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Pancreatic polypeptide, peptide YY, and neuropeptide Y

Rodger A Liddle, MD
Section Editor
J Thomas Lamont, MD
Deputy Editor
Shilpa Grover, MD, MPH, AGAF


Originally isolated in 1968 during the preparation of insulin, pancreatic polypeptide (PP) is the founding member of the pancreatic polypeptide family [1,2]. The PP family of peptides includes peptide YY (PYY) and neuropeptide Y (NPY), which were discovered based upon their chemical structure (possessing a carboxyl-terminal tyrosine amide) [3-5]. PP, PYY, and NPY are all 36 amino acids in length, and despite structural similarities, they are found in different locations throughout the gastrointestinal tract and nervous system and possess different biological actions. PP is expressed in endocrine cells of the gut and pancreas, PYY is located in enteroendocrine cells of the ileum and colon and nerves of the enteric nervous system, and NPY is found in the central and peripheral nervous system. This wide distribution suggests that these peptides regulate many different physiological processes.


The pancreatic polypeptide (PP) peptides share a significant degree of sequence homology that produces a polyproline helix, an amphipathic alpha-helix, and an amidated carboxyl terminus, resulting in a hairpin fold known as the PP-fold (figure 1) [6]. Although unusual for small peptides, it is believed that this tertiary structure is important for the peptides' biological activities.


Pancreatic polypeptide (PP) is secreted by specialized pancreatic islet cells (PP cells) that are distinct from those producing insulin, glucagon, or somatostatin [7].

Neuropeptide Y (NPY) is a principal neurotransmitter found in the central and peripheral nervous systems and is predominantly found in sympathetic neurons [8-10].

Peptide YY (PYY) has been localized to enteroendocrine cells in the mucosa of the gastrointestinal tract and is most highly concentrated in the ileum and colon [11]. PYY is produced by two different cell types within the intestine, namely, L cells where it is colocalized with enteroglucagon and H cells of the colon and rectum. It has long been held that enteroendocrine cells are elongated or "flask"-shaped cells that reside in the intestinal mucosa with their apical surface open to the lumen of the intestine. In this position, enteroendocrine cells can "sense" luminal contents such as food or bacteria. Stimulation of cells causes the release of hormones from the basal surface into the paracellular space, where they are taken up by blood vessels and carried to distant sites of action. However, a new concept for enteroendocrine cell function is now apparent with the discovery that PYY cells possess neuropods that extend from their basal surface (figure 2) [12,13]. Neuropods contain many features typical of neurons, including synaptic boutons, neurofilaments, pre- and post-synaptic proteins, and small, clear synaptic vesicles. Moreover, it has been discovered that enteroendocrine cells connect directly with enteric nerves [14]. This new epithelial-neural circuit provides a pathway for the gut to connect directly to the brain. It is possible that this pathway is involved in how the brain senses gut contents.

