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Neuropeptide Y Receptor Selective Ligands in the Treatment of Obesity

Department of Gastroenterology (M.M.K.), Faculty of Medicine, University of Sao Paulo, Ribeirão Preto Campus 14048-900, Ribeirão Preto-SP, Brazil; and Department of Behavioral Medicine (A.I.), Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan

Correspondence: Address all correspondence and requests for reprints to: Akio Inui, M.D., Ph.D., Department of Behavioral Medicine, Kagoshima University Graduate School of Medicine and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima-City, 890-8520, Japan. E-mail: inui{at}m.kufm.kagoshima-u.ac.jp

	Abstract

Top Abstract I. Introduction II. Obesity: Pharmacological... III. Central Regulation of... IV. Neuropeptide Y (NPY)... V. NPY Receptors VI. Therapeutic Applications of... VII. Transgenic NPY and... VIII. Role of NPY... IX. Conclusion References

 
Obesity is a serious public health problem throughout the world, affecting both developed societies and developing countries. The central nervous system has developed a meticulously interconnected circuitry in order to keep us fed and in an adequate nutritional state. One of these consequences is that an energy-dense environment favors the development of obesity. Neuropeptide Y (NPY) is one of the most abundant and widely distributed peptides in the central nervous system of both rodents and humans and has been implicated in a variety of physiological actions. Within the hypothalamus, NPY plays an essential role in the control of food intake and body weight. Centrally administered NPY causes robust increases in food intake and body weight and, with chronic administration, can eventually produce obesity. NPY activates a population of at least six G protein-coupled Y receptors. NPY analogs exhibit varying degrees of affinity and specificity for these Y receptors. There has been renewed speculation that ligands for Y receptors may be of benefit for the treatment of obesity. This review highlights the therapeutic potential of Y₁, Y₂, Y₄, and Y₅ receptor agonists and antagonists as additional intervention to treat human obesity.

I. Introduction

II. Obesity: Pharmacological Therapy

III. Central Regulation of Food Intake and Energy Homeostasis

IV. Neuropeptide Y (NPY) and Food Intake

V. NPY Receptors

A. General features on NPY receptors

B. Regulation of NPY receptors in feeding behavior and energy balance

VI. Therapeutic Applications of NPY Receptor Ligands

A. NPY receptor antagonists

B. NPY receptor agonists

VII. Transgenic NPY and NPY Receptor Knockout (KO) Rodents

VIII. Role of NPY Receptors in Obesity in Human-Genetic Variations

IX. Conclusion

	I. Introduction

Top Abstract I. Introduction II. Obesity: Pharmacological... III. Central Regulation of... IV. Neuropeptide Y (NPY)... V. NPY Receptors VI. Therapeutic Applications of... VII. Transgenic NPY and... VIII. Role of NPY... IX. Conclusion References

 
OBESITY IS A SERIOUS public health problem throughout the world, affecting both developed societies and developing countries (1). Despite its advance of pandemic proportions, its associated morbidity and mortality, and its financial burden for government and society, obesity remains a major unsolved medical problem (1, 2). Obesity increases the risk for developing chronic diseases, including type 2 diabetes, coronary heart disease, hypertension, osteoarthritis, and certain cancers, besides the social and psychological consequences (3, 4).

The central nervous system (CNS) has developed a meticulously interconnected circuitry to keep us fed and in adequate nutritional state. One of these consequences is that an energy-dense environment favors the development of obesity (5). The brainstem and specific hypothalamus nuclei are important in coordinating peripheral satiety and adiposity signals (6, 7). The arcuate nucleus (ARC), located in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence, represents an essential area interacting peripheral signals and the brain (4). Neuronal projections from the ARC to other areas of the brain, including the paraventricular nucleus (PVN), ventromedial nucleus (VMN), dorsomedial nucleus, and lateral hypothalamic area (LHA)/perifornical area (PFA) are thought to mediate the effects of the ARC neuronal system on energy homeostasis (8). Neuropeptides produced in these regions are released at specific regions to stimulate or inhibit feeding behavior (4, 8).

Neuropeptide Y (NPY) is a 36-amino acid neuropeptide member of the pancreatic polypeptide (PP) family that includes peptide YY (PYY) and PP (9). NPY is one of the most abundant and widely distributed peptides in the CNS of both rodents and humans (10, 11), and it has been implicated in a variety of physiological actions. NPY participates in the control of learning and memory (12), locomotion (13), body temperature regulation (14), sexual behavior (15), emotional behavior (16), neuronal excitability (17), cardiovascular functions (18), circadian rhythms (19, 20), and hormone secretion, such as release and synthesis of catecholamine from the adrenal medulla (21, 22). Within the hypothalamus, NPY plays an essential role in the control of food intake and body weight. Centrally administered NPY causes robust increases in food intake and body weight and, with chronic administration, can eventually produce obesity (23, 24, 25).

NPY activates a population of at least six G protein-coupled Y receptors (26). NPY analogs exhibit varying degrees of affinity and specificity for these Y receptors (27). There has been renewed speculation that ligands for Y receptors may be of benefit for the treatment of obesity (28). This review highlights the therapeutic potential of Y₁, Y₂, Y₄, and Y₅ receptor agonists and antagonists as additional intervention to treat human obesity.

	II. Obesity: Pharmacological Therapy

Top Abstract I. Introduction II. Obesity: Pharmacological... III. Central Regulation of... IV. Neuropeptide Y (NPY)... V. NPY Receptors VI. Therapeutic Applications of... VII. Transgenic NPY and... VIII. Role of NPY... IX. Conclusion References

 
In most cases, successful management of obesity is possible through lifestyle changes in diet and physical activity. However, low compliance with such regimes has encouraged the development of effective therapies, including gastrointestinal surgery and pharmacological interventions (2, 30).

Drugs for weight loss mediate their effects via two main means: 1) outside the CNS, by affecting metabolic and control systems or by reducing absorption of food; or 2) by a central mechanism, decreasing appetite or increasing energy expenditure (30).

Currently available medications include the sympathomimetic amphetamine-like agents diethylproprion, phendimetrazine, and phentermine; the lipase inhibitor orlistat; the serotonin and noradrenaline reuptake inhibitors; sibutramine; and the antiepileptic drugs topiramate and zonisamide (30, 31). All of these medications have side effects, which vary by drug (30). The ethical use of amphetamine-like drugs is rigorously restricted because of their association with increased prevalence of adverse events, such as primary pulmonary hypertension and valvulopathy (32). Side effects of orlistat are related to its action and include fecal urgency/incontinence, diarrhea, fatty oily stools, flatulence, abdominal pain, and potential reduction of fat-soluble vitamin absorption (30). Sibutramine causes increases in heart rate and blood pressure, and topiramate causes paresthesia and changes in taste (31). Orlistat and sibutramine are the only currently approved medications for long-term management of obesity. Even the safety and efficacy of these drugs, however, have not been evaluated in children and elderly populations, and there is limited information in adolescents (32).

Neuronal receptors involved in the central regulation of appetite and energy homeostasis have been targeted in the development of compounds against obesity. Studies with melanocortin receptor agonists, melanocortin, melanin-concentrating hormone antagonists, cannabinoid receptor (CB1) antagonists, ghrelin receptor, ß₃-adrenoceptor agonists, analogs of ciliary neurotrophic factor, and NPY receptor agonists have provided possible molecular targets for pharmaceutical activity (2, 30). The endocannabinoid system appears to regulate food intake and energy balance at distinct functional levels within the brain and periphery, including the hypothalamus and gastrointestinal tract. The effects are mediated by the activation of the CB1 receptor and involve a number of other neuropeptides (1). Among the obesity drugs in development, the CB1 receptor antagonist rimonabant (Acomplia, Sanofi-Aventis, Paris, France) has been approved for a weight-management indication, and CP-945,598 (Pfizer, New York, NY) has been on Phase II clinical trials (30).

7TM Pharma (Horsholm, Denmark) has recently reported results from its clinical phase I/II study with the compound TM30338 and the planning of its phase IIa clinical study (30, 33). TM30338 is a dual NPY Y₂–Y₄ receptor agonist developed for the treatment of obesity and related diseases. According to 7TM Pharma, single sc doses of TM30338 administered to healthy obese subjects were safe and well tolerated. Food intake was suppressed compared with placebo both once a day and twice a day for multiple days. They also reported their previous start on a preclinical development of a selective Y₄ receptor agonist peptide TM30339, which had effect on reduction of food intake and weight loss, and their plan to initiate phase I/II studies.

