peptide?

The above findings suggest that endogenous NPY may control food intake through coordinated activity in many parts of the brain; accordingly injection of NPY into the cerebroventricular system (or even directly into the hypothalamus) may not exactly mirror the effects of the endogenous peptide on food intake (Figure 2B). Some evidence exists to support these possibilities. First, the failure of NPY to increase the consummatory phase of food ingestion after intracerebroventricular (i.c.v.) injection appears to differ from that observed after direct hypothalamic injection where meal size (an index of the consummatory phase) is increased.38,40 Evidently, feeding after i.c.v. vs hypothalamic NPY may not necessary be based on the same underlying mechanisms. Second, both food intake and paradoxical taste aversions are produced after injection of NPY into the ventricular system of the brain, suggesting that sites additional to those involved in food intake are activated.40 This finding is supported by the observation that c-fos expression in the paraventricular nucleus (PVN) of the hypothalamus is increased after i.c.v. injection of NPY, but not after fasting when endogenous NPY levels at this site are increased.59,60

Endogenous NPY and food intake

Changes in food intake after blockade of the actions of endogenous NPY in the brain

Clearly, to adequately answer the question posed by the previous section it is necessary to compare feeding behavior after central injection of NPY with the effects of blocking the actions of endogenous NPY in the brain. The following is a discussion of the approaches that have been used to investigate the role of endogenous NPY in the control of food intake.

Knockout mice

Knockout of the gene encoding for NPY produces a mouse with few metabolic perturbations.61 For example, NPY-deficient mice have a normal hormonal profile, grow and eat normally and have a normal response to both diet and chemically-induced obesity (monosodium glutamate or gold thioglucose).61,62,63 Most studies conducted with these animals show a normal refeeding response to short-term fasting, although one recent study has challenged this conclusion;61,64 the difference between these studies appears due to whether wild-type or heterozygous animals were used as controls. NPY knockout animals do however, express an anxiogenic-like phenotype are hypoalgesic with an increased susceptibility to epilepsy.64,65

Since these findings argue against an important physiological role for NPY in the control of food intake, how can they be interpreted? Two main explanations have been suggested. First, NPY may not be a critical feeding regulator; in its absence, food intake is maintained by the action of other neuropeptides. For example, AGRP expression is increased in the hypothalamic neurons of the NPY knockout mouse.66 Alternatively, during development, other neural pathways may compensate for the lack of the NPY. This is a distinct possibility, since neural pathways in the brain that control food intake are highly redundant and inhibition of one generally leads over time to the return of normal feeding. This point could be addressed by the use of inducible knockout animals, in which the expression of NPY would be prevented at the time of experiment.

Anti-NPY antibodies

Specific antibodies against NPY have been used acutely to block the actions of endogenous NPY on food intake. Injection of anti-NPY antibodies into the brain of rats attenuates spontaneous feeding and that induced by 2-deoxyglucose, ventromedial hypothalamic (VMH) lesions and fasting.14,67,68,69,70,71,72 Spontaneous food intake in the Zucker fa/fa rat is also reduced by administration of NPY antibodies into the brain.21 These studies suggest that endogenous NPY does in fact play a physiologically important role in modulating the activity of brain feeding circuits—at least in the short-term. However, only total food intake was measured in response to antibody administration in most of these studies. Therefore, it cannot be assumed that the observed reduction in food intake was behaviorally specific rather than an aversive effect of the antibodies. Indeed, injection of anti-NPY antibodies directly into the VMH produced a large increase in amphetamine-like motor activity and decreased resting behavior, which is thought to explain the concurrent decrease in food intake observed in that study.73

Antisense oligonucleotides (ODNs)

The results obtained with this approach have been mixed. Initial use of this technology demonstrated that injection of ODNs directly into the arcuate nucleus of the hypothalamus reduced food intake.74 Other studies have also shown central administration of NPY antisense ODNs to decrease food intake, meal size and meal duration without inducing sickness or taste aversion.75 However, side effects and toxicity associated with the use of NPY ODNs are often prominent.75,76,77 For example, a recent comprehensive study of the effect of several different types of ODNs on food intake has shown either no effect on feeding or significant side effects associated with inhibiting the production of NPY.77 The use of different types of ODNs could explain the discrepant results described above,74,75,76,77 but these studies do raise concerns about the specificity and toxicity of antisense molecules within the central nervous system. This remains a particular problem when studying behaviors such as food intake, which can be strongly influenced by both toxic and non-selective interactions.

Miscellaneous approaches

Ventricular injection of the non-selective peptide NPY receptor antagonist 1229U91 has been shown to inhibit NPY-induced food intake, the refeeding response to short-term fasting as well as spontaneous food intake in Zucker fa/fa rats.78,79 By contrast, 1229U91 did not inhibit either spontaneous food intake in normal rats or after the induction of dietary-induced obesity—both cases in which brain NPY levels are low.79 The product 1229U91 has high affinity for NPY Y1 and Y4 receptors and acts as an antagonist of the former and as an agonist at the latter.80 Furthermore, 1229U91 has also been shown to interact with high affinity to the NPFF(2) receptor, a neural substrate related to NPY that may also be involved in feeding.81 These findings should be considered when interpreting the outcome of studies using this molecule.

Other non-selective NPY antagonists such as GI 264879A and WRY amide have also been shown to decrease food intake.18,19 However, since the existence of possible non-NPY actions of these peptides have not been systematically evaluated the results of these studies also need to be interpreted with caution.

An anti-NPY monoclonal antibody has been prepared with cytotoxic molecules attached (ricin A chain and monensin) with the intention of destroying NPY neurons. This modified antibody has been shown to reduce both fasting-induced food intake and spontaneous food intake for 10 days after direct injection into the arcuate nucleus.15

Does endogenous NPY play an important role in the control of food intake?

In view of the discussion above what can be said regarding the role of endogenous NPY in the control of food intake? Firstly, following energy depletion and repletion there is an appropriate change in brain NPY levels and NPY receptors in many of the brain areas activated by exogenous NPY. In addition, a good correlation exists between changes in NPY expression and food intake. These positive observations are supplemented by the ability of anti-NPY antibodies, NPY antisense, immunotoxins and non-selective NPY antagonists to reduce food intake in animal models where brain NPY levels are high. On the other hand, energy balance in NPY knockout mice appears essentially normal, and there are questions regarding the selectivity of all of the approaches used to inhibit the action of NPY. Furthermore, it remains unknown whether blockade of endogenous NPY affects food intake through the same behavioral mechanisms as those produced by exogenous NPY. Certainly, confidence that endogenous NPY is involved in the control of food intake would be considerably enhanced by the use of specific and selective manipulations that also sought to define the behavioral mechanism(s) by which food intake was changed.

NPY receptor subtypes

How many NPY receptor subtypes?

Genes encoding five NPY receptor subtypes have been identified—NPY Y1, NPY Y2, NPY Y4, NPY Y5 and NPY Y6.22,82,83,84 The NPY Y3 receptor has not yet been cloned but has been identified pharmacologically on the basis of a unique in vivo binding profile.85 The NPY Y6 receptor is a pseudogene in primates86,87 and the encoding gene has not been detected in the rat.88 However, in both the mouse and rabbit the NPY Y6 receptor gene encodes for a functional NPY/PYY receptor.86,89 Comparison of the amino acid sequences of the human (h) NPY hY1, NPY hY4 and NPY hy6 receptors shows 41–48% identity (Table 2). By contrast, the deduced amino acid sequences of the NPY hY2 and NPY hY5 receptors reveal significant divergence from the other NPY subtypes (Table 2). However, despite these structural variations all receptor subtypes bind NPY with high affinity.

Table 2 NPY receptor amino acid identity

Evidence for the existence of other NPY receptor subtypes

Several other NPY receptors have been cloned in sub-mammalian species. For example, NPY zYa, NPY zYb and NPY zYc receptors from the zebra fish,90,91 the NPY Yb receptor from Atlantic cod92 and unclassified NPY receptors from Lymnaea stagnalis93 and Drosophila melanogaster.94 The NPY cod, NPY Yb/zYb and NPY zYc receptors display NPY Y1-like pharmacology while the NPY zYa subtype seems to have a pharmacological profile closer to the NPY Y5 receptor.90 However, amino-acid sequence comparisons and phylogenetic analyses have shown that NPY zYb, zYc and zYa receptors are not simple orthologues of existing mammalian NPY receptors.90,91 In addition, neither the NPY receptors from Lymneae stagnalis nor Drosophila have counterparts in mammals. Therefore, it is possible that additional mammalian NPY receptors remain to be discovered. Recently, an orphan receptor named GPR74 has been identified that binds PYY with high affinity and has 25% identity with the NPY Y1 receptor.95,96 This receptor has been provisionally designated as the ‘NPY Y7 receptor’ subtype, a classification that awaits confirmation from other groups.

Gene structure of human neuropeptide Y receptor subtypes

The NPY Y1 and NPY Y5 receptor genes are both localized on human chromosome 4.97,98,99 The 5-untranslated regions of both the NPY Y1 and NPY Y5 receptor genes are encoded by several alternative 5 exons.100 These exons are transcribed under the control of different promoters that allow for the tissue-specific expression of the receptors.100,101 An important observation is that the human NPY Y1 and NPY Y5 receptor genes are transcribed in opposite directions from a common promoter region.98 Therefore, co-regulatory mechanisms controlling both NPY Y1 and Y5 gene transcription may exist. In favor of this hypothesis is the observation that, in rat brain, NPY Y5 receptor mRNA always coincides with the presence of the receptor, although the converse is not necessarily the case. Consequently, pharmacological treatments that modify NPY Y1 receptor expression could also affect that of the NPY Y5 receptor and vice versa.

Evidence for obesity linkage to NPY receptor subtypes.