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Literature review current through: Nov 2017. | This topic last updated: Sep 06, 2017.
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  1. Kimmel JR, Pollock HG, Hazelwood RL. Isolation and characterization of chicken insulin. Endocrinology 1968; 83:1323.
  2. Kimmel JR, Hayden LJ, Pollock HG. Isolation and characterization of a new pancreatic polypeptide hormone. J Biol Chem 1975; 250:9369.
  3. Tatemoto K, Mutt V. Chemical determination of polypeptide hormones. Proc Natl Acad Sci U S A 1978; 75:4115.
  4. Tatemoto K. Neuropeptide Y: complete amino acid sequence of the brain peptide. Proc Natl Acad Sci U S A 1982; 79:5485.
  5. Tatemoto K, Carlquist M, Mutt V. Neuropeptide Y--a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature 1982; 296:659.
  6. Cabrele C, Beck-Sickinger AG. Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family. J Pept Sci 2000; 6:97.
  7. Larsson LI, Sundler F, Håkanson R. Pancreatic polypeptide - a postulated new hormone: identification of its cellular storage site by light and electron microscopic immunocytochemistry. Diabetologia 1976; 12:211.
  8. Wahlestedt C, Reis DJ. Neuropeptide Y-related peptides and their receptors--are the receptors potential therapeutic drug targets? Annu Rev Pharmacol Toxicol 1993; 33:309.
  9. Allen YS, Adrian TE, Allen JM, et al. Neuropeptide Y distribution in the rat brain. Science 1983; 221:877.
  10. Adrian TE, Allen JM, Bloom SR, et al. Neuropeptide Y distribution in human brain. Nature 1983; 306:584.
  11. Lundberg JM, Tatemoto K, Terenius L, et al. Localization of peptide YY (PYY) in gastrointestinal endocrine cells and effects on intestinal blood flow and motility. Proc Natl Acad Sci U S A 1982; 79:4471.
  12. Bohórquez DV, Chandra R, Samsa LA, et al. Characterization of basal pseudopod-like processes in ileal and colonic PYY cells. J Mol Histol 2011; 42:3.
  13. Bohórquez DV, Samsa LA, Roholt A, et al. An enteroendocrine cell-enteric glia connection revealed by 3D electron microscopy. PLoS One 2014; 9:e89881.
  14. Bohórquez DV, Shahid RA, Erdmann A, et al. Neuroepithelial circuit formed by innervation of sensory enteroendocrine cells. J Clin Invest 2015; 125:782.
  15. Michel MC, Beck-Sickinger A, Cox H, et al. XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev 1998; 50:143.
  16. Eva C, Keinänen K, Monyer H, et al. Molecular cloning of a novel G protein-coupled receptor that may belong to the neuropeptide receptor family. FEBS Lett 1990; 271:81.
  17. Rose PM, Fernandes P, Lynch JS, et al. Cloning and functional expression of a cDNA encoding a human type 2 neuropeptide Y receptor. J Biol Chem 1995; 270:29038.
  18. Lee CC, Miller RJ. Is there really an NPY Y3 receptor? Regul Pept 1998; 75-76:71.
  19. Bard JA, Walker MW, Branchek TA, Weinshank RL. Cloning and functional expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY. J Biol Chem 1995; 270:26762.
  20. Weinberg DH, Sirinathsinghji DJ, Tan CP, et al. Cloning and expression of a novel neuropeptide Y receptor. J Biol Chem 1996; 271:16435.
  21. Mullins DE, Guzzi M, Xia L, Parker EM. Pharmacological characterization of the cloned neuropeptide Y y(6) receptor. Eur J Pharmacol 2000; 395:87.
  22. Taylor IL, Impicciatore M, Carter DC, Walsh JH. Effect of atropine and vagotomy on pancreatic polypeptide response to a meal in dogs. Am J Physiol 1978; 235:E443.
  23. Chen MH, Joffe SN, Magee DF, et al. Cyclic changes of plasma pancreatic polypeptide and pancreatic secretion in fasting dogs. J Physiol 1983; 341:453.
  24. Holzer P, Farzi A. Neuropeptides and the microbiota-gut-brain axis. Adv Exp Med Biol 2014; 817:195.
  25. Taylor IL. Distribution and release of peptide YY in dog measured by specific radioimmunoassay. Gastroenterology 1985; 88:731.
  26. Adrian TE, Ferri GL, Bacarese-Hamilton AJ, et al. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 1985; 89:1070.
  27. Ballantyne GH. Peptide YY(1-36) and peptide YY(3-36): Part II. Changes after gastrointestinal surgery and bariatric surgery. Obes Surg 2006; 16:795.
  28. Shah U, Kowalski TJ. GPR119 agonists for the potential treatment of type 2 diabetes and related metabolic disorders. Vitam Horm 2010; 84:415.
  29. Wheway J, Mackay CR, Newton RA, et al. A fundamental bimodal role for neuropeptide Y1 receptor in the immune system. J Exp Med 2005; 202:1527.
  30. Clarke G, Stilling RM, Kennedy PJ, et al. Minireview: Gut microbiota: the neglected endocrine organ. Mol Endocrinol 2014; 28:1221.
  31. Lin TM, Evans DC, Chance RE, Spray GF. Bovine pancreatic peptide: action on gastric and pancreatic secretion in dogs. Am J Physiol 1977; 232:E311.
  32. Hazelwood RL. The pancreatic polypeptide (PP-fold) family: gastrointestinal, vascular, and feeding behavioral implications. Proc Soc Exp Biol Med 1993; 202:44.
