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Gene Review

NPY  -  neuropeptide Y

Homo sapiens

Synonyms: PYY4, Pro-neuropeptide Y
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Disease relevance of NPY

  • In humans and dogs the effects of NPY or PYY were abolished by treatment of cells with Bordetella pertussis toxin, clearly indicating the involvement of a Gi protein in the antilipolytic effects [1].
  • The percentage of ganglion cells containing NPY then increases gradually, reaches adult levels (approximately 55%) by stage XX, and persists at these levels through metamorphosis [2].
  • METHODS: Plasma leptin and cerebrospinal fluid leptin, NPY, and PYY concentrations were measured in women who were recovered from anorexia or bulimia nervosa to determine whether alterations persisted after recovery [3].
  • We conclude that patients with neuroendocrine tumors, especially secreting and or malignant tumors of the sympathochromaffin system, often have elevated plasma NPY concentrations [4].
  • The NPY receptors in pheochromocytomas, paragangliomas, and neuroblastomas are often expressed concomitantly with the NPY hormone detected immunohistochemically [5].

Psychiatry related information on NPY

  • CONCLUSIONS: Alterations in NPY, PYY, and serum leptin concentrations are probably secondary to pathological eating behaviors [3].
  • In summary, NPY promotes sleep and inhibits the hypothalamo-pituitary-adrenocortical (HPA) axis in humans, pointing to a possible role of NPY agonists for the development of novel treatment strategies for affective disorders [6].
  • The most parsimonious interpretation of these findings is that, although NPY inhibits estrous behavior via downstream CRFR2 signaling, food deprivation may exert its inhibition via both CRFR1 and CRFR2 and that redundant neuropeptide systems may be involved [7].
  • NPY-like material was significantly lower (P less than 0.001) in CSF of patients with depressive disorders than in schizophrenic patients or healthy controls [8].
  • During the last two decades, NPY body fluid concentrations and NPY/PYY brain receptor numbers have been demonstrated to be altered during the course of Alzheimer's disease [9].

High impact information on NPY


Chemical compound and disease context of NPY


Biological context of NPY

  • This study indicates that, in addition to alpha 2-adrenergic agonists, NPY and PYY are also involved in the regulation of lipolysis in human and dog adipose tissue as powerful antilipolytic agents [1].
  • Examination of cell hybrids with chromosomal rearrangements assigned PPY to the p11.1-qter region and NPY to the pter-q22 region of their respective chromosomes [17].
  • Double-label experiments in late-stage tadpoles and juvenile bullfrogs revealed that the intensely TH-positive neurons are negative for NPY [2].
  • Neuropeptide Y (NPY) and norepinephrine, found colocalized in sympathetic neurons innervating blood vessels, exert synergistic responses on vasoconstriction [18].
  • Using three different approaches with synthetic peptides, we have probed the importance of the PP-fold structure in the interaction of NPY with two types of binding sites, Y1 and Y2 receptors [19].

Anatomical context of NPY

  • Further studies are needed to characterize the pharmacological nature of the receptor mediating the inhibitory effect of NPY and PYY in fat cells [1].
  • NPY first appears in a few principal neurons (less than 1%) of paravertebral ganglia 9 and 10 at stage XI [2].
  • Pharmacological experiments on isolated temporal artery segments revealed that NPY potentiated the vasoconstrictor responses to noradrenaline, but had no vasoconstrictor ability or only a small vasoconstrictor ability per se [20].
  • In contrast, antisera to NPY and APP labeled local neurons systems in the spinal dorsal horn, in the lateral parts of the brain stem, including the rhombencephalic alar plate, and in the retina [21].
  • To examine the signaling mechanisms involved, free of complications associated with mixed receptor populations, we have established a stable Chinese hamster ovary cell line expressing both Y1-NPY and alpha 1b-adrenergic receptors [18].