Polymorphisms in existing NPY receptor subtypes have been evaluated for linkage to the obese state. In most studies, no linkage between receptor mutations and obesity have been found.102,103,104 For example, neither the polymorphisms Pstl (NPY Y1/Y5)101 and Glu-4-Ala (NPY Y5)104 nor the silent polymorphism Gly-426-Gly (NPY Y5)103 have associations with extremes of body weight. Conversely in a recent study, three novel single nucleotide polymorphisms (P1, P2 and P3) located in the NPY Y5 receptor gene non-coding region had an association with extreme obesity in Pima Indians.105 Although these studies suggest that the NPY Y5 receptor may be linked to some forms of obesity, it remains to be determined whether these mutations have functional consequences, are markers for another obesity locus, or have relevance to human obesity in other populations.

Distribution of NPY receptor subtypes in the brain

NPY receptors are distributed widely throughout the brain. Autoradiographic studies using the non-selective ligand 125I-PYY have revealed the presence of NPY receptors in over 100 different regions from all levels of the brain and spinal cord.106 The fact that these receptors exist as five functional subtypes raises the possibility that one exists only to mediate the effect of NPY on food intake. In this ideal but highly unlikely situation, a clear separation of the actions of NPY on food intake from all other central effects of the peptide could then be obtained (Figure 1). The possibility of making a ‘clean’ drug is an important consideration since regulatory authorities are unlikely to accept major behavioral side effects in an anti-obesity drug.107

One approach to understanding the role of a particular NPY receptor subtype in the control of food intake would be to study its distribution within the brain. The receptor subtype whose distribution best matched the brain areas acted on by NPY to control of food intake (see above) would then be an ideal candidate for drug discovery. One obvious limitation to this approach is the fact that the brain areas utilized by NPY in the control of food intake are not well understood. Furthermore, mRNA's encoding for the NPY Y1, NPY Y2, NPY Y4 and NPY Y5 receptor subtypes all appear to be very widely distributed in rat brain—both in areas known to be involved in the control of food intake and in others that are not (Table 3).108,109,110,111,112,113,114,115 Furthermore, there is uncertainty whether the encoding mRNA accurately represents either the location or degree of expression of the receptor protein, for the following reasons. Firstly, although the receptor protein and the encoding mRNA mostly overlap, they do not coincide perfectly.109,111 Therefore, the level of expression of the mRNA and the protein in a given location could well be markedly different.111 In rat arcuate nucleus, for example, mRNA encoding the NPY Y1 receptor is strongly expressed, while the NPY Y1 protein, revealed either with radiolabelled agonists and antagonists or by immunohistochemistry, is present only at low concentrations.112,113,114 Secondly, the regional distribution and expression of each NPY receptor subtype appears to be species-dependent.110,111,115 Finally, specific tools, such as radiolabeled non-peptide ligands, are available at present only for the NPY Y1 receptor subtype.112 The distribution of this receptor can therefore be mapped with reasonable accuracy, but accurate mapping of other NPY receptor subtypes awaits the use of highly selective ligands.

Table 3 NPY receptor subtype mRNA distribution in rat brain

Additional effort is clearly needed in this area to define more precisely the anatomical distribution of each NPY receptor subtype within the brain. Currently, our knowledge can point mainly to potential side effects. For example, the presence of NPY Y1 receptors in the amygdala which may be linked to anxiety and NPY Y5 receptors in the hippocampus which are implicated in epilepsy.116,117

NPY receptor subtypes in the control of food intake

The NPY Y5 receptor will be considered first, since this subtype has been designated the ‘feeding’ receptor. However, is there any solid evidence to support this assumption?

The NPY Y5 receptor

Amino-acid substitutions within the NPY molecule produce analogs which bind to the various receptor subtypes with different affinities. When the affinity of these modified peptides for the rat NPY Y5 receptor is compared with their ability to stimulate food intake, a significant positive correlation emerges, with those peptides having the highest affinity for the NPY Y5 receptor appearing to produce greater stimulation of food intake (Figure 3).118 The activity of four NPY analogs [K4, RYYSA19-23]PP2-36; [Ala31, Aib32]pNPY; [DTrp34]hNPY and [cPP1-7, NPY19-23, Ala31, Aib32, Gln34]hPP are of considerable interest since they have been shown to have both high affinity and selectivity for the rat NPY Y5 receptor (Table 4) and all potently stimulate food intake.119,120,121

Figure 3

Correlation between in vivo potency (ED50 in nmol) and in vitro affinity (IC50 in nmol) for the NPY Y1, Y2, Y3, Y5 receptor subtypes. Reprinted from Wyss et al.118 Regulatory Peptides 1998; 75–76: 363–371, with permission from Elsevier Science.

Table 4 Affinity of NPY peptide analogs for NPY receptor subtypes

Taken together, the above studies show that single injections of NPY Y5 selective agonists can stimulate food intake for times up to 24 h. However, it is a characteristic of G-protein coupled receptors that they down regulate with long-term stimulation. The results in Figure 4 show that the continuous infusion of hPP (a NPY Y5 and NPY Y4 agonist) into the brain of free-feeding rats results in a continuous hyperphagia which is associated with an increase in body weight. It is unlikely that the effects of hPP in these experiments are due to NPY Y4 receptor stimulation since this receptor subtype does not appear to be correlated with food intake (Figure 3).118 These new findings indicate that, at least over the period of study, stimulation of the NPY Y5 receptor subtype leads to maintained food intake without evidence of tolerance.

Figure 4

Effect of chronic infusion of hPP on food intake and body weight. In these studies, normal Sprague–Dawley rats were prepared with a chronic indwelling catheter implanted into the right lateral cerebroventricle. The cannula was connected to an Alzet osmotic minipump located beneath the skin of the back which dispensed hPP (11 µg/24 h) for 14 days. The cannula was implanted on day 0. After a 7 day recovery period, the infusion of hPP was started and continued until day 14.

The available evidence strongly suggests that stimulation of the NPY Y5 receptor with exogenous peptides increases both short- and long-term food intake. This then raises the question as to whether food intake changes when the action of endogenous NPY on the NPY Y5 receptor is prevented. This answer is crucial for drug discovery, since selective inactivation of the NPY Y5 receptor still leaves all other NPY receptor subtypes implicated in the control of food intake open to the peptide (Figure 5). The following section of the review considers the evidence both for and against a physiologically important role for NPY acting through the NPY Y5 receptor in the control of food intake.

Figure 5

Possible effects of NPY receptor stimulation on food intake. In the hypothalamus, release of NPY from the arcuate nucleus leads to stimulation of NPY receptors in the paraventricular nucleus. The NPY Y1, Y2 and Y5 receptors have both pre- and postsynaptic locations. Blockade of the NPY Y5 receptor, for example, leaves the NPY Y1 and the NPY Y2 receptors open to stimulation. NPY may also activate NPY receptors in other areas of the brain involved in the control of food intake, for example the cortex, hippocampus and hind brain. NPY receptor antagonists may (but should not) have significant interaction with non-NPY receptors (×).

Knockout of the NPY Y5 receptor

Knockout of the NPY Y5 receptor subtype produces a mouse of essentially normal phenotype when young; it grows and feeds normally and has normal feeding responses to both fasting and to centrally administered leptin.122 In these respects it resembles the NPY knockout mouse described above. Interestingly, with age the NPY Y5 receptor knockout mouse becomes hyperphagic and mildly obese. Since neither of these findings are in agreement with a role for the NPY Y5 receptor in mediating NPYs' stimulation of feeding, how can they be reconciled? Two main explanations have been suggested. The initially normal phenotype may be because the NPY Y5 receptor subtype is not a critical feeding receptor; in its absence, food intake is maintained by the action of NPY on other receptor subtypes such as the NPY Y1 receptor for instance (Figure 5). Alternatively, during development the lack of the NPY acting through the NPY Y5 receptor may be compensated for completely by other neural pathways as described above. The late developing obesity has been explained by postulating a presynaptic location for the NPY Y5 receptor. In this position the NPY Y5 subtype could act as an autoreceptor negatively inhibiting the release of NPY. Its absence in the NPY Y5 knockout would then leave the release of NPY unopposed—leading to overproduction of the peptide and to increased food intake (Figure 5). Indeed, there is some evidence for the presence of a presynaptically located NPY Y5 receptor, at least in the subiculum of the rat brain.123

Inhibition of the production of the NPY Y5 receptor with antisense oligodeoxynucleotides (ODNs)

The physiological role of endogenous NPY acting through the NPY Y5 receptor has also been investigated using the antisense approach. Repeated injections of high doses of antisense ODNs to the NPY Y5 receptor over a 2 day period has been shown to reduce NPY-induced food intake, spontaneous food intake and to inhibit the refeeding response to an overnight fast in rats.124,125,126 These data obtained using antisense ODNs in general contradict the conclusion of the knockout mouse that the NPY Y5 receptor has no involvement in the control of fasting-induced and spontaneous food intake. Interestingly, in one of the above studies antisense ODNs directed against the NPY Y5 receptor did not affect either the microstructure of food intake or the food intake response to galanin, indicating some specificity of this approach.124 In general, however, concerns about selectivity and toxicity have not been rigorously addressed. Another criticism leveled at the above studies is their failure to determine whether the antisense molecules actually entered their target cells to reduce NPY Y5 receptor density. In addition, the effect of the antisense molecules on food intake was in some cases faster than the 60–96 h turnover expected for G-protein-coupled receptors, further adding to the problems in data interpretation.

Because of these criticisms, the studies with antisense ODNs that point to a role of the NPY Y5 receptor in the physiological control of food intake need to be verified using another approach.