	III. Central Regulation of Food Intake and Energy Homeostasis

Top Abstract I. Introduction II. Obesity: Pharmacological... III. Central Regulation of... IV. Neuropeptide Y (NPY)... V. NPY Receptors VI. Therapeutic Applications of... VII. Transgenic NPY and... VIII. Role of NPY... IX. Conclusion References

 
The hypothalamus is a prime nervous site for control of energy balance. Distinct hypothalamic nuclei are associated with regulation of energy homeostasis, including the ARC, PVN, VMN, dorsomedial nucleus, and LHA/PFA. Other regions of the brain have been suggested recently to be also important for mediating food reward, such as the nucleus of the tractus solitarius, the nucleus accumbens, and the ventral tegmental area (34).

The ARC is an important hypothalamic nucleus in the control of appetite and plays a primary role in the interaction between peripheral organs and the brain (4, 35). Specific areas in the hypothalamus and the brainstem are important in coordinating signaling molecules such as the hormones insulin and leptin, which circulate in proportion to body fat mass and are critical for normal energy homeostasis (6, 7). Two distinct subsets of neurons are involved in control food intake in the ARC in the hypothalamus (Fig. 1) (36, 37). One group contains neurons expressing the orexigenic peptides, NPY and agouti-related peptide (AgRP) (5, 8, 37). Both NPY and AgRP increase food intake when administered intracerebroventricularly to rats (35). The other group expresses anorexigenic peptides derived from proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART); POMC is a precursor to the anorectic -MSH. Activation of these neurons has the effect of decreasing food intake and increasing energy expenditure (5, 8, 37). The arcuate POMC and NPY/AgRP neurons constitute a functional unit in which neural inputs to NPY/AgRP cells may rapidly affect both NPY/AgRP and POMC neurons (38). NPY neurons provide a dominant inhibitory tone onto POMC (39) and coexpress AgRP, an endogenous melanocortin antagonist (40, 41, 42). At the cell body level, POMC neurons are innervated by NPY-ergic terminals (43) and express the Y₁ receptor (44). The majority of POMC neurons are contacted by terminals containing both -aminobutyric acid (GABA) and NPY (Fig. 1). Neurons in the ARC subsequently innervate other areas of the brain, including the PVN, zona incerta, PFA, and LHA (8). Fasting and weight loss lead to activation of anabolic effectors and inhibition of catabolic effectors in the brain, driving an augment of food intake (5). A decrease in the release of the POMC-derived peptide 3-MSH and an increased release of the AgRP were seen in rats in response to fasting (38, 39). Over time, accumulation of excess calories causes weight gain until body fat content is restored to its original value (37).

View larger version (50K): [in this window] [in a new window]   FIG. 1. Central and peripheral pathways involved in the regulation of food intake and energy stores. Leptin reaches the ARC within the hypothalamus, directly affecting neurons in which either the anorexigenic peptides POMC and CART or the orexigenic peptides NPY and AgRP are colocalized. NPY/AgRP and POMC neurons within the ARC form a coordinately regulated network. For example, leptin depolarizes POMC neurons and simultaneously hyperpolarizes the somata of neuropeptide Y/GABA neurons, diminishing the release from these terminals. This diminished release of GABA disinhibits POMC neurons. Also, some NPY receptors known to regulate the network are indicated as Y1R, Y2R, and Y5R receptors. The POMC-CART- and NPY-AGRP-containing neurons, which are regulated in an opposing manner by leptin, project further to other brain centers. These include the VMH and DMH, which also express NPY, and the PVN and the LHA, which express melanin-concentrating hormone (MCH). The LHA and other brain areas communicate with the cerebral cortex, where feeding behavior is finally coordinated. During and after a meal, signals in the periphery, including taste signals from the oral cavity, gastric distension, and humoral signals from the gastrointestinal tract are generated. These afferent signals are transmitted mainly by the vagus nerve and by the sympathetic nervous system to the hindbrain, particularly the nucleus of the solitary tract (NTS). This brain region communicates with higher brain areas such as the hypothalamus and the cerebral cortex. [Adapted from Trends Pharmacol Sci 22:247–254, 2001 (36 ), with permission from Elsevier Science Ltd.]

	IV. Neuropeptide Y (NPY) and Food Intake

Top Abstract I. Introduction II. Obesity: Pharmacological... III. Central Regulation of... IV. Neuropeptide Y (NPY)... V. NPY Receptors VI. Therapeutic Applications of... VII. Transgenic NPY and... VIII. Role of NPY... IX. Conclusion References

Inhibition of NPY synthesis by antisense oligodeoxynucleotides or blockade of NPY action by NPY antibody results in suppression of food intake (54). Hypothalamic NPY mRNA levels are increased under conditions of acute food deprivation (55, 56) or chronic food restriction (56, 57, 58, 59), and levels return to normal after refeeding (60). Interestingly, NPY gene expression in the dorsomedial hypothalamus (DMH) increases in response to chronic food restriction and long-term exercise (23), but not acute food deprivation (56), suggesting that unlike arcuate NPY, DMH NPY may play an important role in maintaining energy homeostasis only in response to long-term alterations in energy intake or expenditure (56). Recently, it has been demonstrated that, unlike NPY in the ARC, regulation of DMH NPY gene expression is independent of leptin changes (23). It has been suggested that one control of DMH NPY is cholecystokinin (CCK) acting through CCK-1 receptors (23, 61).

Bilateral neural transaction at the level of the mesencephalon and electrolytic lesioning of the ventromedial area of the hypothalamus produce hyperphagia and excess body weight gain, despite an either decreased or unchanged NPY expression (61). These experimental models result in increased sensitivity to the orexigenic effects of NPY, which may be partially due to an increase in NPY receptors (61)

Further factors related to eating behavior that supports NPY contributes to obesity in animals are the role of NPY in promoting palatable food consumption (62, 63), and the response of NPY levels to dietary fat types (64, 65) and to the amount of carbohydrates consumed (66).

	V. NPY Receptors

Top Abstract I. Introduction II. Obesity: Pharmacological... III. Central Regulation of... IV. Neuropeptide Y (NPY)... V. NPY Receptors VI. Therapeutic Applications of... VII. Transgenic NPY and... VIII. Role of NPY... IX. Conclusion References

 
NPY affects a wide variety of physiological functions via the activation of at least five different cloned Y-receptors: Y₁, Y₂, Y₄, Y₅, and Y₆ (67, 68, 69). Y₃ receptor has been postulated from pharmacological experiments and might not exist as a separate gene (70). Y₇ receptor has been more recently discovered and found absent in the mammalian lineage (71, 72). Despite having divergent primary structures (70) and a species-specific distribution, these subtypes belong to the G protein-coupled receptor family and cause excitatory and inhibitory responses to intracellular Ca²⁺ and cAMP, respectively (26, 74).

Comparisons of amino acid sequence show a low homology among the receptor subtypes. The Y₁, Y₄, and Y₆ subtypes appear to exhibit the closest similarity, with no more than approximately 50% sequence identity (11, 75). Y₂ appears to be the least close, having less than 30% sequence identity with any of the other subtypes (75), and 31% sequence identity to Y₄ subtype (76, 77). Y₄ shows greater variability than Y₁, Y₂, or Y₅, which may be related to the fact that its endogenous ligand is more likely to be PP than NPY or PYY (76). With only 27–32% overall identity, the three subtypes Y₁, Y₂, and Y₅ are the most different G protein-coupled receptors that bind the same peptide ligand (77).

These receptors are expressed in the hypothalamus, in the brain stem, and in peripheral tissues, such as blood vessels, lung, kidney, adrenal glands, stomach, colon, heart, pancreas, and intestine (72, 78, 79). Studies on the structure-affinity and structure-activity relationship of peptide analogs, as well as on site-directed mutagenesis and antireceptor antibodies, have partially characterized each receptor subtype concerning its interaction with the ligand and its biological function (80).