Associations of NPY with chemical compounds


Physical interactions of NPY

  • The antiparallel pancreatic polypeptide fold in the binding of neuropeptide Y to Y1 and Y2 receptors [19].
  • 1229U91 potently displaced [125I]-peptide YY (PYY) binding to human NPY Y1 receptors (IC50 = 0.245+/-0.004 nM, n = 4). but displayed little affinity for the human NPY Y2 and Y5 receptors (IC50 > 1000 nM) [23].
  • NPY binds to a family of G-protein coupled receptors whose activation results in inhibition of adenylyl cyclase activity [24].
  • In this study, specific NPY receptor binding sites were identified in the cells by use of [125I]Bolton-Hunter NPY [( 125I]BH-NPY) [25].
  • Significantly increased leptin and galanin levels in postmenopausal obese women coupled with decreased NPY levels revealed some changes in the neuropeptides regulating eating behavior, which may be the reason for the onset of postmenopausal obesity [26].

Co-localisations of NPY

  • Leptin receptor mRNA expression was colocalized with NPY mRNA-containing cell bodies in those regions [27].
  • As neuropeptide Y is co-localized with somatostatin in a considerable proportion of cortical neurons, the loss of immunoreactivity may in part reflect degeneration of these neurons [28].
  • In HUVECs, NPY is co-localized with dipeptidyl peptidase IV (DPPIV) which cleaves Tyr(1)-Pro(2) from NPY(1-36) to form NPY(3-36) resulting in the formation of a non-Y1 receptor agonist, which remains angiogenic [29].

Regulatory relationships of NPY

  • Interestingly, the Tyr(1138) --> STAT3 pathway does not strongly regulate neuropeptide Y (NPY) and thus is not required for the control of reproduction and growth [30].
  • Various NPY analogs inhibited in a dose-dependent manner the spontaneous secretion of alpha-MSH from perifused frog neurointermediate lobes with the following order of potency porcine peptide YY (pPYY) > frog NPY (fNPY) > porcine NPY (pNPY)-2-36) > pNPY-(13-36) > [D-Trp(32)]pNPY > [Leu(31),Pro(34)]pNPY [31].
  • We have studied the involvement of intracellular calcium and calcium-dependent signaling in the NPY-induced CRF release in trophoblastic cells [32].
  • Neuropeptide Y inhibits vasoactive intestinal peptide- and dopamine-induced cyclic AMP formation in human Ewing's sarcoma WE-68 cells [16].
  • In contrast to our recent observation in young normal subjects time awake, ACTH and cortisol remained unchanged in patients and controls in response to NPY [33].

Other interactions of NPY

  • Corticotropin-releasing factor and neuropeptide Y: role in emotional integration [34].
  • Concentrations of vasoactive intestinal polypeptide and cholecystokinin also were reduced in schizophrenia, although not as profoundly as somatostatin or neuropeptide Y [35].
  • Northern blot analysis of poly(A)+ RNA from whole human pituitaries revealed mRNA encoding the precursors for NPY, SP, and VIP whose hybridization characteristics were indistinguishable from those of the same mRNAs described in previously characterized human tissues [36].
  • Role of neuropeptides in the regulation of feeding behavior: a review of cholecystokinin, bombesin, neuropeptide Y, and galanin [37].
  • These studies demonstrate that in man, the NPY-, AGRP-, and alphaMSH-IR neuronal systems in the infundibular and paraventricular nuclei are highly reminiscent of that observed in the rat and may similarly be involved in regulating the hypothalamo-pituitary-thyroid axis in the human brain [38].

Analytical, diagnostic and therapeutic context of NPY

  • A Y1 receptor has been cloned, and this receptor appears to mediate several effects of NPY, including vasoconstriction and anxiolysis in animal models [39].
  • Fluorescence-labelled analogs of NPY, a 36-amino acid peptide amide, were synthesized by solid-phase peptide synthesis and used for fluorescence-resonance energy transfer studies to investigate the conformation [40].
  • Recently, we have found in young normal male controls after repetitive administration of NPY a shortened sleep latency and a decrease of time awake and, in the second half of the night, EEG delta-power; cortisol and ACTH levels were blunted [33].
  • In a clinically-typical gastrinoma, resected from the head of pancreas, the concentration of NPY immunoreactivity was 3.4 nmol/g. Reverse phase HPLC analysis of extracts of this tumour resolved a single immunoreactive peptide coeluting with synthetic human NPY [41].
  • The NPY- and TH-IR nerves in quadriceps muscle of the guinea pig were absent after treatment with 6-hydroxydopamine [42].