Inhibition of the NPY Y5 receptor with non-peptide antagonists

This is currently an area of intense interest to pharmaceutical companies, who would view a selective NPY Y5 antagonist that safely reduced food intake as a potential blockbuster anti-obesity drug. Since pharmaceutical companies closely guard the identity and activity of proprietary compounds, it is perhaps understandable why little of real relevance has been published in this area. At the time of writing, many different compounds from a variety of different chemical series had been described as NPY Y5 antagonists.127,128,129,130,131,132,133 The activity of only a few of these compounds has been described in detail, although more information is now starting to appear in the literature. The following examples illustrate the current problems facing drug discovery in this area.

CGP 71683A—an example of an active NPY Y5 receptor antagonist

Perhaps the most extensively studied of the known NPY Y5 receptor antagonists is CGP 71683A (Figure 6).134 This product has very high affinity for the NPY Y5 receptor and very low affinity for the NPY Y1, Y2 and Y4 receptor subtypes (Table 5). In LMTK mouse fibroblasts expressing the NPY Y5 receptor CGP 71683A attenuates NPY-induced intracellular calcium transients, thus attesting to its antagonistic properties. At first sight, the effects of this compound appear very promising since after intraperitoneal administration CGP 71683A strongly inhibits NPY-induced food intake. Furthermore, in both fasted and streptozotocin diabetic rats, animal models associated with elevated activity of hypothalamic NPY neurons, CGP 71683A significantly suppressed the attendant hyperphagia.

Figure 6

Molecular structure of some currently known non-peptide Y receptor antagonists.

Table 5 Specificity of selected NPY receptor antagonists

Non-selectivity and non-overt toxicity

To investigate its cross-reactivity, CGP 71683A has recently been studied in a series of both NPY and non-NPY receptor binding assays (Table 5).135 Surprisingly, CGP 71683A was found to have equally high affinity for the serotonin reuptake recognition site and for cholinergic muscarinic receptors in the rat brain as for the NPY Y5 receptor. Reasonably high affinity for α2-adrenergic receptors was also observed—a finding in agreement with the original published studies on this compound.134 Since increased serotonin as well as changes in muscarinic and α-adrenergic receptor activity can affect food intake, these observations call into doubt the conclusion that the hypophagia observed with CGP 71683A is due only to inhibition of NPY Y5 receptors.136,137,138 In the original description of this compound, CGP 71683A did not appear to be overtly toxic and did not change the microstructure of feeding behavior, induce significant taste aversion or produce anxiety.134,139 However, when injected into the brain, CGP 71683A induced a dose-dependent inflammatory response that appeared to correlate with the fall in food intake.135 Inflammatory mediators have been shown to negatively affect food intake and could be a further explanation for the decreased appetite observed with this compound.140 In accordance with the above studies, CGP 71683A has recently been shown to reduce food intake equally in both wild type and in NPY-knockout mice.64 This latter result confirms that the activity of CGP 71683A resides in a mechanism or mechanisms of action other than NPY Y5 receptor blockade.

Other examples of active NPY Y5 receptor antagonists

Both of the compounds Banyu X and Novartis 10 have recently appeared in the patent literature as NPY Y5 receptor antagonists (Figure 6).141,142 Both products decrease fasting-induced food intake after a single intraperitoneal injection (Table 5), consistent with the suggested role of the NPY Y5 receptor in the control of food intake. However, Banyu X (despite having a different chemical structure from CGP 71683A) also had significant cross-reactivity for the serotonin reuptake site, the norepinephrine uptake site and for muscarinic receptors (Table 5). In our hands, Novartis 10, produced a strong conditioned taste aversion when given at a dose that also lowered food intake. Thus, many of the products reported in the literature have been shown to affect food intake, but all have the potential to do so by mechanisms that are additional or even alternative to NPY Y5 receptor blockade.

L 152804—an example of a non-active NPY Y5 receptor antagonist

L 152804 is a potent and selective NPY Y5 receptor antagonist which, after oral administration, enters the hypothalamus in concentrations high enough to block the NPY Y5 receptor (Figure 6).143 L 152804 appears to bind specifically to the NPY Y5 receptor subtype since it has no significant affinity for over 120 different binding assays and seven enzyme assays. When injected into the brain or administered orally, L 152804 blocked the increase in food intake produced by the NPY Y5 selective agonist bPP but not the increase in food intake produced by NPY. Finally, when administered orally to Zucker fa/fa rats and to db/db mice, L 152804 did not affect spontaneous food intake.144 Recently, other potent and highly selective NPY Y5 antagonists have been described, which enter the brain in high concentrations.145,146 However, like L 152804, all of these compounds are ineffective at reducing food intake after acute oral administration to both spontaneously feeding and food deprived rodents as well as to ob/ob mice.

The results presented in this section show definitively that stimulation of the NPY Y5 receptor, either acutely or chronically, can enhance food intake. It is also possible to block the effects of ligands acting at the NPY Y5 receptor with selective antagonists. However, it is less certain that the action of endogenous NPY acting through this receptor plays an indispensable role in the maintenance of food intake. Therefore the NPY Y5 receptor subtype may not be a target for drug discovery (ie may not be ‘drugable’). However, NPY acting through the NPY Y5 receptor may well play a less critical role in the control of food intake, but after blockade its role is immediately taken over by NPY acting through another NPY receptor. Furthermore, as pointed out several times in this review, appetite is a very complex motivated behavior and further investigation may reveal a function of the NPY Y5 receptor subtype in an aspect of acute and perhaps long-term food intake. Clearly extensive studies of NPY Y5 antagonists in a variety of different animal models, both alone and in combination with antagonists of other NPY receptors, are now needed to define the role of NPY acting through this receptor subtype in the control of food intake.

The NPY Y2 receptor

Although a significant positive correlation exists between the affinity of modified NPY peptides for the rat NPY Y5 receptor subtype and their ability to stimulate food intake, no such correlation exists for the NPY Y2 receptor (Figure 3).118 Indeed, an analog of NPY (NPY13-36) with some selectivity for the NPY Y2 receptor subtype (Table 4) has very little, if any, effect on food intake when injected into the brain.147 The recent discovery of cyclo S-S [Cys20, Cys24]pNPY—a highly selective ligand of the NPY Y2 receptor may allow further study of the role of this subtype in the control of food intake (Table 4).148

Knockout of the NPY Y2 receptor

Knockout of the NPY Y2 receptor produces an animal which is both hyperphagic and obese.149 The exact mechanism or mechanisms underlying the phenotype of these animals is unclear at the present time. However, evidence is accumulating to support the idea that the NPY Y2 subtype has a presynaptic location and may act to inhibit NPY release from hypothalamic neurons.150 Thus the simplest explanation of the observed phenotype is that chronically increased NPY release after knockout of the NPY Y2 receptor is the cause of the hyperphagia and obesity of these animals (Figure 5). Furthermore, since NPY acting through the NPY Y2 receptor also controls the presynaptic release of catecholamines, increased monoamine release may also contribute to the changes in food intake and energy expenditure observed in the NPY Y2 knockout model.

Acute injection of NPY into the cerebral ventricles has been shown to induce a similar increase in food intake in both wild-type and NPY Y2 receptor knockout mice. These observations confirm that the NPY Y2 receptor is not a critical component for the expression of NPY-induced food intake. Interestingly, NPY Y2 receptor knockout mice have a normal feeding response to acute starvation.149 This is further evidence supporting the suggestion that the NPY Y2 receptor subtype does not modify the acute feeding response—in this case to endogenous NPY.

Inhibition of the NPY Y2 receptor with non-peptide antagonists

Recently, a non-peptide NPY Y2 receptor antagonist, BIIE0246 has been described as a selective high affinity antagonist of the NPY Y2 receptor.151 This compound also has significant affinity for muscarinic receptors (Table 5). If confirmed, these findings may make BIIE0246 a questionable tool to investigate the role of the NPY Y2 receptor in the control of food intake.

The NPY Y4 receptor

As with the NPY Y2 receptor, no correlation exists between NPY Y4 receptor affinity and food intake for a wide range of NPY peptide analogs (Figure 3).118 Rat pancreatic polypeptide (PP) which has very high affinity and reasonably good selectivity for the NPY Y4 receptor has little or no effect on food intake in rats.118,147 In addition, the NPY Y4 receptor has the lowest level of expression in rat brain when compared to other NPY receptor subtypes.110

The NPY Y1 receptor

Stimulation of the NPY Y1 receptor

The NPY Y1 receptor is pharmacologically characterized by high affinity for NPY and PYY and progressively lower affinity for the N-terminally truncated analogs: NPY2-36, NPY3-36, NPY13-36 and PP.118 The first apparently selective NPY Y1 receptor agonist was created by replacing both Ile31 and Glu34 in porcine NPY with the corresponding residues from hPP. Subsequently, only the Pro34 substitution was found necessary for Y1 selectivity (Y1 vs Y2). Use of these tools—[Leu31, Pro34] NPY and [Pro34] NPY—in rodents has shown that both strongly stimulate food intake.118,147 Although both have recently been shown to have significant affinity for both the NPY Y4 and the Y5 receptor subtypes118 their in vitro profiles on cloned Y-receptors (Y1, Y2, Y4 and Y5) based on negative coupling to cAMP appears to show some functional NPY Y1 selectivity.118,152 However, recently described NPY ligands with improved selectivity for the NPY Y1 receptor, such as c[D-Cys29-L-Cys34]NPY and in particular [Phe7, Pro34]pNPY and [Arg6, Pro34]pNPY should prove very useful for further elucidating the effect of this receptor subtype in the control of food intake (Table 4).148,153

Interestingly, when the affinity of modified NPY peptides for the NPY Y1 receptor is compared with their ability to stimulate food intake after i.c.v. administration, a significant positive correlation emerges (Figure 3).118 However, this correlation is not as tight as for the NPY Y5 receptor and other approaches have been used to examine the role of the NPY Y1 receptor in controlling food intake.

