NeuropeptideY.com

A 36-amino-acid peptide, found in 1982

Neuropeptide Y was isolated from porcine brain and reported in Nature in 1982 by Tatemoto, Carlquist and Mutt.1 The same year Tatemoto published the full sequence: 36 amino acids, beginning and ending with tyrosine, with an amidated C-terminus.2 Tyrosine’s one-letter code is Y, and the NLM’s MeSH thesaurus still lists “neuropeptide tyrosine” as a synonym.5 The sequence is about 70% identical to peptide YY (PYY) and 50% to pancreatic polypeptide (PP), which is why the three are grouped as one peptide family.2

In humans the NPY gene sits at 7p15.34 and encodes a 97-residue precursor; the mature peptide is residues 29 to 64.3 UniProt describes it as one of the most abundant peptides in the nervous system.3

Where it is made

The first maps, by radioimmunoassay and immunocytochemistry, found NPY in cortical, limbic and hypothalamic regions of rat brain at concentrations above any peptide then known,6 and human brain gave the same picture, with dense NPY neurons in the basal ganglia, amygdala and nucleus accumbens.7 In the hypothalamic arcuate nucleus, NPY is co-expressed with agouti-related peptide (AgRP): AgRP cells make up about 95% of the arcuate NPY neurons, and both peptides drive feeding.8 Outside the brain, NPY was identified in peripheral noradrenergic neurons in 19829 and is now described as an abundant sympathetic co-transmitter;10 it is present in chromaffin cells of the adrenal medulla3 and in enteric neurons and primary afferent neurons of the gut.11

Five Y receptors, one family

NPY signals through G protein-coupled receptors. The IUPHAR/BPS Guide to Pharmacology lists Y1, Y2, Y4 and Y5 receptors plus a y6 receptor that is functional in mouse, absent in rat and non-functional in primates because of a frame-shift mutation.12 A receptor once called Y3 turned out to be the chemokine receptor CXCR4.12 The nomenclature dates from a 1998 IUPHAR committee report,13 six years after the first human Y receptor was cloned.14

All Y receptors respond to NPY, PYY and PP, but in different orders: Y1 and Y2 prefer NPY and PYY, Y4 prefers PP, and N-terminally shortened fragments such as NPY(3-36) and PYY(3-36) favour Y2.12 Receptor activation inhibits adenylyl cyclase and lowers cAMP.3 Three-dimensional structures have been solved for Y1, Y2 and Y4.12

What NPY does

The published physiology maps onto the fields a buyer of NeuropeptideY.com might work in:

• Feeding and energy balance. Injected into the brain, NPY induced feeding in every rat tested, three times the intake seen with pancreatic polypeptide.15 Light-activating only about 800 arcuate AgRP/NPY neurons evokes voracious feeding within minutes.16 NPY centrally promotes feeding and reduces energy expenditure, while PYY and PP signal satiety.17
• Stress and anxiety. NPY counters the behavioural effects of stress; Y1 stimulation is anxiolytic and Y2 activation anxiogenic.18 In soldiers at a military survival school, plasma NPY rose after interrogation stress and was higher in Special Forces soldiers,20 and reviews frame NPY as a candidate resilience factor in PTSD research.19
• Blood pressure and vessels. As a sympathetic co-transmitter NPY causes vasoconstriction and is studied in hypertension, ischaemia and heart failure.10 MeSH names vasoconstrictor and natriuretic activity in its definition.5
• Bone. Mice lacking Y2 receptors have twice the trabecular bone volume of controls, and deleting hypothalamic Y2 alone reproduces the effect.21 NPY knockout mice have increased bone mass, and osteoblasts themselves express NPY.22
• Circadian rhythm and excitability. NPY injected near the suprachiasmatic nucleus phase-shifts the circadian activity rhythm of hamsters.23 NCBI Gene lists circadian rhythms and cortical excitability among its influences,4 and NPY-deficient mice are more susceptible to seizures.26
• Angiogenesis and tumours. NPY is angiogenic through Y1 and Y2 receptors, and endothelium makes its own NPY.24 In neuroblastoma and Ewing sarcoma research, NPY acting on Y2 and Y5 receptors stimulates proliferation and vessel growth, and hypoxia turns the axis up.25

Drug development: what has been tried

For years NPY biology was hard to pin down because no antagonists existed,26 so receptor functions were worked out mainly in knockout and transgenic mice before selective agonists and antagonists arrived.29 Obesity was the obvious target. A selective, orally active Y5 antagonist reached a 52-week randomized, placebo-controlled trial in 1,661 overweight and obese adults; weight loss was statistically significant but not clinically meaningful, and the authors concluded that targeting Y5 alone was unlikely to work.27

The Y2 route came from the gut. PYY(3-36), released after meals in proportion to calories, is a Y2 agonist that inhibits food intake in rodents but not in Y2-null mice, and reduced intake in human volunteers by a third over 24 hours in a 2002 study.28 A 2010 review found no NPY receptor ligand yet approved as a medicine, while noting new small-molecule Y2 antagonists.30