  1. Neuropeptide Y and peptide YY inhibit lipolysis in human and dog fat cells through a pertussis toxin-sensitive G protein. Valet, P., Berlan, M., Beauville, M., Crampes, F., Montastruc, J.L., Lafontan, M. J. Clin. Invest. (1990) [Pubmed]
  2. Expression of neuropeptide-Y-like immunoreactivity begins after adrenergic differentiation and ganglionic synaptogenesis in developing bullfrog sympathetic neurons. Stofer, W.D., Horn, J.P. J. Neurosci. (1990) [Pubmed]
  3. Leptin, neuropeptide Y, and peptide YY in long-term recovered eating disorder patients. Gendall, K.A., Kaye, W.H., Altemus, M., McConaha, C.W., La Via, M.C. Biol. Psychiatry (1999) [Pubmed]
  4. Plasma neuropeptide Y concentrations in patients with neuroendocrine tumors. Grouzmann, E., Comoy, E., Bohuon, C. J. Clin. Endocrinol. Metab. (1989) [Pubmed]
  5. High expression of neuropeptide y receptors in tumors of the human adrenal gland and extra-adrenal paraganglia. Körner, M., Waser, B., Reubi, J.C. Clin. Cancer Res. (2004) [Pubmed]
  6. Neuropeptide Y promotes sleep and inhibits ACTH and cortisol release in young men. Antonijevic, I.A., Murck, H., Bohlhalter, S., Frieboes, R.M., Holsboer, F., Steiger, A. Neuropharmacology (2000) [Pubmed]
  7. Corticotropin-releasing factor receptor subtypes mediating nutritional suppression of estrous behavior in Syrian hamsters. Seymour, P.L., Dettloff, S.L., Jones, J.E., Wade, G.N. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2005) [Pubmed]
  8. Neuropeptide Y and peptide YY as possible cerebrospinal fluid markers for major depression and schizophrenia, respectively. Widerlöv, E., Lindström, L.H., Wahlestedt, C., Ekman, R. Journal of psychiatric research. (1988) [Pubmed]
  9. Neuropeptide Y, peptide YY and aluminum in Alzheimer's disease: is there an etiological relationship? Croom, J., Taylor, I.L. J. Inorg. Biochem. (2001) [Pubmed]
  10. The hypothalamus and hypertension. de Wardener, H.E. Physiol. Rev. (2001) [Pubmed]
  11. A role for ghrelin in the central regulation of feeding. Nakazato, M., Murakami, N., Date, Y., Kojima, M., Matsuo, H., Kangawa, K., Matsukura, S. Nature (2001) [Pubmed]
  12. Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels. Karvonen, M.K., Pesonen, U., Koulu, M., Niskanen, L., Laakso, M., Rissanen, A., Dekker, J.M., Hart, L.M., Valve, R., Uusitupa, M.I. Nat. Med. (1998) [Pubmed]
  13. Changes in diurnal sympathoadrenal balance and pituitary hormone secretion in subjects with Leu7Pro polymorphism in the prepro-neuropeptide Y. Kallio, J., Pesonen, U., Jaakkola, U., Karvonen, M.K., Helenius, H., Koulu, M. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  14. Characterization of functional neuropeptide Y receptors in a human neuroblastoma cell line. Gordon, E.A., Kohout, T.A., Fishman, P.H. J. Neurochem. (1990) [Pubmed]
  15. Subtype selectivity of the novel nonpeptide neuropeptide Y Y1 receptor antagonist BIBO 3304 and its effect on feeding in rodents. Wieland, H.A., Engel, W., Eberlein, W., Rudolf, K., Doods, H.N. Br. J. Pharmacol. (1998) [Pubmed]