Knockout of the NPY Y1 receptor

Compared with controls, the feeding response of the NPY Y1 receptor knockout mouse to acute i.c.v. bolus injections of hNPY is reduced, as are the responses to hPYY3-36 as well as to h, b and rPP.154 That a residual component to the feeding response of some of these peptides remains is not surprising, since none is totally selective for the mouse NPY Y1 receptor.154 Thus it is entirely possible that each of these peptides had sufficient interaction with the remaining NPY receptor subtypes to maintain a partial feeding response (Figure 5). However, the observation that after knockout the feeding response to NPY analogs is attenuated provides evidence that stimulation of the NPY Y1 receptor subtype may be involved in the control of food intake.

The experiments described above demonstrate that blockade of the NPY Y1 receptor can inhibit NPY-induced food intake. Seemingly in line with these conclusions is the observation that knockout of the NPY Y1 subtype produces an animal with slightly reduced food intake and a significantly reduced refeeding response to short-term fasting.155 Paradoxically, NPY Y1 receptor knockout animals also have increased body fat and are hyperinsulinemic.155,156 The increased fat mass is thought to be due to decreased activity-associated thermogenesis and/or the concurrent hyperinsulinemia.156 Hyperinsulinemia could also be the reason underlying the decreased food intake observed in these animals.157

Inhibition of NPY Y1 receptor production with antisense oligodeoxynucleotides (ODNs)

The data obtained from the use of this approach have been conflicting, with antisense ODNs directed against the NPY Y1 receptor either increasing, decreasing or producing no change in food intake.158,159,160,161 However, a paradoxical increase in food intake has been the consistent finding in the majority of studies utilizing this approach.158,159,160

Inhibition of the NPY Y1 receptor with non-peptide antagonists

Recently, several non-peptide antagonists of the NPY Y1 receptor have been synthesized. Of these, BIBP3226 was the first highly-potent, high affinity NPY Y1 antagonist that had low affinity for other NPY Y receptor subtypes.162,163 After administration into the brain, this compound either partially or completely reversed the increase in food intake produced by NPY, [Leu31, Pro34] NPY and hPYY3-36. BIBP3226 and also decreased the refeeding response to short-term fasting and the intake of highly palatable food.164 However, BIBP3226 has also been shown to produce an anxiety-like state—presumably linked to blockade of NPY Y1 receptors in the amygdala and induced other behaviors such as barrel rolling and catatonia.162,165 Thus, the conclusion that the changes in food intake produced by BIBP3226 were behavioral may not be correct. Complicating matters further, BIBP3226 has recently been shown to act as an antagonist of the NPFF(2) receptor, which is also implicated in feeding modulation.81 Thus, BIBP3226 may affect food intake by mechanisms both related and unrelated to NPY Y1 receptor inhibition.162

Recently, BIBO3304, a derivative of BIBP3226, has been synthesized (Figure 6, Table 5), and has high affinity for the NPY Y1 receptor and very low affinity for the NPY Y2, NPY Y4 and NPY Y5 receptors.166 To avoid causing an anxiety-like state by blockade of NPY Y1 receptors in the amygdala, BIBO3304 has been injected directly into the PVN, and there inhibited both the refeeding response to fasting and the increase in food intake produced by NPY, [Leu31, Pro34]NPY, NPY2-36 and NPY3-36.166 The fact that BIBO3304 diminished the feeding response to peptide agonists with affinity towards both the NPY Y1 and the NPY Y5 receptor subtype has been taken as in vivo evidence for interplay between these two receptor subtypes in the control of food intake.166 A similar decrease in the agonist response to supposedly NPY Y5 selective analogs such as hPP is also observed in the NPY Y1-knockout mouse.154 An indication of the improved specificity over BIBP3226 is provided by the observations that the increase in food intake produced either by galanin or by norepinephrine is unaffected by BIBO3304.166

Other NPY Y1 receptor antagonists have been synthesized with oral activity. For example, J-104870, a compound with high affinity for the hNPY Y1 receptor and very low affinity for the hNPY Y2, hNPY Y4 and hNPY Y5 receptors, has been reported (Figure 6).167 Relatively high doses of this product were shown to block the increase in food intake produced by concurrent injection of NPY into the lateral ventricle of satiated normal rats.167 Spontaneous food intake in Zucker fa/fa rats can be decreased by administering high doses of J-104870 into the lateral ventricle (200 µg) or after oral administration at 100 mg/kg.167

Another potent and selective NPY Y1 antagonist from the same group, J-115814, has recently been shown to decrease food intake in db/db and normal mice but not in NPY Y1-knockout mice.144,168 This latter observation is very important since in general a systematic evaluation of the cross-reactivity of each compound with non-NPY receptors has not usually been performed. The potential of individual compounds to produce changes in food intake by non-specific mechanisms is clearly illustrated by the example of AMG 68, an NPY Y1 receptor antagonist, which paradoxically lowers food intake in the NPY knockout mouse.64

In conclusion, evidence exists to suggest that NPY acting through the NPY Y1 receptor is important for modulating short-term food intake—for example, after fasting and in monogenetic models of obesity. Nonetheless, concerns must remain about the ability of NPY Y1 receptor antagonists to reduce food intake without eliciting side effects such as increased anxiety or changed blood pressure.


We have attempted to assess critically the available evidence that blockade of the actions of NPY represents an attractive new drug discovery target.

Current drug discovery efforts have produced a number of highly selective NPY receptor antagonists. These have been used to establish the NPY Y1 subtype as apparently the most critical in regulating short-term food intake. However, additional work is needed to clarify the role of the NPY Y2 and NPY Y5 receptors in mediating the actions of NPY on food intake and will need to be performed using antagonists possessing the properties outlined in Table 6. It may turn out that combinations of NPY receptor antagonists represent the best approach to the modulation of the complex sequence of physiological and behavioral events that underlie normal and disordered appetite.169 Clearly, care will also have to be exercised in the extrapolation of animal data using NPY antagonists to humans, where each NPY receptor subtype may have a different distribution and function. Therefore, the final answer as to whether any NPY receptor antagonist will be useful in the control of food intake, without producing unacceptable side effects, can only be definitively answered by clinical studies in man.

Table 6 Criteria for accepting changes in food intake as due to NPY Yx receptor blockade

Finally, will a drug based on blockade of NPY receptor subtypes eventually produce an attractive appetite suppressant? Only time can answer this question, but any new drug that has the potential both to decrease food intake and increase sexual appetite16,31 would seem to be worth the effort.


  1. 1

    Levine AS, Morley JE . Neuropeptide Y: a potent inducer of consummatory behavior in rats Peptides 1984 5: 1025–1029.

  2. 2

    Stanley BG, Leibowitz SF . Neuropeptide Y: stimulation of feeding and drinking by injection into the paraventricular nucleus Life Sci 1984 24: 2635–2642.

  3. 3

    Allen LG, Kalra PS, Crowley WR, Kalra SP . Comparison of the effects of neuropeptide Y and adrenergic transmitters on LH release and food intake in male rats Life Sci 1985 37: 617–623.

  4. 4

    Beck B, Stricker-Krongrad A, Nicolas JP, Burlet C . Chronic and continuous intracerebroventricular infusion of neuropeptide Y in Long–Evans rats mimics the feeding behaviour of obese Zucker rats Int J Obes Relat Metab Disord 1992 16: 295–302.

  5. 5

    Sainsbury A, Cusin I, Rohner-Jeanrenaud F, Jeanrenaud B . Adrenalectomy prevents the obesity syndrome produced by chronic central neuropeptide Y infusion in normal rats Diabetes 1997 46: 209–214.

  6. 6

    McKibbin PE, Rogers P, Williams G . Increased neuropeptide Y concentrations in the lateral hypothalamic area of the rat after the onset of darkness: possible relevance to the circadian periodicity of feeding behavior Life Sci 1991 48: 2527–2533.

  7. 7

    Jhanwar-Uniyal M, Beck B, Burlet C, Leibowitz SF . Diurnal rhythm of neuropeptide Y-like immunoreactivity in the suprachiasmatic, arcuate and paraventricular nuclei and other hypothalamic sites Brain Res 1990 536: 331–334.

  8. 8

    Sahu A, Sninsky CA, Kalra SP . Evidence that hypothalamic neuropeptide Y gene expression and NPY levels in the paraventricular nucleus increase before the onset of hyperphagia in experimental diabetes Brain Res 1997 755: 339–342.

  9. 9

    Boswell T, Dunn IC, Corr SA . Hypothalamic neuropeptide Y mRNA is increased after feed restriction in growing broilers Poultry Sci 1999 78: 1203–1207.

  10. 10

    Jones PM, Pierson AM, Williams G, Ghatei MA, Bloom SR . Increased hypothalamic neuropeptide Y messenger RNA levels in two rat models of diabetes Diabetic Med 1992 9: 76–80.

  11. 11

    Lambert PD, Wilding JP, Turton MD, Ghatei MA, Bloom SR . Effect of food deprivation and streptozotocin-induced diabetes on hypothalamic neuropeptide Y release as measured by a radioimmunoassay-linked microdialysis procedure Brain Res 1994 656: 135–140.

  12. 12

    Jang M, Romsos DR . Neuropeptide Y and corticotropin-releasing hormone concentrations within specific hypothalamic regions of lean but not ob/ob mice respond to food-deprivation and refeeding: 1 J Nutr 1998 128: 2520–2525.

  13. 13

    Dryden S, Pickavance L, Frankish HM, Williams G . Increased neuropeptide Y secretion in the hypothalamic paraventricular nucleus of obese (fa/fa) Zucker rats Brain Res 1995 690: 185–188.

  14. 14

    Lambert PD, Wilding JP, al-Dokhayel AA, Bohuon C, Comoy E, Gilbey SG, Bloom SR . A role for neuropeptide Y, dynorphin, and noradrenaline in the central control of food intake after food deprivation Endocrinology 1993 133: 29–32.