A. General features of NPY receptors
1. Y₁ receptor.
Many physiological actions of NPY are likely mediated by Y₁ receptors as suggested on the basis of knockout (KO) studies, and the use of selective agonists and antagonists (27, 81, 82). High amounts of [¹²⁵I][Leu³¹,Pro³⁴]PYY, an agonist of Y₁, Y₄, and Y₅ receptor labeling were detected in the superficial layers of the cortex in the rat, mouse, and guinea pig brain, and in moderate levels in cortical areas in the marmoset (83).

A widespread expression of Y₁ receptor mRNA was observed throughout the rat brain. Within the forebrain, most apparent expression is found in the cortex, hippocampus, thalamus, and specific nuclei of the hypothalamus and amygdala. A strong hybridization signal of Y₁ receptor mRNA expression was displayed in the supraoptic nucleus and ARC of the hypothalamus (78). Coexpression of NPY with the Y₁ receptor was displayed in rat hypothalamic ARC by immunohistochemistry and in situ hybridization (85). Y₁ is present in arterioles of various peripheral tissues, such as the thyroid and parathyroid glands, heart, spleen, and digestive system of rat and mouse (86).

In the human brain, cRNA in situ hybridization revealed high levels of Y₁ receptor mRNA in the human hypothalamus, including the ARC and the PVN (87). Different findings were obtained by binding of [¹²⁵I][Leu³¹,Pro³⁴]PYY as preferential radioligands of the Y₁ (88), which revealed a low amount of this ligand in the cortical areas and in the hypothalamic and the thalamic nuclei, and, in contrast, high amounts in the stratum granulosum of the dentate gyrus (88). In the postmortem human brain, analysis of the regional distribution of NPY RNA-expressing cells found that NPY mRNA was abundant in layers II and VI of the neocortex, polymorphic layer of the dentate gyrus, basal ganglia, and amygdale. In these NPY-expressing cells, a lack of Y₁ mRNA coexpression was detected (89).

The Y₁ subtype displays preferential activation by the NPY analog [Leu³¹,Pro34] NPY and low affinity for the C-terminal fragments of NPY such as NPY_13–36 and NPY_3–36. Y₁ requires a complete N terminus but tolerates substitutions in the middle and C-terminal parts of the molecule (27, 90). Substitution of the tyrosine residue at position 100 by an alanine results in loss of peptide binding (91, 92). Exchange of the phenylalanine (Phe²⁸⁶) with a glutamic residue causes reduction of porcine NPY and of selective antagonist BIBP3226 affinity for the receptor; the antagonist SR120819A binding was completely lost. Also, the position His²⁹⁸ seems to be vital for peptide binding (93). Variations of position 6, especially [Arg⁶,Pro³⁴]pNPY and variations within positions 20 ± 23 of NPY were found to result in further analogs with significant Y₁ preference (94), such as [Phe⁷,Pro³⁴]pNPY, which showed a subnanomolar affinity to the receptor (94). Studies using Y₁ receptor antisense oligodeoxynucleotides have reported that although feeding was not decreased in intracerebroventricular antisense-treated rats (95, 96), hypothalamus injection in rat with antisense for Y₁ receptor could suppress food intake, suggesting that Y₁ is a crucial mediator of the spontaneous feeding caused by NPY (97, 98). Demonstration that the Y₁ signaling plays a prominent role in the stimulation of feeding and obesity also comes from the observation that changes in feeding behavior and energy balance induce a marked plasticity in the Y₁ function and expression in specific regions of the hypothalamus (99). Y₁ receptors situated in the dorsal vagal complex seem to mediate central administered NPY-induced relaxation of the proximal stomach in rats (100).

2. Y₂ receptor.
Binding studies using Y₂ selective ligand [¹²⁵I]PYY_3–36 revealed higher levels of Y₂ receptor than Y₁ in most hypothalamic nuclei of rat, including the medial preoptical area, anterior hypothalamic nucleus, PVN, LHA, ARC, and lower levels in the mammillary nuclei (101).

Hypothalamic distribution of Y₂ receptor mRNA in the rat studied by oligoprobe and ³⁵S-labeled riboprobe in situ hybridization showed the strongest signal in the medial preoptic nucleus and ARC (102, 103). Immunohistochemistry of ß-galactosidase, a gene reporter molecule for Y₂ receptor in Y₂ receptor-KO mouse, reported that ß-galactosidase immunoreactivity was distributed in numerous neurons of the medial preoptic nucleus, in the lateral anterior, PVN, dorsomedial, tuberal, perifornical, and ARC of the mouse hypothalamus (104).

In guinea pig, moderate to high densities of [¹²⁵I]PYY_3–36 binding sites were restricted to the dorsolateral geniculate nucleus, the zona lateralis of the substantia nigra (83), and the cerebellum (74). The cortical area of the green vervet monkey contained large amounts of specific [¹²⁵I]PYY_3–36 binding sites (83).

In the human hypothalamus, the highest level of labeled [¹²⁵I]PYY_3–36-binding sites was found in the medial preoptical area (88). Double labeling in situ hybridization showed the coexpression of NPY mRNA with the Y₂, but not with the Y₁, mRNA in the human cerebral cortex, hippocampus, amygdala, striatum, and nucleus accumbens, and the existence of coexpression of the Y₁ receptor and Y₂ receptor mRNAs in the cerebral cortex and amygdale (104). This wide expression of Y₂ in the CNS with a particularly high level in an area of the ARC with a permeable blood brain barrier makes the receptor a potential mediator of peripheral signals on the regulation of energy homeostasis (105, 106, 107, 108) and may be relevant to feeding and body weight control (102, 104).

The Y₂ receptor has the typical heptahelix receptor structure including potential glycosylation sites in the amino-terminal portion, two extracellular cysteines that presumably form a single disulfide bridge, and one cysteine in the cytoplasmic tail for N-linked carbohydrate is present (77, 109). Y₂ was originally identified by vascular preparations by using the activity of terminally truncated fragments of NPY and PYY. NPY_3–36 and NPY_13–36 are full agonists with similar potency as the full length peptides (110). Substitutions of positions 31 (Ile) and 34 (Gln) of NPY with the corresponding amino acids in PP, Leu, and Pro, respectively, result in specific high-affinity ligands for Y₁, which do not react with Y₂ receptor (111, 112). Pro³⁴ substitution of NPY and PYY prevented Y₂ receptor binding (113). Y₂ subtypes seem to mediate inhibitory effects of NPY on gastric emptying, observed by central administration of NPY and Y₂ agonist in rats (114, 115), although it was also found that receptors with a pharmacological profile similar to the rat Y₂-mediated NPY induced changing of duodenal fed pattern contractions into fasted pattern phasic contractions (116).

3. Y₄ receptor.
NPY and PYY bind to Y₁, Y₂, and Y₅ receptors with similar potency, which is lower than PP affinity. In contrast, Y₄ demonstrates a pharmacological profile characterized by a higher affinity for PP than for NPY and PYY and is regarded as the PP receptor (110, 117); such characteristic selectivity is more pronounced in rat and mouse than in other mammalian species (118).

Binding studies with PP receptors selective ligand [¹²⁵I]PP (119) and double-labeling immunocytochemistry/in situ hybridization for orexin, Y₄-like immunoreactivity (120) revealed a wide distribution of PP receptors in the rat brain. Saturable PP binding was identified in the hypothalamus (ARC and PVN), the rostral forebrain, the medial amygdaloid nucleus, the thalamus, the interpeduncular red nucleus, the substantia nigra, the parabrachial nucleus, the locus coeruleus, the mesencephalic trigeminal nucleus, the dorsal motor nucleus of the vagus, the nucleus solitary tract, and the area postrema (119).

In rats, in situ hybridization histochemistry study with ³⁵S-labeled riboprobes revealed numerous Y₄ receptor mRNA-expressing cells in the area postrema, in the dorsal motor nucleus of the vagus, and in the subnucleus gelatinosus of the nucleus of the solitary tract (121). Supporting data were found by nonradioactive riboprobe in situ hybridization, which showed a limited distribution Y₄ receptor mRNA in the rat brain stem, hypothalamus, and hippocampus area in the CNS (75).

Most of the NPY receptors present in the guinea pig brain, including the hippocampal formation, were labeled by [¹²⁵I] [Leu³¹, Pro ³⁴] PYY (27). Low levels of [¹²⁵I] [Leu³¹, Pro³⁴] PYY binding sites were seen in the green vervet monkey and human brain, except for the dentate gyrus of the hippocampus, although the marmoset monkey brain was enriched in [¹²⁵I] [Leu³¹, Pro³⁴] PYY in the cortex, cerebellum, and hippocampal formation (83).