  16. Neuropeptide Y inhibits vasoactive intestinal peptide- and dopamine-induced cyclic AMP formation in human Ewing's sarcoma WE-68 cells. van Valen, F., Keck, E., Jürgens, H. FEBS Lett. (1989) [Pubmed]
  17. Genes encoding pancreatic polypeptide and neuropeptide Y are on human chromosomes 17 and 7. Takeuchi, T., Gumucio, D.L., Yamada, T., Meisler, M.H., Minth, C.D., Dixon, J.E., Eddy, R.E., Shows, T.B. J. Clin. Invest. (1986) [Pubmed]
  18. Synergistic interaction of Y1-neuropeptide Y and alpha 1b-adrenergic receptors in the regulation of phospholipase C, protein kinase C, and arachidonic acid production. Selbie, L.A., Darby, K., Schmitz-Peiffer, C., Browne, C.L., Herzog, H., Shine, J., Biden, T.J. J. Biol. Chem. (1995) [Pubmed]
  19. The antiparallel pancreatic polypeptide fold in the binding of neuropeptide Y to Y1 and Y2 receptors. Fuhlendorff, J., Johansen, N.L., Melberg, S.G., Thøgersen, H., Schwartz, T.W. J. Biol. Chem. (1990) [Pubmed]
  20. Localization and effects of neuropeptide Y, vasoactive intestinal polypeptide, substance P, and calcitonin gene-related peptide in human temporal arteries. Jansen, I., Uddman, R., Hocherman, M., Ekman, R., Jensen, K., Olesen, J., Stiernholm, P., Edvinsson, L. Ann. Neurol. (1986) [Pubmed]
  21. Multiple forms of pancreatic polypeptide-related compounds in the lamprey CNS: partial characterization and immunohistochemical localization in the brain stem and spinal cord. Brodin, L., Rawitch, A., Taylor, T., Ohta, Y., Ring, H., Hökfelt, T., Grillner, S., Terenius, L. J. Neurosci. (1989) [Pubmed]
  22. Contingent tolerance to the anticonvulsant effects of carbamazepine: relationship to loss of endogenous adaptive mechanisms. Weiss, S.R., Clark, M., Rosen, J.B., Smith, M.A., Post, R.M. Brain Res. Brain Res. Rev. (1995) [Pubmed]
  23. The neuropeptide Y Y1 antagonist, 1229U91, a potent agonist for the human pancreatic polypeptide-preferring (NPY Y4) receptor. Schober, D.A., Van Abbema, A.M., Smiley, D.L., Bruns, R.F., Gehlert, D.R. Peptides (1998) [Pubmed]
  24. Activation of extracellular signal regulated protein kinase by neuropeptide Y and pancreatic polypeptide in CHO cells expressing the NPY Y(1), Y(2), Y(4) and Y(5) receptor subtypes. Mullins, D.E., Zhang, X., Hawes, B.E. Regul. Pept. (2002) [Pubmed]
  25. Neuropeptide Y receptor in cultured vascular smooth muscle cells: ligand binding and increase in cytosolic free Ca2+. Mihara, S., Shigeri, Y., Fujimoto, M. Biochem. Int. (1990) [Pubmed]
  26. Influence of obesity and menopausal status on serum leptin, cholecystokinin, galanin and neuropeptide Y levels. Milewicz, A., Bidzińska, B., Mikulski, E., Demissie, M., Tworowska, U. Gynecol. Endocrinol. (2000) [Pubmed]
  27. The role of leptin in nutritional status and reproductive function. Keisler, D.H., Daniel, J.A., Morrison, C.D. J. Reprod. Fertil. Suppl. (1999) [Pubmed]
  28. Neuropeptide Y immunoreactivity is reduced in cerebral cortex in Alzheimer's disease. Beal, M.F., Mazurek, M.F., Chattha, G.K., Svendsen, C.N., Bird, E.D., Martin, J.B. Ann. Neurol. (1986) [Pubmed]
  29. Critical role of dipeptidyl peptidase IV in neuropeptide Y-mediated endothelial cell migration in response to wounding. Ghersi, G., Chen, W., Lee, E.W., Zukowska, Z. Peptides (2001) [Pubmed]