  15. 15

    Burlet A, Grouzmann E, Musse N, Fernette B, Nicolas JP, Burlet C . The immunological impairment of arcuate neuropeptide Y neurons by ricin A chain produces persistent decrease of food intake and body weight Neuroscience 1995 66: 151–159.

  16. 16

    Hulsey MG, Pless CM, White BD, Martin RJ . ICV administration of anti-NPY antisense oligonucleotide: effects on feeding behavior, body weight, peptide content and peptide release Regul Pept 1995 59: 207–214.

  17. 17

    Chance WT, Sheriff S, Peng F, Balasubramaniam A . Antagonism of NPY-induced feeding by pretreatment with cyclic AMP response element binding protein antisense oligonucleotide Neuropeptides 2000 34: 167–172.

  18. 18

    Chance WT, Tao Z, Sheriff S, Balasubramaniam A . WRYamide, a NPY-based tripeptide that antagonizes feeding in rats Brain Res 1998 803: 39–43.

  19. 19

    Danielsa AJ, Chance WT, Grizzle MK, Heyer D, Matthews JE . Food intake inhibition and reduction in body weight gain in rats treated with GI264879A, a non-selective NPY-Y1 receptor antagonist Peptides 2001 22: 483–491.

  20. 20

    Ishihara A, Tanaka T, Kanatani A, Fukami T, Ihara M, Fukuroda T . A potent neuropeptide Y antagonist, 1229U91, suppressed spontaneous food intake in Zucker fatty rats Am J Physiol 1998 274: R1500–1504.

  21. 21

    Marin-Bivens CL, Kalra SP, Olster DH . Intraventricular injection of neuropeptide Y antisera curbs weight gain and feeding, and increases the display of sexual behaviors in obese Zucker female rats Regul Pept 1998 75–76: 327–334.

  22. 22

    Gehlert DR . Multiple receptors for the pancreatic polypeptide (PP-fold) family: physiological implications Proc Soc Exp Biol Med 1998 218: 7–22.

  23. 23

    Weingarten HP . Stimulus control of eating: implications for a two-factor theory of hunger Appetite 1985 6: 387–401.

  24. 24

    Harris RB . Role of set-point theory in regulation of body weight FASEB J 1990 4: 3310–3318.

  25. 25

    Bray GA . Afferent signals regulating food intake Proc Nutr Soc 2000 59: 373–384.

  26. 26

    Hansen BC, Ortmeyer HK . Obesity, diabetes, and aging: lessons from life-time studies in monkeys. In: Guy-Grand B, Aihaud G (eds). Progress in obesity research Libbey: London 1999 525–544.

  27. 27

    Berridge KC . Food reward: brain substrates of wanting and liking Neurosci Biobehav Rev 1996 20: 1–25.

  28. 28

    Collier G, Johnson DF . The time window of feeding Physiol Behav 1990 48: 771–777.

  29. 29

    Waterhouse J, Minors D, Atkinson G, Benton D . Chronobiology and meal times: internal and external factors Br J Nutr 1997 77(Suppl 1): S29–38.

  30. 30

    Leibowitz SF, Hoebel BG . Behavioral neuroscience of obesity. In: Bray GA, Bouchard C, James WPT (eds). Handbook of Obesity Marcel Dekker: New York 1997 313–358.

  31. 31

    Flatt JP . What do we most need to learn about food intake regulation Obes Res 1998 6: 307–310.

  32. 32

    Brown CM, Fletcher PJ, Coscina DV . Neuropeptide Y-induced operant responding for sucrose is not mediated by dopamine Peptides 1998 19: 1667–1673.

  33. 33

    Brown CM, Coscina DV, Fletcher PJ . The rewarding properties of neuropeptide Y in perifornical hypothalamus vs. nucleus accumbens Peptides 2000 21: 1279–1287.

  34. 34

    Heilig M, McLeod S, Koob GK, Britton KT . Anxiolytic-like effect of neuropeptide Y (NPY), but not other peptides in an operant conflict test Regul Pept 1992 41: 61–69.

  35. 35

    Flood JF, Morley JE . Increased food intake by neuropeptide Y is due to an increased motivation to eat Peptides 1991 12: 1329–1332.

  36. 36

    Seeley RJ, Benoit SC, Davidson TL . Discriminative cues produced by NPY do not generalize to the interoceptive cues produced by food deprivation Physiol Behav 1995 58: 1237–1241.

  37. 37

    Jewett DC, Schaal DW, Cleary J, Thompson T, Levine AS . The discriminative stimulus effects of neuropeptide Y Brain Res 1991 561: 165–168.

  38. 38

    Ammar AA, Sederholm F, Saito TR, Scheurink AJ, Johnson AE, Sodersten P . NPY-leptin: opposing effects on appetitive and consummatory ingestive behavior and sexual behavior Am J Physiol Regul Integr Comp Physiol 2000 278: R1627–1633.

  39. 39

    Altizer AM, Davidson TL . The effects of NPY and 5-TG on responding to cues for fats and carbohydrates Physiol Behav 1999 65: 685–690.

  40. 40

    Woods SC, Figlewicz DP, Madden L, Porte D Jr, Sipols AJ, Seeley RJ . NPY and food intake: discrepancies in the model Regul Pept 1998 75–76: 403–408.

  41. 41

    Cabeza De Vaca S, Holiman S, Carr KD . A search for the metabolic signal that sensitizes lateral hypothalmic self-stimulation in food restricted rats Physiol Behav 1998 64: 251–260.

  42. 42

    Hagan MM, Moss DE . Effect of peptide YY (PYY) on food associated conflict Physiol Behav 1995 58: 731–735.

  43. 43

    Mauri MC, Rudelli R, Somaschini E, Roncoroni L, Papa R, Mantero M, Longhini M . Penati Neurobiological and psychopharmacological basis in the therapy of bulimia and anorexia Prog Neuropsychopharmac Biol Psychiat 1996 20: 207–240.

  44. 44

    Pages N, Orosco M, Rouch C, Yao O, Jacquot C, Bohuon C . Refeeding after 72 hour fasting alters neuropeptide Y and monoamines in various cerebral areas in the rat Comp Biochem Physiol Comp Physiol 1993 106: 845–849.

  45. 45

    Pages N, Orosco M, Rouch C, Yao O, Jacquot C, Bohuon C . Fasting affects more markedly neuropeptide Y than monoamines in the rat brain Pharmac Biochem Behav 1993 44: 71–75.

  46. 46

    Beck B, Jhanwar-Uniyal M, Burlet A, Chapleur-Chateau M, Leibowitz SF, Burlet C . Rapid and localized alterations of neuropeptide Y in discrete hypothalamic nuclei with feeding status Brain Res 1990 528: 245–249.

  47. 47

    Widdowson PS, Upton R, Henderson L, Buckingham R, Wilson S, Williams G . Reciprocal regional changes in brain NPY receptor density during dietary restriction and dietary-induced obesity in the rat Brain Res 1997 774: 1–10.

  48. 48

    Widdowson PS . Regionally-selective down-regulation of NPY receptor subtypes in the obese Zucker rat. Relationship to the Y5 ‘feeding’ receptor Brain Res 1997 758: 17–25.

  49. 49

    Xin XG, Huang XF . Down-regulated NPY receptor subtype-5 mRNA expression in genetically obese mouse brain Neuroreport 1998 9: 737–741.

  50. 50

    Benoit SC, Schwartz MW, Lachey JL, Hagan MM, Rushing PA, Blake KA, Yagaloff KA, Kurylko G, Franco L, Danhoo W, Seeley RJ . A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences J Neurosci 2000 20: 3442–3448.

  51. 51

    Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS . Neurons containing hypocretin (orexin) project to multiple neuronal systems J Neurosci 1998 18: 9996–10015.

  52. 52

    Vrang N, Tang-Christensen M, Larsen PJ, Kristensen P . Recombinant CART peptide induces c-Fos expression in central areas involved in control of feeding behaviour Brain Res 1999 818: 499–509.

  53. 53

    Van Dijk G, Thiele TE, Donahey JC, Campfield LA, Smith FJ, Burn P, Bernstein IL, Woods SC, Seeley RJ . Central infusions of leptin and GLP-1-(7-36) amide differentially stimulate c-FLI in the rat brain Am J Physiol 1996 271: R1096–1100.

  54. 54

    Stanley BG, Chin AS, Leibowitz SF . Feeding and drinking elicited by central injection of neuropeptide Y: evidence for a hypothalamic site(s) of action Brain Res Bull 1985 14: 521–524.

  55. 55

    McGregor IS, Menendez JA, Atrens DM . Metabolic effects of neuropeptide Y injected into the sulcal prefrontal cortex Brain Res Bull 1990 24: 363–367.

  56. 56

    Hagan MM, Castaneda E, Sumaya IC, Fleming SM, Galloway J, Moss DE . The effect of hypothalamic peptide YY on hippocampal acetylcholine release in vivo: implications for limbic function in binge-eating behavior Brain Res 1998 805: 20–28.

  57. 57

    Steinman JL, Gunion MW, Morley JE . Forebrain and hindbrain involvement of neuropeptide Y in ingestive behaviors of rats Pharmac Biochem Behav 1994 47: 207–214.

  58. 58

    Cummings SL, Truong BG, Gietzen DW . Neuropeptide Y and somatostatin in the anterior piriform cortex alter intake of amino acid-deficient diets Peptides 1998 19: 527–535.

  59. 59

    Li BH, Xu B, Rowland NE, Kalra SP . c-fos expression in the rat brain following central administration of neuropeptide Y and effects of food consumption Brain Res 1994 665: 277–284.

  60. 60

    Lambert PD, Phillips PJ, Wilding JP, Bloom SR, Herbert J . c-fos expression in the paraventricular nucleus of the hypothalamus following intracerebroventricular infusions of neuropeptide Y Brain Res 1995 670: 59–65.