Human Y₄ receptor mRNA is most expressed in skeletal muscle (122), coronary artery (123), colon, small intestine (123, 124), pancreas, prostate (124), uterus (122), and, to a lesser extent, in lung (123), pancreas, and kidney (122). Besides peripheral tissues, human Y₄ mRNA was detected in total brain, including the hypothalamus (122).

There is a low degree of Y₄ sequence identity between species (77). Sequences of rat and mouse share only 74–78% identity with the other orders of mammals which in turn share 83–86% identity. This rapid divergence of rodent Y₄ correlates with the rapid divergence of the receptor’s preferred ligand, PP, which is also most divergent in rat and mouse among all mammals (77).

4. Y₅ receptor.
The Y₅ receptor was cloned in 1996 and was postulated as the mediator of the feeding response to NPY and related peptides (125). The transcription of Y₁ and Y₅ receptor genes from opposite strands of the same DNA sequence suggested the occurrence of a coordinate expression of these receptors’ specific genes (126).

The first analogs that allowed for selective activation and recognition of the Y₅ receptor were the synthetic peptides [Ala³¹, Aib³²]NPY, [human PP (hPP)_1–17, Ala³¹, Aib³²]NPY, and [chicken PP (cPP)_1–7, NPY_19–23, Ala³¹, Aib³², Gln³⁴]hPP (121, 122, 127). The agonist [hPP_1–17, Ala³¹, Aib³²]NPY (128) was iodinated (129), with development of the first Y₅ radioligand, which bound with high affinity to the Y₅ receptor protein, although being devoid of affinity for the Y₁, Y₂, and Y₄ subtypes. However, because the probe displayed rather high nonspecific binding, less than optimal for autoradiographic studies (130), [cPP_1–7, NPY_19–23, Ala³¹, Aib³², Gln³⁴]hPP was then radiolabeled. This radioligand bound with high affinity to the Y₅ receptor protein, and specific binding sites were found in the lateral septum and area postrema of the rat brain (130).

Preliminary investigations on the distribution of Y₅ in the brain indicated that it was localized in consistent areas for a role of this receptor in NPY-induced feeding (78, 131, 132). [¹²⁵I][Leu³¹, Pro³⁴]PYY/BIBP3226-insensitive Y₅ sites were revealed in the rat brain, with enrichment of the external plexiform layer of the olfactory bulb, the lateral septum, the anteroventral thalamic nucleus, the ventral hippocampus, the nucleus tractus solitarius, and the area postrema. Low densities of the Y₅ binding sites were detected in the hypothalamus (131).

Y₅-like immunoreactivity was observed throughout the hypothalamus, thalamus, hippocampus, and cortex of the rat brain (133). Y₅ receptor mRNA was seen to be widely distributed in CNS, but less abundantly than either the Y₁ or the Y₂ mRNA. In the rat brain, distribution of Y₅ receptor mRNA was primarily restricted to specific hippocampal, hypothalamic, and associated regions of the rat forebrain, with minimal to negligible expression levels in the majority of the brain stem nuclei. Y₅ receptor mRNA was highly expressed in neurons of the ventrolateral portion of the suprachiasmatic nucleus (78, 134).

Using in situ hybridization, virtually all areas containing neurons positive for Y₅ receptor mRNAs in the mouse brain and periphery also expressed Y₁ receptor mRNAs, whereas many Y₁-positive cells do not express Y₅ (135). The medial preoptic nucleus and the ARC contained neurons expressing the Y₁, Y₂, or Y₅ messages; the PVN appears to express all four cloned subtypes, including the Y₄ receptor (136). A comparison of the distribution of Y₁ and Y₅ by single- and double-label immunohistochemistry in the rat brain revealed colocalization of both receptors, with relatively high concentrations of cell bodies and fibers, within the cortex, hippocampus, hypothalamus, amygdala, and brainstem corresponding with some of the major actions of NPY. Varying degrees of colocalization were exhibited in different brain regions, which may reflect an overall difference in Y₁ vs. Y₅ receptor tone in a given area (137).

In guinea pigs (138), in situ hybridization with ³⁵S-labeled oligonucleotides revealed a prominent labeling in specific regions of the hypothalamus, the hippocampus, and the brain stem. In the hypothalamus, strong to moderate labeling was seen in the PVN, the suprachiasmatic nucleus, and the supraoptic nucleus (78, 139).

NPY and NPY_2–36 equally produce a large increase in feeding after intracerebroventricular administration (140), which suggests a receptor mediating the feeding response to NPY different from Y₁, Y₂, and Y₄. An order of potency of NPY > PYY = [Pro³⁴]-substituted analogs = NPY_2–36 = PYY_3–36 NPY_13–36 has been observed for Y₅ activation (69). The Y₅ receptor protein is larger than the other NPY receptors due to the extended third cytoplasmic loop, with about 100 amino acids more than the other PP-fold receptors; otherwise its carboxy-terminal tail is much shorter than in Y₁, Y₂, and Y₄ (110). Rat PP had low potency at the rat Y₅ and the human Y₅ receptors, whereas human and bovine PP had affinities similar to those of NPY and PYY (142). This may be important when extrapolating effects produced by PP-fold peptides in rodents to physiological and behavioral effects in humans (110).

B. Regulation of NPY receptors in feeding behavior and energy balance
Studies have been devoted to the identification of NPY receptor subtypes responsible for the regulation of energy homeostasis and the development of obesity (143, 144). According to the genetic or nutritional state, the various hypothalamic nuclei seem to be differently involved in changes in the expression of NPY receptors (145).

Changes in feeding behavior and energy balance induce a marked plasticity in the Y₁ function and expression in specific regions of the hypothalamus, reinforcing the involvement of this receptor in stimulation of food intake (99). Fasting induced an increase in NPY orexigenic activity and a decrease in Y₁ receptor expression in the ARC and PVN in rats (99). Neither Y₂ (146) nor Y₅ (147) mRNA levels were affected by fasting. Decreased activity of Y₁ in ARC (146) and PVN (148) induced by food deprivation was attenuated by glucose ingestion (146, 148) and counteracted by leptin treatment, supporting the regulation of NPY-Y₁ system by leptin in the PVN (148).

In some studies investigating the anorexigenic mechanism of ciliary neurotropic factor in rat models of hypophagia, Y₁ R mRNA and immunoreactivity in the hypothalamus were decreased (147), although a suppression of NPY expression was also observed (149). The results suggested a deficit in NPY supply and a suppression of NPY-induced feeding by treatment with ciliary neurotropic factor (149).

Furthermore, genetic background may be important in determining the animal’s response, including molecular expression, to food restriction (150). In a study (150) comparing three different inbred mouse strains, C57BL/6J, A/J, and DBA/2J, under food restriction, only DBA/2J mice had an up-regulation of hypothalamic Y₁ receptor. This strain exhibited an increase in locomotor activity and a substantial drop in body temperature, which was accompanied by a decrease in white and brown adipose tissue masses and in plasma leptin levels. Y₁ receptor may mediate the antithermogenic effect of NPY.

In a state of positive energetic balance, the NPY inhibitory signal to POMC is also inhibited, triggering the up-regulation of Y₁ in ARC (99). Pregnancy in humans and rodents is associated with positive energy balance primarily due to an increase in food intake despite high levels of leptin, suggesting a state of leptin resistance in the hypothalamus (145). Pregnant transgenic mice carrying the Y₁ gene promoter linked to the LacZ reporter gene (Y₁R/LacZ) showed decreased NPY immunoreactivity and increased Y₁ receptor gene expression in the PVN. Also, the mice presented a significant increase in Y₁R/LacZ transgene expression and Y₁ receptor mRNA but no change in NPY immunoreactivity in the ARC. However, it was observed that an induction of NPY content was accompanied by a reduction of Y₁ expression in the VMN, which may contribute to the increase in food intake during pregnancy (145). Indeed, Y₁R/LacZ transgenic mice showed decreased Y₁ gene expression in the dorsomedial and ventromedial nuclei after a high-fat diet, which was not prevented by leptin administration (99). Diet-induced obese mice exhibited a profound induction of NPY expression in the dorsomedial and ventromedial hypothalamic nuclei and a reduction of NPY mRNA in the ARC (151).