How it is measured

Radioimmunoassays for NPY appeared within two years of its discovery; antisera raised to the C-terminus cross-react with PYY, so specific assays target the N-terminal region.31 Two-site enzyme immunoassays using paired monoclonal antibodies followed, with detection limits near 1 pM, and their authors warned that measured levels depend on sampling conditions.32 Radiolabelled PYY and NPY label Y1, Y2, Y5 and y6 receptors non-selectively, and a modified PP analogue labels Y5 preferentially.12 The standard animal tools are NPY knockout mice (normal intake and weight, hyperphagic after fasting, leptin-sensitive, seizure-prone),26 Y2 knockouts and conditional hypothalamic Y2 knockouts,21 and optogenetic control of AgRP/NPY neurons.16

Who builds around the name

Who publishes on neuropeptide Y is a fair guide to who might want NeuropeptideY.com:

• Peptide-research suppliers: synthetic NPY, fragments such as NPY(3-36) and PYY(3-36), receptor-selective analogues, radioligands, antibodies and immunoassay kits.1232
• Metabolic and obesity biotech working on Y receptors.2729
• Neuroscience and stress-biology groups, including PTSD and resilience research.1819
• Cardiovascular, bone and oncology research groups.102125
• Diagnostics and assay developers measuring NPY in plasma or tissue.2032
• A scientific society, review site or course, since the domain is the search term itself.

Neuropeptide Y, NPY, neuropeptide tyrosine

Journals write neuropeptide Y in full on first mention and NPY after that. The gene is NPY,4 and MeSH’s synonym is neuropeptide tyrosine.5 NeuropeptideY.com holds the spelled-out form, the one a non-specialist can read and a search engine can match.

1. Tatemoto K, Carlquist M, Mutt V. Neuropeptide Y: a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide.Nature, 1982
2. Tatemoto K. Neuropeptide Y: complete amino acid sequence of the brain peptide.Proceedings of the National Academy of Sciences, 1982
3. P01303, NPY_HUMAN: Pro-neuropeptide Y.UniProt
4. NPY neuropeptide Y [Homo sapiens], Gene ID 4852.NCBI Gene, National Library of Medicine
5. Neuropeptide Y, MeSH descriptor D009478.Medical Subject Headings, National Library of Medicine
6. Allen YS et al. Neuropeptide Y distribution in the rat brain.Science, 1983
7. Adrian TE et al. Neuropeptide Y distribution in human brain.Nature, 1983
8. Broberger C et al. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice.Proceedings of the National Academy of Sciences, 1998
9. Lundberg JM et al. Neuropeptide Y (NPY)-like immunoreactivity in peripheral noradrenergic neurons and effects of NPY on sympathetic function.Acta Physiologica Scandinavica, 1982
10. Tan CMJ et al. The role of neuropeptide Y in cardiovascular health and disease.Frontiers in Physiology, 2018
11. Holzer P, Reichmann F, Farzi A. Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis.Neuropeptides, 2012
12. Alexander SPH et al. The Concise Guide to Pharmacology 2023/24: G protein-coupled receptors, section Neuropeptide Y receptors.IUPHAR/BPS Guide to Pharmacology, British Journal of Pharmacology, 2023
13. Michel MC et al. XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors.Pharmacological Reviews, 1998
14. Blomqvist AG, Herzog H. Y-receptor subtypes: how many more?Trends in Neurosciences, 1997
15. Clark JT et al. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats.Endocrinology, 1984
16. Aponte Y, Atasoy D, Sternson SM. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training.Nature Neuroscience, 2011
17. Loh K, Herzog H, Shi YC. Regulation of energy homeostasis by the NPY system.Trends in Endocrinology and Metabolism, 2015
18. Reichmann F, Holzer P. Neuropeptide Y: a stressful review.Neuropeptides, 2016
19. Sah R, Geracioti TD. Neuropeptide Y and posttraumatic stress disorder.Molecular Psychiatry, 2013
20. Morgan CA et al. Plasma neuropeptide-Y concentrations in humans exposed to military survival training.Biological Psychiatry, 2000
21. Baldock PA et al. Hypothalamic Y2 receptors regulate bone formation.Journal of Clinical Investigation, 2002
22. Baldock PA et al. Neuropeptide Y knockout mice reveal a central role of NPY in the coordination of bone mass to body weight.PLoS One, 2009
23. Albers HE, Ferris CF. Neuropeptide Y: role in light-dark cycle entrainment of hamster circadian rhythms.Neuroscience Letters, 1984
24. Zukowska-Grojec Z et al. Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium.Circulation Research, 1998
25. Tilan J, Kitlinska J. Neuropeptide Y (NPY) in tumor growth and progression: lessons learned from pediatric oncology.Neuropeptides, 2016
26. Erickson JC, Clegg KE, Palmiter RD. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y.Nature, 1996
27. Erondu N et al. Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults.Cell Metabolism, 2006
28. Batterham RL et al. Gut hormone PYY(3-36) physiologically inhibits food intake.Nature, 2002
29. Yulyaningsih E et al. NPY receptors as potential targets for anti-obesity drug development.British Journal of Pharmacology, 2011
30. Brothers SP, Wahlestedt C. Therapeutic potential of neuropeptide Y (NPY) receptor ligands.EMBO Molecular Medicine, 2010
31. Allen JM et al. Radioimmunoassay of neuropeptide Y.Regulatory Peptides, 1984
32. Grouzmann E et al. A sensitive and specific two-site, sandwich-amplified enzyme immunoassay for neuropeptide Y.Peptides, 1992