  61. 61

    Palmiter RD, Erickson JC, Hollopeter G, Baraban SC, Schwartz MW . Life without neuropeptide Y Rec Prog Horm Res 1998 53: 163–199.

  62. 62

    Erickson JC, Ahima RS, Hollopeter G, Flier JS, Palmiter RD . Endocrine function of neuropeptide Y knockout mice Regul Pept 1997 70: 199–202.

  63. 63

    Hollopeter G, Erickson JC, Seeley RJ, Marsh DJ, Palmiter RD . Response of neuropeptide Y-deficient mice to feeding effectors Regul Pept 1998 75–76: 383–389.

  64. 64

    Bannon AW, Seda J, Carmouche M, Francis JM, Norman MH, Karbon B, McCaleb ML . Behavioral characterization of neuropeptide Y knockout mice Brain Res 2000 868: 79–87.

  65. 65

    Baraban SC, Hollopeter G, Erickson JC, Schwartzkroin PA, Palmiter RD . Knock-out mice reveal a critical antiepileptic role for neuropeptide Y J Neurosci 1997 89: 8927–8936.

  66. 66

    Marsh DJ, Miura GI, Yagaloff KA, Schwartz MW, Barsh GS, Palmiter RD . Effects of neuropeptide Y deficiency on hypothalamic agouti-related protein expression and responsiveness to melanocortin analogues Brain Res 1999 848: 66–77.

  67. 67

    Stanley BG, Magdalin W, Seirafi A, Nguyen MM, Leibowitz SF . Evidence for neuropeptide Y mediation of eating produced by food deprivation and for a variant of the Y1 receptor mediating this peptide's effect Peptides 1992 13: 581–587.

  68. 68

    Shibasaki T, Oda T, Imaki T, Ling N, Demura H . Injection of anti-neuropeptide Y gamma-globulin into the hypothalamic paraventricular nucleus decreases food intake in rats Brain Res 1993 601: 313–316.

  69. 69

    Borisova EV, Kadar T, Telegdy G . Bimodal effect of neuropeptide Y on feeding, and its antagonism by receptor blocking agents in rats Acta Physiol Hung 1991 78: 301–308.

  70. 70

    Dube MG, Kalra PS, Crowley WR, Kalra SP . Evidence of a physiological role for neuropeptide Y in ventromedial hypothalamic lesion-induced hyperphagia Brain Res 1995 690: 275–278.

  71. 71

    Dube MG, Xu B, Crowley WR, Kalra PS, Kalra SP . Evidence that neuropeptide Y is a physiological signal for normal food intake Brain Res 1994 646: 341–344.

  72. 72

    He B, White BD, Edwards GL, Martin RJ . Neuropeptide Y antibody attenuates 2-deoxy-D-glucose induced feeding in rats Brain Res 1998 781: 348–350.

  73. 73

    Walter MJ, Scherrer JF, Flood JF, Morley JE . Effects of localized injections of neuropeptide Y antibody on motor activity and other behaviors Peptides 1994 15: 607–613.

  74. 74

    Akabayashi A, Wahlestedt C, Alexander JT, Leibowitz SF . Specific inhibition of endogenous neuropeptide Y synthesis in arcuate nucleus by antisense oligonucleotides suppresses feeding behavior and insulin secretion Brain Res Mol Brain Res 1994 21: 55–61.

  75. 75

    Kalra PS, Kalra SP . Use of antisense oligodeoxynucleotides to study the physiological functions of neuropeptide Y Methods 2000 22: 249–254.

  76. 76

    Agrawal S, Zhao Q, Jiang Z, Oliver C, Giles H, Heath J, Serota D . Toxicologic effects of an oligodeoxynucleotide phosphorothioate and its analogs following intravenous administration in rats Antisense Nucleic Acid Drug Dev 1997 7: 575–584.

  77. 77

    Dryden S, Pickavance L, Tidd D, Williams G . The lack of specificity of neuropeptide Y (NPY) antisense oligodeoxynucleotides administered intracerebroventricularly in inhibiting food intake and NPY gene expression in the rat hypothalamus J Endocrinol 1998 157: 169–175.

  78. 78

    Kanatani A, Ito J, Ishihara A, Iwaasa H, Fukuroda T, Fukami T, MacNeil DJ, Van der Ploeg LH, Ihara M . NPY-induced feeding involves the action of a Y1-like receptor in rodents Regul Pept 1998 75–76: 409–415.

  79. 79

    Widdowson PS, Henderson L, Pickavance L, Buckingham R, Tadayyon M, Arch JR, Williams G . Hypothalamic NPY status during positive energy balance and the effects of the NPY antagonist, BW 1229U91, on the consumption of highly palatable energy-rich diet Peptides 1999 20: 367–372.

  80. 80

    Schober DA, Gackenheimer SL, Heiman ML, Gehlert DR . Pharmacological characterization of (125)I-1229U91 binding to Y1 and Y4 neuropeptide Y/Peptide YY receptors J Pharmac Exp Ther 2000 293: 275–280.

  81. 81

    Mollereau C, Gouarderes C, Dumont Y, Kotani M, Detheux M, Doods H, Parmentier M, Quirion R, Zajac JM . Agonists and antagonist activities on human NPFF(2) receptors of the NPY ligands GR231118 and BIBP3226 Br J Pharmac 2001 133: 1–4.

  82. 82

    Blomqvist AG, Herzog H . Y-receptor subtypes-how many more? TINS 1997 20: 294–298.

  83. 83

    Balasubramaniam A . Neuropeptide Y family of hormones: receptor subtypes and antagonists Peptides 1997 18: 445–457.

  84. 84

    Larhammar D . Extraordinary structural diversity of NPYfamily receptors Academic Press: London 1997 88–105.

  85. 85

    Glaum SR, Miller RJ, Rhim H, Maclean D, Georgic LM, MacKenzie RG, Grundemar L . Characterisation of Y3 receptor-mediated synaptic inhibition by chimeric neuropeptide Y-peptide YY peptides in the rat brainstem Br J Pharmac 1997 120: 481–487.

  86. 86

    Matsumoto M, Nomura T, Momose K, Ideka Y, Kondou Y, Akiho H, Togami J, Kimura Y, Okada M, Yamaguchi T . Inactivation of a novel neuropeptide Y/Peptide YY receptor gene in primate species J Biol Chem 1996 271: 27217–27220.

  87. 87

    Rose PM, Lynch JS, Frazier ST, Fisher SM, Chung W, Battaglino P, Fathi Z, Leibel R, Fernandes P . Molecular genetic analysis of a human neuropeptide Y receptor. The human homolog of the murine Y5 receptor maybe a pseudogene J Biol Chem 1997 272: 3622–3627.

  88. 88

    Burkhoff AM, Linemeyer DL, Salon JA . Distribution of a novel hypothalamic neuropeptide Y receptor gene and its absence in rat Mol Brain Res 1998 53: 311–316.

  89. 89

    Mullins DE, Guzzi M, Xia L, Parker EM . Pharmacological characterisation of the cloned neuropeptide Y y6 receptor Eur J Pharmac 2000 395: 87–93.

  90. 90

    Starbäck P, Lundell I, Fredriksson R, Berglund MM, Yan YL, Wraith A, Söderberg C, Postlethwait JH, Larhammar D . Neuropeptide Y receptor subtype with unique properties cloned in the zebrafish: the zYa receptor Mol Brain Res 1999 70: 242–252.

  91. 91

    Ringvall M, Berglund MM, Larhammar D . Multiplicity of neuropeptide Y receptors: cloning of a third distinct subtype in the zebrafish Biochem Biophys Res Commun 1997 241: 749–755.

  92. 92

    Arvidsson AK, Wraith A, Jönsson-Rylander AC, Larhammar D . Cloning of neuropeptide Y/peptide YY receptor from the atlantic cod: the Yb receptor Regul Peptides 1998 75–76: 39–43.

  93. 93

    Tensen CP, Cox KJA, Burke JF, Leurs R, van der Schors RC, Geraerts WPM, Vreugdenhil E, van Heerikhuizen H . Molecular cloning and characterization of an invertebrate homologue of a neuropeptide Y receptor Euro J Neurosci 1998 10: 3409–3416.

  94. 94

    Li XJ, Wu YN, North RA, Fortes M . Cloning, functional expres-sion, and developmental regulation of a neuropeptide Y receptor from Drosophila melanogaster J Biol Chem 1992 267: 9–12.

  95. 95

    Herzog H . NPY-Y7 receptor gene International application published under the patent cooperation treaty (PCT). International publication number: WO 00/00606 2000.

  96. 96

    Parker RMC, Copeland NG, Eyre HJ, Liu M, Gilbert DJ, Crawford J, Couzens M, Sutherland GR, Jenkins NA, Herzog H . Molecular cloning and characterisation of GPR74 a novel G-protein coupled receptor closest related to the Y-receptor family Mol Brain Res 2000 77: 199–208.

  97. 97

    Herzog H, Baumgartner M, Vivero C, Selbie LA, Auer B, Shine J . Genomic organization, localization, and allelic differences in the gene for the human neuropeptide Y Y1 receptor J Biol Chem 1993 268: 6703–6707.

  98. 98

    Herzog H, Darby K, Ball H, Hort Y, Beck-Sickinger A, Shine J . Overlapping gene structure of the human neuropeptide Y receptor subtypes Y1 and Y5 suggests coordinate transcriptional regulation Genomics 1997 41: 315–319.

  99. 99

    Lutz CM, Frankel WN, Richards JE, Thompson DA . Neuropeptide Y receptor genes on human chromosome 4q31-q32 Map to conserved linkage groups on mouse chromosomes 3 and 8 Genomics 1997 41: 498–500.