  33. Adrian TE, Mitchenere P, Sagor G, Bloom SR. Effect of pancreatic polypeptide on gallbladder pressure and hepatic bile secretion. Am J Physiol 1982; 243:G204.
  34. Asakawa A, Inui A, Yuzuriha H, et al. Characterization of the effects of pancreatic polypeptide in the regulation of energy balance. Gastroenterology 2003; 124:1325.
  35. Lloyd KC, Grandt D, Aurang K, et al. Inhibitory effect of PYY on vagally stimulated acid secretion is mediated predominantly by Y1 receptors. Am J Physiol 1996; 270:G123.
  36. Sheikh SP. Neuropeptide Y and peptide YY: major modulators of gastrointestinal blood flow and function. Am J Physiol 1991; 261:G701.
  37. Wen J, Phillips SF, Sarr MG, et al. PYY and GLP-1 contribute to feedback inhibition from the canine ileum and colon. Am J Physiol 1995; 269:G945.
  38. Mannon P, Taylor IL. The Pancreatic Polypeptide Family. In: Gut Peptides, Biochemistry and Physiology, Walsh JH, Dockray JG (Eds), Raven Press Ltd, New York 1994. p.341.
  39. Näslund E, Kral JG. Impact of Gastric Bypass Surgery on Gut Hormones and Glucose Homeostasis in Type 2 Diabetes. Diabetes 2006; 55:S2.
  40. Sala PC, Torrinhas RS, Giannella-Neto D, Waitzberg DL. Relationship between gut hormones and glucose homeostasis after bariatric surgery. Diabetol Metab Syndr 2014; 6:87.
  41. Hwa JJ, Witten MB, Williams P, et al. Activation of the NPY Y5 receptor regulates both feeding and energy expenditure. Am J Physiol 1999; 277:R1428.
  42. Loh K, Herzog H, Shi YC. Regulation of energy homeostasis by the NPY system. Trends Endocrinol Metab 2015; 26:125.
  43. Pheng LH, Regoli D. Receptors for NPY in peripheral tissues bioassays. Life Sci 2000; 67:847.
  44. Dimitrijević M, Stanojević S, Vujić V, et al. Neuropeptide Y and its receptor subtypes specifically modulate rat peritoneal macrophage functions in vitro: counter regulation through Y1 and Y2/5 receptors. Regul Pept 2005; 124:163.
  45. Ueno N, Inui A, Iwamoto M, et al. Decreased food intake and body weight in pancreatic polypeptide-overexpressing mice. Gastroenterology 1999; 117:1427.
  46. Boey D, Lin S, Enriquez RF, et al. PYY transgenic mice are protected against diet-induced and genetic obesity. Neuropeptides 2008; 42:19.
  47. Boey D, Lin S, Karl T, et al. Peptide YY ablation in mice leads to the development of hyperinsulinaemia and obesity. Diabetologia 2006; 49:1360.
  48. Inui A. Neuropeptide Y feeding receptors: are multiple subtypes involved? Trends Pharmacol Sci 1999; 20:43.
  49. Kuo LE, Kitlinska JB, Tilan JU, et al. Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med 2007; 13:803.
  50. Broom DR, Batterham RL, King JA, Stensel DJ. Influence of resistance and aerobic exercise on hunger, circulating levels of acylated ghrelin, and peptide YY in healthy males. Am J Physiol Regul Integr Comp Physiol 2009; 296:R29.
  51. Marsh DJ, Hollopeter G, Kafer KE, Palmiter RD. Role of the Y5 neuropeptide Y receptor in feeding and obesity. Nat Med 1998; 4:718.
  52. Pedrazzini T, Seydoux J, Künstner P, et al. Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor. Nat Med 1998; 4:722.
  53. Naveilhan P, Hassani H, Canals JM, et al. Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor. Nat Med 1999; 5:1188.
  54. Nguyen AD, Herzog H, Sainsbury A. Neuropeptide Y and peptide YY: important regulators of energy metabolism. Curr Opin Endocrinol Diabetes Obes 2011; 18:56.
  55. Shintani M, Ogawa Y, Ebihara K, et al. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 2001; 50:227.
  56. Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature 2001; 409:194.
  57. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402:656.
  58. Inui A. Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2001; 2:551.
  59. Strader AD, Woods SC. Gastrointestinal hormones and food intake. Gastroenterology 2005; 128:175.
  60. Batterham RL, Cohen MA, Ellis SM, et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 2003; 349:941.
  61. Nguo K, Walker KZ, Bonham MP, Huggins CE. Systematic review and meta-analysis of the effect of meal intake on postprandial appetite-related gastrointestinal hormones in obese children. Int J Obes (Lond) 2016; 40:555.
  62. Ahituv N, Kavaslar N, Schackwitz W, et al. A PYY Q62P variant linked to human obesity. Hum Mol Genet 2006; 15:387.
  63. Stadlbauer U, Woods SC, Langhans W, Meyer U. PYY3-36: Beyond food intake. Front Neuroendocrinol 2015; 38:1.
  64. Duarte-Neves J, Pereira de Almeida L, Cavadas C. Neuropeptide Y (NPY) as a therapeutic target for neurodegenerative diseases. Neurobiol Dis 2016; 95:210.
  65. Tasan RO, Verma D, Wood J, et al. The role of Neuropeptide Y in fear conditioning and extinction. Neuropeptides 2016; 55:111.
  66. Persaud SJ, Bewick GA. Peptide YY: more than just an appetite regulator. Diabetologia 2014; 57:1762.
  67. Muller KE, Tafe LJ, Gonzalez JL, et al. Ovarian strumal carcinoid producing peptide YY associated with severe constipation: a case report and review of the literature. Int J Gynecol Pathol 2015; 34:30.