Brainstem Y₄ receptor mRNA levels respond to alterations in nutritional status or treatment with leptin in rats (152). Peripheral administration of leptin and refeeding after 48 h of fasting up-regulate Y₄ mRNA level in brainstem in rats. Similarly, food deprivation decreased and refeeding increased plasma leptin level, suggesting an involvement of brainstem Y₄ in the leptin-mediated anorexia (152).

Besides preliminary studies on Y₅ distribution, the involvement of the Y₅ in feeding regulation came from studies with antisense oligodeoxynucleotides, which predicted the existence of an additional NPY receptor, besides the Y₁, to transduce the NPY orexigenic signal (94). Furthermore, the central administration of Y₅ antisense oligodeoxynucleotides resulted in weight loss and a decrease in food intake, and it inhibited the increase in food intake after intracerebroventricular injection of NPY in rats (153, 154, 155).

Genetically obese rodents carrying a mutation at the leptin receptor presented increased hypothalamic NPY mRNA expression and enhanced inhibition of POMC neurons by NPY (157, 158). The increase in the hypothalamic NPY activity in the obese ob/ob and Zucker rats was associated with down-regulation of Y₁ (157, 158) and Y₅ receptor expression (157, 159, 160).

Y₁, Y₂, and Y₅ receptors may affect energy homeostasis through different mechanisms, which have been demonstrated by sustained activation of these receptors in the brain (161). Activation of central Y₅ receptors led to weight gain and adiposity through a combination of hyperphagic and nutrient-partitioning effects, by metabolizing carbohydrate and decreasing energy metabolized per energy ingested. Chronic activation of central Y₁ causes weight gain by altering nutrient partitioning alone, and chronic activation of central Y₂ causes transient weight loss mainly through hypophagia and has little effect on energy expenditure (161).

	VI. Therapeutic Applications of NPY Receptor Ligands

Top Abstract I. Introduction II. Obesity: Pharmacological... III. Central Regulation of... IV. Neuropeptide Y (NPY)... V. NPY Receptors VI. Therapeutic Applications of... VII. Transgenic NPY and... VIII. Role of NPY... IX. Conclusion References

 
There has been considerable progress in the development of novel selective peptide and nonpeptide analogs of NPY, which have been useful in elucidating the role of NPY receptors in the feeding regulation (110). Most analogs have been tested in experimental studies, and few clinical trials have been performed so far (Table 1).

The first selective Y₂ antagonist presented was BIIE0246((S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6 h)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-3,5(4H)-dioxo-1,2-diphenyl-³H-1,2,4-triazol-4-yl] ethyl]-argininamide), which has high affinity for the Y₂ and is devoid of affinity for Y₁, Y₄, and Y₅ receptors (182). Since then, evidence has been presented for prejunctional Y₂ receptors regulating transmitter release in several tissues (183, 184, 185, 186, 187). In these studies (183, 184, 185, 186, 187), stimulation of the receptor by exogenous agonists was required to elicit inhibition of transmitter release, which in turn could be antagonized by BIIE0246; however, the antagonist BIIE0246 did not alter transmission per se (186). Endogenous neurogenical NPY regulates its own release via activation of sympathetic prejunctional inhibitory Y₂ receptors in both spleen and kidney in the reserpinized pig. Depletion of noradrenaline (reserpine treatment in combination with transection of sympathetic nerves) was used to present evidence that endogenous, neuronally released NPY mediated sympathetic vasoconstriction (186). Efficacy and favorable side effect profile studies may consider the involvement of Y₂ receptors in cardiovascular function. By using Y₂ antagonist BIIE0246 in the pig in vivo, prejunctional activation of Y₂ inhibited the release of both noradrenaline and NPY. Moreover, when basal release of NPY was enhanced after blockade of prejunctional 2-adrenoceptors, endogenous NPY acting on Y₂ seems to be involved in the regulation of basal splenic vascular tone (186).

Y₅-specific ligands that modulate NPY receptor signaling have been investigated, with gradual development of potent and selective Y₅ receptor antagonists (188, 189, 190, 191, 192, 193, 194, 195, 196). The use of selective Y₅ antagonists, such as CGP 71683A (197, 198, 199), GW438014A (200), and the orally available FMS586 (201) has been described to inhibit spontaneous food intake, fasted food intake, free-feeding rats, or NPY-induced food intake in rats and guinea pigs (199). No effect, however, was seen on NPY-induced food intake with other antagonists, such as compound (–)-7, which features a novel chiral 2,3-dihydro-1H-cyclopenta[a]naphthalene moiety (202), or tricyclic thiazole derivatives (203), which indicates that the Y₅ receptor alone has no significant role in feeding in these models (203). Y₅ antagonists, such as L-152,804 (204) and S 25585 (205), selectively inhibited NPY-induced food intake in rats, but not through blockade of the Y₅ receptor. Y₅ receptor may not be the major feeding receptor through which exogenously applied NPY elicits its effects on feeding in rodents (194, 206).

Antagonist for Y₅ receptor has been found to selectively ameliorate diet-induced obesity (DIO) in rodents by suppressing body weight gain and adiposity while improving hyperinsulinemia associated with DIO (205). However, the antagonist did not affect the body weight of lean mice fed a regular diet or genetically obese leptin receptor-deficient mice or rats, despite similarly high brain Y₅ receptor occupancy. The authors (205) suggested that Y₅ is involved in the regulation and development of DIO. The conflicting results may be explained by differences of pharmacological characteristics of the antagonists studied or the particular Y₅ pathway that seems to be specifically activated and effective in DIO mice, but not in genetically obese models (207). In a pair-feeding study in DIO mice, chronic oral administration of L-152,804 decreased body weight with a moderate feeding suppression, as well as increased energy expenditure, by mediating thermogenic effects in brown adipose tissue and white adipose tissue (207).

In a study (208) using both Y₁ (120562A, BIBO 3304) and Y₅ antagonists (CGP 71683A, JCF 104, and JCF 109), Y₁ antagonist inhibited NPY-induced feeding. Y₅ antagonists, however, did not reduce feeding induced by NPY in rats, although it reduced the hyperphagic response to a higher dose of NPY, during the period from 2 to 4 h after injection. The authors (208) suggested that Y₅ receptors may be involved in the maintenance of the pronounced orexigenic effect induced by NPY. Pretreatment of guinea pigs with the antagonists for Y₁ (BIBO 3304 and H 409/22) and Y₅ (CGP 71683A) attenuated feeding responses to NPY (199). Interestingly, the effect of the antagonists tended to cause different feeding behavior. Although Y₁ caused a reduction in eating time after NPY but caused no change in the number of meals, Y₅ antagonist tended to decrease the time spent on eating and the meal frequency in NPY-treated animals (199).

These findings were contradicted by another study (209) which demonstrated that oral administration of NPY5RA-972, a selective and potent (<10 nmol/liter) Y₅ receptor antagonist, had no effect on food intake in rats. This was observed in Wistar rats induced to feed by either intracerebroventricular NPY or 24-h fasting, in free-feeding Wistar or in obese Zucker rats (209).

2. Clinical trials.
A multicenter, randomized, double-blind, placebo-controlled trial was performed to analyze the efficacy of Y₅ antagonism in leading body weight loss in humans (211). One milligram per day of MK-0557, a highly selective, orally active Y₅ receptor, was used in overweight and obese patients during a 52-wk treatment. Although a statistically significant weight loss was observed, its degree was less than that observed for several other weight-loss drugs and was not considered clinically meaningful by the authors (215). Also, the same therapy with this Y₅ antagonist was not efficacious in reducing weight regain after a very-low-calorie diet-induced weight loss in overweight and obese patients (212)

B. NPY receptors agonists
1. Experimental studies.
Numerous selective Y₁ agonists could stimulate food intake dose responsively in rats after intracerebroventricular administration (213). Rats treated with NPY, Y₁ antagonist [Phe⁷,Pro³⁴]pNPY, and Y₅ receptor agonist [cPP_1–7, NPY_19–23, Ala³¹, Aib³², Q34]hPP, consumed more food and presented higher weight gain than controls (215). Both Y₁ and Y₅ could mediate the inhibitory effects of NPY on the hypothalamic-pituitary-thyroid (143, 215).