  100. 100

    Ball HJ, Shine J, Herzog H . Multiple promoters regulate tissue-specific expression of the human NPY-Y1 receptor gene T J Biol Chem 1995 270: 27272–27276.

  101. 101

    Herzog H, Selbie LA, Zee RYL, Morris B, Shine J . Neuropeptide-Y Y1 receptor gene polymorphism: cross-sectional analyses in essential hypertension and obesity Biochem Biophys Res Commun 1993 196: 902–906.

  102. 102

    Parker EM, Xia L . Extensive alternative splicing in the 5'-untranslated region of the rat and human neuropeptide Y Y5 receptor genes regulates receptor expression J Neurochem 1999 73: 913–920.

  103. 103

    Roche C, Boutin P, Dina C, Gyapay G, Basdevant A, Hager J, Guy-Grand B, Clement K, Froguel P . Genetic studies of neuropeptide Y and neuropeptide Y receptors Y1 and Y5 regions in morbid obesity Diabetologia 1997 40: 671–675.

  104. 104

    Rosenkranz K, Hinney A, Ziegler A, von Prittwitz S, Barth N, Roth H, Mayer H, Siegfried W, Lehmkuhl G, Poustka F, Schmidt M, Schäfer H, Remschmidt H, Hebebrand J . Screening for mutations in the neuropeptide Y Y5 receptor gene in cohorts belonging to different weight extremes Int J Obes Relat Metab Disord 1998 22: 157–163.

  105. 105

    Jenkinson CP, Cray K, Walder K, Herzog H, Hanson R, Ravussin E . Novel polymorphisms in the neuropeptide-Y Y5 receptor associated with obesity in Pima Indians Int J Obes Relat Metab Disord 2000 24: 580–584.

  106. 106

    Lynch DR, Walker MW, Miller RJ, Snyder SH . Neuropeptide Y receptor binding sites in rat brain: differential autoradiographic localizations with 125I-peptide YY and 125I-neuropeptide Y imply receptor heterogeneity J Neuroscienc 1989 9: 2608–2612.

  107. 107

    Poston WS Jr, Foreyt JP, Borrell L, Haddock CK . Challenges in obesity management South Med J 1998 91: 710–720.

  108. 108

    Durkin MM, Walker MW, Smith KE, Gustafson EL, Gerld C, Branchek TA . Expression of a novel neuropeptide Y receptor subtype involved in food intake: an in situ hybridization study of Y5 mRNA distribution in rat brains Exp Neurol 2000 165: 90–100.

  109. 109

    Parker RM, Herzog H . Regional distribution of Y-receptor subtype mRNAs in rat brain Eur J Neurosci 1999 11: 1431–1448.

  110. 110

    Dumont Y, Jacques D, St-Pierre J-A, Quirion R . Neuropeptide Y receptor subtypes in the mammalian brain: species differences and status in the human central nervous system. In: Grundemar L & Bloom SR (eds). Neuropeptide Y and drug development Academic Press: London 1997 57–86.

  111. 111

    Dumont Y, Jacques D, St-Pierre J-A, Tong Y, Parker R, Herzog H, Quirion R . Neuropeptide Y, peptide YY and pancreatic polypeptide receptor proteins and mRNAs in mammalian brain. In: Quirion R, Björklund A, Hökfelt T (eds). Handbook of chemical neuroanatomy 16: Elsevier: Amsterdam 2000 375–475.

  112. 112

    Dumont Y, St-Pierre J-A, Quirion R . Comparative autoradiographic distribution of neuropeptide Y Y1 receptors visualized with the Y1 receptor agonist [125I][Leu31, Pro34] PYY and the non peptide antagonist [3H]BIBP3226 Neuroreport 1996 7: 901–904.

  113. 113

    Tong Y, Dumont Y, Shen SH, Quirion R . Comparative developmental profile of the neuropeptide Y Y1 receptor gene and protein in the rat brain Brain Res Mol Brain Res 1997 48: 323–332.

  114. 114

    Caberlotto L, Tinner B, Brunneman B, Aagnati L, Fuxe K . On the relationship of neuropeptide Y Y1 receptor-immunoreactive neuronal structure to the neuropetide Y-immunoreactive nerve terminal networks. A double immunolabelling analysis in the rat brain Neuroscience 1998 86: 827–845.

  115. 115

    Dumont Y, Fournier A, Quirion R . Expression and characterization of the neuropeptide Y Y5 receptor subtype in the rat brain J Neurosci 1998 18: 5565–5574.

  116. 116

    Marsh DJ, Baraban SC, Hollopeter G, Palmiter RD . Role of the Y5 neuropeptide Y receptor in limbic seizures Proc Natl Acad Sci USA 1999 96: 13518–13523.

  117. 117

    Thorsell A, Michalkiewicz M, Dumont Y, Quirion R, Caberlotto L, Rimondini R, Mathe AA, Heilig M . Behavioral insensitivity to restraint stress, absent fear suppression of behavior and impaired spatial learning in transgenic rats with hippocampal neuropeptide Y overexpression Proc Natl Acad Sci USA 2000 97: 12852–12857.

  118. 118

    Wyss P, Stricker-Krongrad A, Brunner L, Miller J, Crossthwaite A, Whitebread S, Criscione L . The pharmacology of neuropeptide Y (NPY) receptor-mediated feeding in rats characterizes better Y5 than Y1, but not Y2 or Y4 subtypes Regul Pept 1998 75–76: 363–371.

  119. 119

    Parker EM, Balasubramaniam A, Guzzi M, Mullins DE, Salisbury BG, Sheriff S, Witten MB, Hwa JJ . [D-Trp(34)] neuropeptide Y is a potent and selective neuropeptide Y Y(5) receptor agonist with dramatic effects on food intake Peptides 2000 21: 393–399.

  120. 120

    Cabrele C, Langer M, Bader R, Wieland HA, Doods HN, Zerbe O, Beck-Sickinger AG . The first selective agonist for the neuropeptide YY5 receptor increases food intake in rats J Biol Chem 2000 275: 36043–36048.

  121. 121

    McCrea K, Wisialowski T, Cabrele C, Church B, Beck-Sickinger A, Kraegen E, Herzog H . 2-36[K4,RYYSA(19-23)]PP a novel Y5-receptor preferring ligand with strong stimulatory effect on food intake Regul Pept 2000 87: 47–58.

  122. 122

    Marsh DJ, Hollopeter G, Kafer KE, Palmiter RD . Role of the Y5 receptor in feeding and obesity Nature Med 1998 4: 718–721.

  123. 123

    Ho MW, Beck-Sickinger AG, Colmers WF . Neuropeptide Y(5) receptors reduce synaptic excitation in proximal subiculum, but not epileptiform activity in rat hippocampal slices J Neurophysiol 2000 83: 723–734.

  124. 124

    Schaffhauser AO, Stricker-Krongrad A, Brunner L, Cumin F, Gerald C, Whitebread S, Criscione L, Hofbauer KG . Inhibition of food intake by neuropeptide Y Y5 receptor antisense oligodeoxynucleotides Diabetes 1997 46: 1792–1798.

  125. 125

    Tang-Christensen M, Kristensen P, Stidsen CE, Brand CL, Larsen PJ . Central administration of Y5 receptor antisense decreases spontaneous food intake and attenuates feeding in response to exogenous neuropeptide Y J Endocrinol 1998 159: 307–312.

  126. 126

    Flynn MC, Turrin NP, Plata-Salaman CR, Ffrench-Mullen JM . Feeding response to neuropeptide Y-related compounds in rats treated with Y5 receptor antisense or sense phosphothiooligodeoxynucleotide Physiol Behav 1999 66: 881–884.

  127. 127

    Patent WO 9962892 to Novartis Pharmaceuticals

  128. 128

    Patent WO 9827063 to Banyu Pharmaceuticals

  129. 129

    Patent WO 0020376 to Ortho-McNeil Pharmaceuticals

  130. 130

    Patent WO 9964394 to Schering Corporation

  131. 131

    Patent WO 9835957 to Bayer Corporation

  132. 132

    Norman MH, Chen N, Chen Z, Fotsch C, Hale C, Han N, Hurt R, Jenkins T, Kincaid J, Liu L, Lu Y, Moreno O, Santora VJ, Sonnenberg JD, Karbon W . Structure–activity relationships of a series of Pyrrolo[3, 2-d]pyrimidine derivatives and related compounds as neuropeptide Y5 receptor antagonists J Med Chem 2000 43: 4288–4312.

  133. 133

    McNally JJ, Youngman MA, Lovenberg TW, Nepomuceno D, Wilson S, Dax SL . N-acylated alpha-(3-pyridylmethyl)-beta-aminotetralin antagoinists of the human neuropeptide Y Y5 receptor Bioorg Med Chem Lett 2000 10: 1641–1643.

  134. 134

    Criscione L, Rigollier P, Batzl-Hartmann C, Rueger H, Stricker-Krongrad A, Wyss P, Brunner L, Whitebread S, Yamaguchi Y, Gerald C, Heurich RO, Walker MW, Chiesi M, Schilling W, Hofbauer KG, Levens N . Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor J Clin Invest 1998 102: 2136–2145.

  135. 135

    Della Zuana O, Sadlo M, Germain M, Félétou M, Chamorro S, Tisserand F, de Montrion C, Boivin JF, Duhault J, Boutin JA, Levens N . Reduced food intake in response to CGP 71683A may be due to mechanisms other than NPY Y5 receptor blockade Int J Obes Relat Metab Disord 2000 24: 1–11.

  136. 136

    Meguid MM, Fetissov SO, Varma M, Sato T, Zhang L, Laviano A, Rossi-Fanelli F . Hypothalamic dopamine and serotonin in the regulation of food intake Nutrition 2000 16: 843–857.

  137. 137

    Zarrindast MR, Oveisi MR . Effects of monoamine receptor antagonists on nicotine-induced hypophagia in the rat Eur J Pharmac 1997 321: 157–162.