  30. Leptin receptor signaling and the regulation of mammalian physiology. Myers, M.G. Recent Prog. Horm. Res. (2004) [Pubmed]
  31. Neuropeptide Y inhibits spontaneous alpha-melanocyte-stimulating hormone (alpha-MSH) release via a Y(5) receptor and suppresses thyrotropin-releasing hormone-induced alpha-MSH secretion via a Y(1) receptor in frog melanotrope cells. Galas, L., Tonon, M.C., Beaujean, D., Fredriksson, R., Larhammar, D., Lihrmann, I., Jegou, S., Fournier, A., Chartrel, N., Vaudry, H. Endocrinology (2002) [Pubmed]
  32. Characterization of neuropeptide Y-mediated corticotropin-releasing factor synthesis and release from human placental trophoblasts. Robidoux, J., Simoneau, L., St-Pierre, S., Masse, A., Lafond, J. Endocrinology (2000) [Pubmed]
  33. Neuropeptide Y (NPY) shortens sleep latency but does not suppress ACTH and cortisol in depressed patients and normal controls. Held, K., Antonijevic, I., Murck, H., Kuenzel, H., Steiger, A. Psychoneuroendocrinology (2006) [Pubmed]
  34. Corticotropin-releasing factor and neuropeptide Y: role in emotional integration. Heilig, M., Koob, G.F., Ekman, R., Britton, K.T. Trends Neurosci. (1994) [Pubmed]
  35. Neuropeptide deficits in schizophrenia vs. Alzheimer's disease cerebral cortex. Gabriel, S.M., Davidson, M., Haroutunian, V., Powchik, P., Bierer, L.M., Purohit, D.P., Perl, D.P., Davis, K.L. Biol. Psychiatry (1996) [Pubmed]
  36. Expression of messenger ribonucleic acids encoding neuropeptide-Y, substance-P, and vasoactive intestinal polypeptide in human pituitary. Byrne, J.M., Jones, P.M., Hill, S.F., Bennet, W.M., Ghatei, M.A., Bloom, S.R. J. Clin. Endocrinol. Metab. (1992) [Pubmed]
  37. Role of neuropeptides in the regulation of feeding behavior: a review of cholecystokinin, bombesin, neuropeptide Y, and galanin. Lee, M.C., Schiffman, S.S., Pappas, T.N. Neuroscience and biobehavioral reviews. (1994) [Pubmed]
  38. Hypophysiotropic thyrotropin-releasing hormone-synthesizing neurons in the human hypothalamus are innervated by neuropeptide Y, agouti-related protein, and alpha-melanocyte-stimulating hormone. Mihály, E., Fekete, C., Tatro, J.B., Liposits, Z., Stopa, E.G., Lechan, R.M. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  39. Expression cloning of a human brain neuropeptide Y Y2 receptor. Gehlert, D.R., Beavers, L.S., Johnson, D., Gackenheimer, S.L., Schober, D.A., Gadski, R.A. Mol. Pharmacol. (1996) [Pubmed]
  40. The neuropeptide Y monomer in solution is not folded in the pancreatic-polypeptide fold. Bettio, A., Dinger, M.C., Beck-Sickinger, A.G. Protein Sci. (2002) [Pubmed]
  41. Neuropeptide Y and neuropeptide Y 3-36: isolation from human pancreatic endocrine tumours. Shaw, C., Cormican, K., Thim, L., Maule, A.G., Sloan, J.M., Buchanan, K.D. Regul. Pept. (1993) [Pubmed]
  42. Neuropeptide Y: presence in perivascular noradrenergic neurons and vasoconstrictor effects on skeletal muscle blood vessels in experimental animals and man. Pernow, J., Ohlén, A., Hökfelt, T., Nilsson, O., Lundberg, J.M. Regul. Pept. (1987) [Pubmed]
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