Y₂ receptors appear to modulate NPY anxiogenic effect induced by intracerebroventricular (216) and intraamygdaloid (217) application of Y₂ agonists and anxiolytic response to injections of Y₂ agonists close to the locus coeruleus (217, 218). Studies with Y₂-KO mice indicate that Y₂ receptors are involved in the regulation of anxiety-like behaviors by NPY. Mice lacking Y₂ showed reduced anxiety and improved stress coping ability (219), deterioration in learning and memory processing (220), reduced attention and increased impulsivity (221), and anxiolytic-like profile and lower immobility scores (222). The particular presynaptical location of Y₂ receptor may explain why NPY agonists specific for the Y₁ receptor and Y₂ agonists like NPY_13–36 and C2-NPY exert opposing effects (109).

Binding of Y₄ ligands, rat PP, hPP, Pro³⁴PYY, and GR231118 demonstrated an inhibitory role of the Y₄ in mouse and human colonic mucosae ion transport (223). GR231118 is a homodimeric peptide based on the C-terminal sequence of NPY, originally identified as a competitive Y₁ antagonist with low Y₂ affinity (224), which also exhibits potent Y₄ agonist activity (225, 226, 227, 228). Y₄ receptors, as well as presynaptic Y₂ receptors, seem to mediate endogenous NPY inhibition of vagal afferent signaling of gastric acid challenge to the mouse brain stem (229).

Sub[-Tyr-Arg-Leu-Arg-Tyr-NH₂]₂, a Y₄-selective agonist with picomolar affinity to Y₄ receptors, inhibited food intake in fasted mice in a dose-dependent manner (230). Distinct data have been described concerning whether Y₄ receptor is internalized or not after agonist stimulation (231, 232, 233). Also, Y₄ seems to dissociate upon agonist stimulation, which suggests that homodimerization is an important component in the regulation of the Y₄ receptor (234). Because PP is the preferential Y₄ receptor agonist, this receptor might mediate some of the effects produced by PP (110). Peripheral administration of PP inhibits gastric emptying and decreases food intake in rodents (235) and in humans (28, 236). The mechanism by which peripheral administration of PP reduces food intake has been the subject of research but has not been definitively determined (237).

The first Y₅ receptor-selective ligands with subnanomolar affinity, [Ala³¹,Aib³²]pNPY, and the Ala-Aib-containing PP/NPY chimera such as [cPP_1–7,NPY_19–23,Ala³¹,Aib³²,Gln³⁴]hPP significantly stimulated feeding in rats (128). In contrast to rat studies, [Ala³¹,Aib³²]pNPY had only a modest effect on food consumption in guinea pigs, which is possibly due to its lower affinity than [cPP_1–7,NPY_19–23,Ala³¹,Aib³²,Gln³⁴]hPP to the Y₅ receptor (239). The Y₅ analogs _2–36[K⁴,RYYSA_19–23]PP (240) and Bis(31/31'){[Cys³¹,Nva³⁴]NPY_(27–36)-NH2} (BWX-46) have been reported to stimulate feeding in rat, the latter with a latent stimulatory effect on food intake (241). Controversial reports have described the effect of Y₅ antagonists on food intake (209, 242, 243), and the role of the receptor in the regulation of food intake and energy homeostasis was also investigated by using D-Trp³⁴NPY (244), a potent and selective Y₅ agonist, and the receptor antagonist L-152,804 (204). Chronic intracerebroventricular infusion of D-Trp³⁴NPY produced hyperphagia, body weight gain, hypercholesterolemia, hyperinsulinemia, and hyperleptinemia in mice, changes that were suppressed by oral administration of L-152,804. There was no increase in body weight when D-Trp³⁴NPY-induced food intake was restricted by pair-feeding; however, an increase in adipose tissue was seen. Also, the obesity-related plasma parameters were still increased in the D-Trp³⁴NPY-infused pair-fed group, indicating that the Y₅ receptor mediates metabolic changes, such as decreased lipolysis and thermogenesis, as well as hyperphagia (244). Also, Y₁ and Y₅ agonists induced hyperinsulinemia in rats by different mechanisms (245). Y₁ agonist-induced hyperinsulinemia was not dependent on food intake, whereas Y₅ agonist-induced hyperinsulinemia depended on food ingestion. NPY can inhibit insulin secretion by central and peripheral mediation (245, 246, 247) and, in fact, expression of the Y₁ receptor, but not the Y₅ receptor, has been detected in Langerhans islet cells (248). In addition, plasma glucose levels were significantly reduced by central infusion of the Y₁ agonist, but not the Y₅ agonist (245).

2. Clinical trials.
Infusion of PYY_3–36 resulted in decreased energy intake in both obese and lean subjects (249, 250, 251). A 90-min infusion of PYY_3–36 at 0.8 pmol/kg·min caused an approximately 36% reduction in energy intake during a buffet lunch offered 2 h after the infusion and a 33% reduction in total 24-h food intake (251). The same authors investigated the effect of a 90-min infusion of PYY at 2 nmol/m² of body surface area in obese and lean subjects. An approximately 30% reduction in energy intake was observed in both groups. No gastrointestinal side effects were reported in these studies (249).

The effect of graded iv doses (0, 0.2, 0.4, and 0.8 pmol·kg^–1·min^–1) of PYY_3–36 on food intake was investigated in healthy male volunteers. The infusions resulted in a dose-dependent 32% reduction in energy intake and 18% reduction in fluid ingestion. However, nausea and fullness were observed especially at the highest dose of PYY (250).

Recently, a study using an intranasal formulation of PYY_3–36, an orally bioavailable, nonpeptide Y₂ receptor agonist, was performed in an attempt to induce weight loss in obese subjects. PYY_3–36 was administered as a 200- or 600-µg intranasal spray 20 min before meals in conjunction with a hypocaloric diet and exercise. Adverse events, including nausea and vomiting, were limiting at the high dose, and at the low dose, no significant weight loss was observed (252).

The effect of two 90-min infusions of PP at 100 pmol·kg^–1·h^–1 on food intake was assessed in 10 children with Prader-Willi syndrome. Thirty minutes into each infusion, a 60-min appetite test was given 1 h after a 275-kcal breakfast meal. PP and saline infusions caused similar eating behavior, suggesting that the excessive food intake could not be prevented by a short-term normalization of blood PP concentrations (253).

Intravenous infusions of PP (90 min, 50 pmol/kg·h) restored normal serum PP levels and reduced food intake by approximately 12% in Prader-Willi subjects. The results were observed only in female subjects, suggesting that enhanced satiation rather than suppression of food intake may have occurred (254).

As mentioned previously in this article, TM30338, a dual Y₂-Y₄ receptor agonist, was studied on healthy obese subjects to assess the effect on food intake (30, 33). According to 7TM Pharma, single sc doses of TM30338 suppressed the food intake of these subjects. 7TM Pharma also reported their previous start on a preclinical development of TM30339, a Y₄ receptor selective agonist peptide that would reduce food intake and body weight.

	VII. Transgenic NPY and NPY Receptor Knockout (KO) Rodents

Top Abstract I. Introduction II. Obesity: Pharmacological... III. Central Regulation of... IV. Neuropeptide Y (NPY)... V. NPY Receptors VI. Therapeutic Applications of... VII. Transgenic NPY and... VIII. Role of NPY... IX. Conclusion References

 
The first description of NPY-deficient mice due to targeted NPY gene disruption revealed them to have normal levels of daily food intake and body weight and to exhibit normal refeeding after a fast (161). Under these circumstances, neural control over feeding is sufficiently redundant that the loss of NPY might have been compensated by other responses (255). KO of the NPY gene attenuated the hyperphagic response of mice with uncontrolled insulin-deficient diabetes induced by the cell toxin streptozotocin, which was accompanied by a stronger reduction of POMC mRNA levels compared with diabetic NPY⁺/⁺ mice. NPY may be required for both the increase of food intake and the decrease of hypothalamic POMC gene expression induced by uncontrolled diabetes (255). Genetic deficiency of NPY also attenuated DIO in mice prone to obesity (256) and the endocrine alterations of leptin-deficient ob/ob mice (154), suggesting that NPY is an important mediator of central leptin signaling (5). NPY may contribute to the mechanism whereby food intake increases in response to circadian and palatability cues (19). Mice lacking NPY showed reduced dark cycle 4-h food intake but did not differ in 24-h consumption compared to NPY-positive controls. NPY-deficient mice also showed lower feeding response to exposure to a highly palatable diet (19). In response to moderate insulin-induced hypoglycemia, feeding is markedly attenuated in mice lacking NPY (257). Neither the increase of plasma glucagon and corticosterone levels induced by hypoglycemia nor the time to recovery of euglycemia was altered by NPY deficiency, suggesting that NPY is a key mediator of hyperphagic rather then neuroendocrine responses to hypoglycemia (257).