  138. 138

    Wellman PJ . Norepinephrine and the control of food intake Nutrition 2000 16: 837–842.

  139. 139

    Kask A, Vasar E, Heidmets LT, Allikmets L, Wikberg JE . Neuropeptide Y Y(5) receptor antagonist CGP71683A: the effects on food intake and anxiety-related behavior in the rat Eur J Pharmac 2001 414: 215–224.

  140. 140

    Pu S, Dhillon H, Moldawer LL, Kalra PS, Kalra SP . Neuropeptide Y counteracts the anorectic and weight reducing effects of ciliary neurotropic factor J Neuroendocrinol 2000 12: 827–832.

  141. 141

    Patent Fast-Alert December 24, 1999.

  142. 142

    Patent Fast-Alert October 9, 1998.

  143. 143

    Kanatani A, Ishihara A, Iwaasa H, Nakamura K, Okamoto O, Hidaka M, Ito J, Fukuroda T, MacNeil DJ, Van der Ploeg LH, Ishii Y, Okabe T, Fukami T, Ihara M . L-152,804: orally active and selective neuropeptide Y Y5 receptor antagonist Biochem Biophys Res Commun 2000 272: 169–173.

  144. 144

    Kanatani A, Fukami T, Ishihara A, Ishii Y, MacNeil DJ, Van der Ploeg LHT, Ihara K . Anorexigenic effects of orally-active NPY antagonists: participation of Y1 and Y5 receptors in feeding behavior Abstract presented at the 6th International NPY Conference Sydney, Australia April 2001.

  145. 145

    Elliott RL, Oliver RM, Hammond M, Patterson TA, She L, Hargrove DM, Martin KA, Maurer TS, Kalvass JC, Morgan BM, DaSilva-Jardine P, Stevenson RW, Mack C, Cassella J . The in vitro and in vivo characterization of 3-{2-[6-(2-tert-butoxyethoxy)-pyridin-3-yl]-1H-imidazol-4-yl}-benzonitrile (I), a potent and selective NPY Y5 antagonist Abstract presented at the 6th International NPY Conference Sydney, Australia April 2001.

  146. 146

    Antal-Zimanyi, Ortiz AA, Rassnick S, Hogan JB, Huang Y, Bruce MA, Gillman KW, Poindexter GS . Evidence supporting the role of the Y1, but not the Y5 receptor in food intake in rats Abstract presented at the 6th International NPY Conference Sydney, Australia April 2001.

  147. 147

    Haynes AC, Arch JR, Wilson S, McClue S, Buckingham RE . Characterization of the neuropeptide Y receptor that mediates feeding in the rat: a role for the Y5 receptor? Regul Pept 1998 75–76: 355–361.

  148. 148

    Soll RM, Dinger MC, Lundell I, Larhammer D, Beck-Sickinger AG . Novel analogues of neuropeptide Y with a preference for the Y1-receptor Eur J Biochem 2001 268: 2828–2837.

  149. 149

    Naveilhan P, Hassani H, Canals JM, Ekstrand AJ, Larefalk A, Chhajlani V, Arenas E, Gedda K, Svensson L, Thoren P, Ernfors P . Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor Nature Med 1999 5: 1188–1193.

  150. 150

    Broberger C, Landry M, Wong H, Walsh JN, Hokfelt T . Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus Neuroendocrinology 1997 66: 393–408.

  151. 151

    Dumont Y, Cadieux A, Doods H, Pheng LH, Abounader R, Hamel E, Jacques D, Regoli D, Quirion R . BIIE0246, a potent and highly selective non-peptide neuropeptide Y Y(2) receptor antagonist Br J Pharmac 2000 129: 1075–1088.

  152. 152

    Gerald C, Walker MW, Criscione L, Gustafson EL, Batzl-Hartmann C, Smith KE, Vaysse P, Durkin MM, Laz TM, Linemeyer DL, Schaffhauser AO, Whitebread S, Hofbauer KG, Taber RI, Branchek TA, Weinshank R . A receptor subtype involved in neuropeptide-Y-induced food intake Nature 1996 382: 168–171.

  153. 153

    Takebayashi Y, Koga H, Togami J, Inui A, Kurihara H, Koshiya K, Furuya T, Tanaka A, Murase K . Design of the Y1-receptor-selective cyclic peptide based on the C-terminal sequence of neuropeptide Y J Pept Res 2000 56: 409–415.

  154. 154

    Kanatani A, Mashiko S, Murai N, Sugimoto N, Ito J, Fukuroda T, Fukami T, Morin N, MacNeil DJ, Vand der Ploeg LH, Saga Y, Nishimura S, Ihara M . Role of the Y1 receptor in the regulation of neuropeptide Y-mediated feeding: comparison of wild-type, Y1 receptor-deficient, and Y5 receptor-deficient mice Endocrinology 2000 141: 1011–1016.

  155. 155

    Pedrazzini T, Seydoux J, Kunstner P, Aubert JF, Grouzmann E, Beermann T, Brunner HR . Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor Nature Med 1998 4: 722–726.

  156. 156

    Kushi A, Sasai H, Koizumi H, Takeda N, Yokoyama M, Nakamura M . Obesity and mild hyperinsulinemia found in neuropeptide-Y1 receptor-deficient mice Proc Natl Acad Sci USA 1998 95: 15659–15664.

  157. 157

    Baskin DG, Figlewicz Lattermann D, Seeley RJ, Woods SC, Porte D Jr, Schwartz MW . Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight Brain Res 1999 848: 114–123.

  158. 158

    Heilig M . Antisense inhibition of neuropeptide Y (NPY)-Y1 receptor expression blocks the anxiolytic-like action of NPY in amigdala and paradoxically increases feeding Regul Pept 1995 59: 201–205.

  159. 159

    Schaffhauser AO, Whitebread S, Haener R, Hofbauer KG, Stricker-Krongrad A . Neuropeptide Y Y1 receptor antisense oligodeoxynucleotides enhance food intake in energy-deprived rats Regul Pept 1998 75–76: 417–423.

  160. 160

    Lopez-Valpuesta FJ, Nyce JW, Myers RD . NPY-Y1 receptor antisense injected centrally in rats caused hyperthermia and feeding Neuropharmac Neurotoxicol 1996 7: 343–368.

  161. 161

    Lopez-Valpuesta FJ, Nyce JW, Griffin-Biggs TA, Ice JC, Myers RD . Antisense to NPY-Y1 demonstrates that Y1 receptors in the hypothalamus underlie NPY hypothermia and feeding in rats Proc R Soc Lond B Biol Sci 1996 263: 881–886.

  162. 162

    Doods HN, Wieland HA, Engel W, Eberlein W, Willim K-D, Enteroth M, Wienen W, Rudolf K . BIBP 3226, the first selective neuropeptide Y1 receptor antagonist: a review of its pharmacological properties Regul Pept 1996 65: 71–77.

  163. 163

    Rudolf K, Eberlein W, Engel W, Wieland HA, Willim K, Entzeroth M, Wienen W, Beck-Sickinger AG, Doods HN . The first highly potent and selective non-peptide neuropeptide Y Y1 receptor antagonist: BIBP 3226 Eur J Pharmac 1994 271: R11–13.

  164. 164

    Kask A, Rago L, Harro J . Evidence for involvement of neuropeptide Y receptors in the regulation of food intake: studies with Y1-selective antagonist BIBP3226 Br J Pharmac 1998 124: 1507–1515.

  165. 165

    Kask A, Rägo L, Harro J . Anxiogenic-like effect of the neuropeptide Y Y1 receptor antagonist BIBP 3226: antagonism with diazepam Eur J Pharmac 1996 317: R3–4.

  166. 166

    Wieland HA, Engel W, Eberlein W, Rudolf K, Doods HN . Subtype selectivity of the novel nonpeptide neuropeptide Y Y1 receptor antagonist BIBO 3304 and its effect on feeding in rodents Br J Pharmac 1998 125: 549–555.

  167. 167

    Kanatani A, Kanno T, Ishihara M, Sakuraba A, Tanaka T, Tsuchiya Y, Mase T, Fukuroda T, Fukami T, Ihara M . The novel neuropeptide Y Y(1) receptor antagonist J-104870: a potent feeding suppressant with oral bioavailability Biochem Biophys Res Commun 1999 266: 88–91.

  168. 168

    Kanatani A, Hata M, Mashiko S, Ishihara A, Okamoto O, Haga Y, Ohe T, Kanno T, Murai N, Ishii Y, Fukuroda T, Fukami T, Ihara M . A typical Y1 receptor regulates feeding behaviors: effects of a potent and selective Y1 antagonist, J-115814 Mol Pharmac 2001 59: 501–505.

  169. 169

    Duhault J, Boulanger M, Chamorro S, Boutin JA, Della Zuana Odile, Douillet E, Fauchere J-L, Feletou M, Germain M, Husson B, Vega Monge A, Renard P, Tisserand F . Food intake regulation in rodents: Y5 or Y1 NPY receptors or both? Can J Physiol Pharmacol 2000 78: 173–185.

  170. 170

    Dumont Y, Cadieux A, Doods H, Fournier A, Quiron R . Potent and selective tools to investigate neuropeptide Y receptors in the central and peripheral nervous systems: BIBO3304 (Y1) and CGP71683A (Y5) Can J Physiol Pharmac 2000 78: 116–125.

Download references

Author information



Corresponding author

Correspondence to N Levens.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chamorro, S., Della-Zuana, O., Fauchère, J. et al. Appetite suppression based on selective inhibition of NPY receptors. Int J Obes 26, 281–298 (2002).

Download citation


  • neuropeptide Y
  • food intake
  • reward; NPY receptor knockout
  • NPY receptor antagonists
  • NPY antisense oligodeoxynucleotides
  • NPY antibodies

Further reading