Generation of transgenic NPY overexpressing mice did not affect feeding or food intake (258, 259). However, on a sucrose-loaded diet, NPY-overexpressing mice had increased body weight gain, transient increased food intake, and hyperglycemia and hyperinsulinemia without altered glucose excursion, suggesting that hypothalamic NPY levels are important for the development of obesity (260).

Genetic manipulations have been made to create mice deficient in individual NPY receptor subtypes (Table 2). This approach enables a selective elimination of the endogenous receptor, and the resulting phenotype can be studied to understand the physiological role of the receptor (110). Also, it presents a valid alternative to pharmacological investigations (26, 110, 261).

Inactivation of the Y₂ receptor in mice resulted in increased body weight, food intake, and fat deposition (268). The Y₂ KO mice also showed a blunted response to leptin but a normal response to NPY-induced food intake and intact regulation of refeeding and body weight after fasting (268), which suggests the involvement of this receptor in the regulation of hypothalamic NPY release in a tonic fashion (110). Peripheral injection of PYY_3–36 in rats inhibited food intake and reduced weight gain, which was not seen in mice lacking Y₂, suggesting the role of the receptor in the anorectic effect of PYY_3–36 (251). In contrast, specific and permanent deletion of hypothalamic Y₂ receptors in conditional mice resulted in transient reduced body weight despite an increase in food intake, which was associated with an increase in mRNA levels for NPY, AgRP, POMC, and CART in the ARC. Deletion of the receptor also resulted in increased plasma levels of PP (269). The authors suggested that the transient effect of gene deletion on body weight and food intake weight despite the permanent deletion of the Y₂ receptor in the hypothalamus may have reflected an adaptation to maintain homeostasis (270). Crossing the Y₂^–/^– mice onto the ob/ob strain attenuated increased adiposity and the type 2 diabetic syndrome, reducing hypothalamo-pituitary-adrenal axis activity, hyperinsulinemia, hyperglycemia, and hypercholesterolemia (270, 271).

First results of deletion of Y₄ receptor (272) showed a decreased body weight and lower white adipose mass especially in males, which, differently from the females, also presented a decrease in the 24-h food intake. Both male and female Y₄^–/^– mice presented increased plasma levels of PP compared with wild-type controls, with significantly greater basal plasma PP concentrations in males than in females (272). Intraperitoneal injection of Y₄ receptor selective agonist Sub[-Tyr-Arg-Leu-Arg-Tyr-NH₂]₂ potently inhibited food intake in wild-type fasted mice and not in Y₄^–/– mice, confirming that the actions of the compound on food intake are specifically mediated by Y₄ receptors (230). Peripheral Y₄ receptors are an attractive target system for drug development (273). Because this appears to be a peripheral signaling pathway, there is the potential advantage of developing agents that would have little CNS involvement (273).

In a study (274) with Y₂ and Y₄ KO mice, it has been suggested that both receptors are involved in the circadian control of spontaneous water intake. Y₂ receptor mediates circadian phase-shifting effects of NPY measured in vitro (275) and in vivo (276) in hamsters. Deletion of Y₂ and Y₄ receptor genes led to enhanced consumption of water specifically during the dark phase (274). Generation of Y₂- and Y₄-deficient mice has been performed in the attempt to elucidate, among others, the interactions among these receptors in the regulation of energy balance (26, 110, 261), with controversial results. Deletion of both Y₂ and Y₄ receptors resulted in greater reductions in adiposity, leptinemia, and insulinemia, and increased food intake compared with Y₂ KO mice or Y₄ KO mice, demonstrating a synergistic effect between the receptors (277). Interestingly, Y₂Y₄ double KO mice presented an even greater increase in NPY mRNA levels than Y₂-deficient mice, with significant increases in AgRP mRNA and significant decreases in CART mRNA in the ARC (277). The synergy between Y₂ and Y₄ in the regulation of adiposity demonstrates a lack of compensation for the roles of these receptors by other regulators of energy balance when both Y₂ and Y₄ are missing. The increase in food consumption was accompanied by decreased adiposity in Y₂^–/^– Y₄^–/^– mice, similarly demonstrated by germ-line Y₂-KO mice (269), indicating a distinct mechanism that decreased fuel efficiency in the double KO animals (277). The authors (277) discuss the possibility that the elevated plasma PP levels in these KO models may influence energy homeostasis and insulin effects by activating other peripheral Y receptors besides Y₄, with lower but still significant affinity for PP. This hypothesis had also been mentioned in the study on Y₄-KO mouse (272). However, because no molecular cloning of any of these potential Y receptors has been reported, it is a matter of controversy (278). Another possibility is the existence of adaptive changes during development, consequent to removal of one component of the NPY family system (279). Due to their overlapping mRNA expression pattern and similar affinity for NPY, the remaining Y receptors could compensate when one of the others is missing (278). However, double KO of the Y₂ and Y₄ as well as germ-line deletion of the Y₄ does not seem to influence the overall expression level of other Y receptors (278). Deletion of Y₂ and Y₄ receptors has synergistically protected against DIO in mice also (144). Y₂Y₄ KO was associated with reduced food intake and improved glucose tolerance, whereas Y₁ KO, Y₁Y₂ KO, and Y₁Y₄ KO developed DIO syndrome under the same conditions. In this study (144), hypothalamic POMC induced by the high-fat diet significantly decreased in obesity-prone Y₁-KO mice but did not decrease in obesity-resistant Y₂Y₄-KO mice. This change may contribute to the DIO observed in Y₁–KO mice by decreasing secretion of -MSH (144).

The role of different Y₁, Y₂, and Y₄ receptors in the NPY-induced obesity syndrome has been investigated by recombinant adeno-associated viral vector (rAAV) to overexpress NPY in mice deficient of single or multiple receptors (280). The degree of body weight gain in rAAV-NPY-treated mice was different between genotypes, with body weight gain being less in Y₁^–/^– and even less in Y₁Y₂Y₄^–/^– mice compared with wild-type mice. The authors suggest that Y₁, Y₂, Y₄ receptors may compensate one another in mediation of the obesogenic effects of NPY and that the existence of other unidentified Y receptors could not be discarded (280).

Although a role for the Y₁ and Y₅ in feeding behavior has been established through acute administration of selective agonists, mice deficient for the Y₁ or Y₅ receptor have not presented a lean phenotype (143). Mice lacking Y₅ developed mild late-onset obesity characterized by increased body weight, food intake, and adiposity (281), and either reduced or absent response to intracerebroventricular administration of NPY and related peptides (281). NPY-induced feeding is predominantly mediated by the Y₁ rather than the Y₅ receptor in mice (242). Feeding induced by NPY intracerebroventricular injection was reduced in Y₁^–/^– mice, but not in Y₅^–/^– mice, compared with that in wild-type mice (242). NPY infusion reduced NPY mRNA expression in Y₅-KO mice but had only a modest effect in Y₁-deficient mice (282). These data may suggest an activation of compensatory orexigenic pathway or even an absence of a role of Y₅ in the stimulation of feeding (264).

However, in the situation of chronic NPY administration, central NPY administration stimulated feeding and resulted in a significant body weight gain in both Y₁ and Y₅ KO mice to an extent similar to that seen in wild-type animals (282). Distinct findings (242, 282) might be due to distinct pathways operated in short (241) vs. long-term responses (282) to NPY.

Different mechanisms seem to be involved in the development of high body weight and increased body fat in both Y₁- and Y₅-deficient mice when compared with wild-type mice (263, 281). Y₅^–/^– mice exhibited hyperphagia, whereas Y₁^–/^– mice did not (281). Interestingly, Y₁ and Y₅ antagonists tended to produce different effects in increased feeding behavior in NPY-treated animals (191, 202), and Y₁ and Y₅ agonists induced hyperinsulinemia in rats by different mechanisms (245).

	VIII. Role of NPY Receptors in Obesity in Human-Genetic Variations

Top Abstract I. Introduction II. Obesity: Pharmacological... III. Central Regulation of... IV. Neuropeptide Y (NPY)... V. NPY Receptors VI. Therapeutic Applications of... VII. Transgenic NPY and... VIII. Role of NPY... IX. Conclusion References

 
Genetic variation studies have also supported the possibility of NPY receptors contributing to obesity in humans. Ma et al. (283) sequenced PYY and Y₂ receptor genes in a group of 83 extremely obese Pima Indians. Variants were analyzed for association with obesity in a case-control study. A G/A polymorphism, predicting an alanine-to-threonine substitution, and two additional variants, both C/T predicting a silent (isoleucine) substitution [single nucleotide polymorphism (SNP)10 and SNP11, respectively], were identified and were in genotypic concordance among the case-control samples. In the association analysis, at least one variant in each of the three haplotype blocks of Y₂ was modestly associated with severe obesity, but variants in the third haplotype block (SNP10/11) showed a greater difference in men (283). Previously, it had been shown that Pima Indian children presented higher fasting PP concentrations than Caucasian children, and that adult Pima Indians had markedly higher early and late phase PP responses than Caucasians (284). Also, in a prospective study (285), fasting and postprandial PP secretion in Pima Indian male subjects associated negatively with obesity, similar to another study involving obese children and another population (286). It may be interesting if genetic studies with Y₄ receptor among Pima Indians were performed.

Similar genetic variations were described by Hung et al. (287) in a large group from an ethnically homogeneous white population. An association between Y₂ SNPs and human obesity was associated with two SNPs, the same detected by Ma et al. (283) [SNP10/11, rs1047214 (nt585C/T), and rs2880415 (nt936C/T)]; such association was only present in men (287). Also, a lower allele and homozygosity frequency of the common allele 585T>C:T was observed among Swedish Caucasian obese men (288). In this study, it has been suggested that the common Y₂ receptor variant has a protective role against obesity.

Familial linkage analyses of these loci as well as strand conformation polymorphism of NPY and Y₁ in French Caucasian families with morbid obesity (289) and screening for mutations in the Y₅ receptor gene in cohorts belonging to different weight extremes (290) have not supported a role of Y₁ and Y₅ in the pathogenesis of human obesity.

	IX. Conclusion

Top Abstract I. Introduction II. Obesity: Pharmacological... III. Central Regulation of... IV. Neuropeptide Y (NPY)... V. NPY Receptors VI. Therapeutic Applications of... VII. Transgenic NPY and... VIII. Role of NPY... IX. Conclusion References

 
Progress in our understanding of the involvement of NPY receptor subtypes in the feeding behavior and in weight control has been made. Since initial reports on these receptors identification, studies with ligand binding techniques, in situ hybridization, immunohistochemistry, and other available approaches have contributed to elucidating the localization of Y₁, Y₂, Y₄, and Y₅ receptors, as well as the neurochemical phenotype of some of their receptor-expressing neurons. Transgenic overexpressing animals and receptor KO models have facilitated the comprehension of their roles in food ingestion behavior and in regulation of DIO. In addition, genetic variation studies have reinforced the possible influence of Y₂ and Y₄ receptors on body weight in humans. Y₁ and Y₅ receptor antagonists and Y₂ and Y₄ receptor agonists may become options for treating human obesity, but increasing information provided by recent studies involving multiple receptors reveals that many questions remain to be answered.

There is increasing evidence that Y₁, Y₂, Y₄, and Y₅ are involved in the regulation of body energy and affect energy homeostasis through different mechanisms. Activation of different receptors may achieve similar outcome results, although by distinct pathways, and deletion and activation of multiple but different receptors still present distinct results. For example, chronic activation of central Y₅ receptors can lead to weight gain through a combination of hyperphagic and nutrient-partitioning effects, activation of central Y₁ causes weight gain by altering nutrient partitioning alone, and activation of central Y₂ causes weight loss through hypophagia and little effect on energy expenditure (143). Central activation of Y₁ or Y₅ revealed that Y₅-induced hyperinsulinemia is dependent on food ingestion, whereas Y₁-induced hyperinsulinemia is independent of the presence of food (245).

Deletion of Y₁, Y₂, and Y₄ indicates that hyperinsulinemic effects of high NPY condition are mediated via actions at Y₁, Y₂, and Y₄ receptors (277). However, activation of central Y₁ or Y₅, but not Y₂ or Y₄, receptor subtypes induced hyperinsulinemia (245).

Therefore, information provided by studies involving multiple receptors indicates that there is still much to know about how Y receptors modulate food intake and energy expenditure. It is still not clear whether there is synergy, biological redundancy or compensation among the receptors, or the regulation by other regulators of energy balance, for the roles of energy balance control, in mediation of the effects of NPY. Simultaneously, inhibition and activation of different Y receptors should be considered in the development of new treatments for obesity. Yet, it will be important to carry out analysis of the synaptology of NPY and Y₂- and Y₄ receptor-positive neurons (104).

Very few pharmacological antagonists are available so far; development of specific receptor antagonists with appropriate pharmacokinetic properties is required. Also, because NPY is involved in a wide variety of physiological processes, many of which are mediated via Y₁ and Y₅ receptors, it is possible that Y₁ and Y₅ receptor antagonists developed for the treatment of obesity will be associated with specific mechanism-based side effects (244).

In addition, the NPY system acts both in central and peripheral target tissues (291), playing a regulatory role among the sympathetic, vascular (292, 293, 294), and immune systems (238, 295). NPY is an inhibitory neurotransmitter coreleased with norepinephrine in variant proportions (238), causing prolonged vasoconstriction and vascular remodeling in response to prolonged and/or intense stress (238, 292, 293, 294, 295). NPY is involved in lymphocyte proliferation (156), phagocytosis (141), and modulation of macrophage (295) in the regulation of the immune system, and also exerts an epileptic effect (29, 73, 84). Although no serious side effects have been reported in clinical trials involving an antiobesity drug mediated by NPY Y₂ and Y₄ receptors applied sc (30), administration of an intranasal Y₂ agonist formulation in certain dosages induced nausea and vomiting, and some of the patients also experienced dizziness, palpitations, tachypnea, and tremors (254). Besides, clinical tests involving other antiobesity drugs that mediate their effects via central mechanisms reported a number of side effects including nausea, dizziness, diarrhea, joint pain, anxiety, depression, and insomnia (30). Thus, studies of long-term efficacy and favorable side effect profile will be essential in the development of NPY-based drugs. Activation of Y₂ and Y₄ receptors with proper agonists probably combined with inhibition of Y₁ or Y₅ receptor could provide new treatments to improve the efficiency of lifestyle interventions for obesity in the future. NPY regulates energy homeostasis through activation of multiple receptor subtypes. Interaction among NPY receptors should be necessary for an effective therapeutic strategy for obesity. Further investigations involving simultaneous activation and inhibition of Y receptors are required.

	Footnotes

 
Disclosure Statement: M.M.K. and A.I. have nothing to declare.

First Published Online September 4, 2007

Abbreviations: AgRP, Agouti-related peptide; ARC, arcuate nucleus; CART, cocaine- and amphetamine-regulated transcript; CB1, cannabinoid receptor; CNS, central nervous system; cPP, chicken PP; DIO, diet-induced obesity; DMH, dorsomedial hypothalamus; GABA, aminobutyric acid; hPP, human PP; KO, knockout; LHA, lateral hypothalamic area; NPY, neuropeptide Y; PFA, perifornical area; POMC, proopiomelanocortin; PP, pancreatic polypeptide; PVN, paraventricular nucleus; PYY, peptide YY; SNP, single nucleotide polymorphism; VMH, ventromedial hypothalamus.

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Top Abstract I. Introduction II. Obesity: Pharmacological... III. Central Regulation of... IV. Neuropeptide Y (NPY)... V. NPY Receptors VI. Therapeutic Applications of... VII. Transgenic NPY and... VIII. Role of NPY... IX. Conclusion References

 

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