NPY (neuropeptide Y)

2009-05-01 Massimiliano Ruscica , Elena Dozio , Paolo Magni Affiliation

Identity

HGNC

NPY

LOCATION

7p15.3

LOCUSID

4852

ALIAS

PYY4

FUSION GENES

Show Gene Fusions

DNA/RNA

Note

History: NPY, first discovered in 1982 from pig brain, has been characterized as one of the most highly conserved neuroendocrine peptides throughout evolution. Its name derives from the single-letter code (Y) for the amino acid (aa) tyrosine, since it contains five tyrosine residues including an amidated C-terminal tyrosine residue. Moreover, there is 92% aa sequence identity for NPY between the cartilaginous fish, Torpedo marmorata, and mammals, which are separated by an evolutionary distance of more than 400 million years. These evidences indicate that NPY presumably has a critical physiological function and that interindividual variation at this locus is likely to be minimal. The NPY gene is about 8 kilobases (kb) in length with four small exons (each,

Description

NPY encompasses 7,669 bp of DNA on chromosome 7 (7p15.1) between 24290334 and 24298002 from pter.

Transcription

The NPY RNA transcript contains 4 exons and it is 551 bp, in lenght. In details, Exon 1 (86 bp) contains the 5-UTR, Exon 2 (188 bp) encodes the signal peptide and the main part of the mature NPY sequence, except the last base of arginine codon 35 and the last tyrosine codon. Exon 3 (82 bp) contains the last base of the arginine codon, the last tyrosine codon from the mature peptide, the glycine amide donor site, the dibasic cleavage site, and the main portion of C-terminal flanking peptide of NPY (CPON). Finally, Exon 4 (21 + 174 bp) includes the end of CPON and the 3-UTR.

Proteins

Description

The coding sequence (291 bp) of NPY gene synthetizes the pre-pro NPY (see diagram), a precursor peptide of 97 aa residues (size 10.8 kDa), which is cleaved after 28-aa, resulting in the pro-NPY, a 69-aa peptide. Pro-NPY undergoes cleavage by the proconverting enzymes (PC)1/3 and/or PC2 at a single dibasic site (Lys³⁸-Arg³⁹), releasing a 30-aa carboxyl terminal peptide, the C-flanking peptide of NPY (CPON), with so far unknown function and NPY1-39, which is further processed by a carboxypeptidase-like enzyme. The resulting NPY1-37 is finally amidated at its C-terminal end by the peptidylglycine-amidating monooxygenase (PAM) in a process that removes an additional aa (glycine) and produces the mature and biologically active peptide NPY1-36. Moreover, NPY can be further process, by two enzymes, dipeptidyl peptidase IV (DPPIV) and aminopeptidase P, into NPY3-36 and NPY2-36, respectively. NPY exhibits a three-dimensional structure called PP-fold, which is characterized by a harpin-like structure and by a type II beta-turn, connecting a polyproline-like type II helix (residues 14 to 30), thus leading to a close proximity of N- and C-terminal ends of the peptide.

A schematic drawing of 97 aa pre-pro NPY which is further process up to the release of the mature and biologically active peptide NPY1-36 and the 30-aa CPON peptide.

Expression

The 36-aa NPY is one of the most abundant peptides expressed in numerous brain regions (i.e, hypothalamus, amygdala, hippocampus and cerebral cortex), as well as in the periphery (i.e, liver, heart, spleen, endothelial cells of blood vessels), showing both pre- and post-synaptic actions. However, the adrenal medulla is the primary source of circulating NPY.
In details, in the brain, it is synthesized by neurons of the arcuate (ARC) nucleus and it is active on the paraventricular (PVN), on the dorsomedial (DMN) nucleus, and on the A1 and C1 areas of the median preoptic area. In particular, in human, high levels of NPY mRNA were found in the dentate gyrus, caudate nucleus and putamen. In cerebral cortex the amount of NPY-immunoreactivity (NPY-ir) is present at the highest concentration in the cingulated and temporal cortices and at the lowest in the occipital lobe. NPY-labeled cells are also found in subcortical white matter, whereas this expression is negative in white matter areas away from the cortex. The striatum shows heterogeneous levels of NPY mRNA with a higher expression in the nucleus accumbens and the ventral region of the caudate. In general, NPY neurons also coexpress various neurotransmitters. In fact, ARC NPY subpopulation coexpresses the neuropeptide agouti-related peptide (AgRP) and the amino acid gamma-aminobutyric acid (GABA), whereas the brain stem subpopulation coexpresses the adrenergic transmitters, epinephrine and norepinephrine.
In the periphery, NPY is expressed in the sympathetic nervous system, co-stored and co-released with norepinephrine, as well as in non-sympathetic neurons in several organs including gastrointestinal tract, salivary glands, thyroid gland, pancreas, urogenital system, Schwann cells and heart. NPY is also present in cholinergic and non-cholinergic neurons (both central and peripheral) with anti-depressant, anti-convulsant and anti-nociceptive actions. In the mammalian intestine, NPY is present in both myenteric and submucous neurones that provide an extensive intrinsic innervation to smooth muscle layers and mucosal targets, respectively. NPY has been detected in glial cells and in olfactory Schwann cells, thereby potentially affording trophic support. NPY-ir appears mainly found in the renal tubules, whereas it seems absent in the glomerules. Interestingly, in infant colon, 41% of submucous plexus (a combination of Henles, intermediate and Meissners plexi) cell bodies are NPY-positive and co-localised with nitric oxide synthase immunoreactivity.

Localisation

Stored in cytoplasmatic secretory granules within the cell body and peptidergic nerve terminals. It is secreted upon specific stimuli.

Function

NPY has been involved in the regulation of a wide range of physiological central effects like the control of appetite, body weight homeostasis, the modulation of reproductive processes, the regulation of growth hormone secretion. Moreover, it is involved in the anxyolytic effect and sedation, in the endogenous anticonvulsant activity, in the circadian rhythm regulation, in learning and memory, in analgesia and hyperalgesia.
1) Food Intake
Being NPY a very potent stimulant of food ingestion, and mainly of carbohydrates, among these NPY-mediated actions, the major one is its role in the control of appetite, body weight homeostasis, and obesity. All these functions are mediated in humans by different receptor subtypes, so-called Y receptors: Y1-R, Y2-R, Y4-R, Y5-R and y6-R (a pseudogene in primates, with no shown activity as yet), which all belong to the large family of Gi-protein coupled receptors.
2) Cardiovascular function
NPY has also been described to mediate peripheral effects including the regulation of the cardiovascular system, vasoconstriction, the release of catecholamines by the adrenal medulla and vascular motility. About 25% of patients with acute heart failure were found to display an increase in circulating NPY levels. NPY has been proposed to be an useful marker for estimating the condition of patients suffering from cardiac diseases. In fact, plasma NPY immunoreactivity appeared elevated in patients with acute myocardial ischemia and in those with congestive heart failure. Moreover, NPY appears to enhance diuresis and natriuresis through direct tubular effects independent of its hemodynamic properties.
The vasopressive properties of NPY as well as its capacity to potentiate adrenergic responsiveness suggests that this peptide might be beneficial in the management of endotoxic shock. Indeed, in humans experiencing sepsis and septic shock, plasma levels of NPY are significantly increased and NPY-mediated vasoconstriction was shown to be preserved during endotoxemia.
3) Cancer
Besides these physiological events, in the context of the biology of cancer progression, recent evidence has extended the oncological relevance of NPY to endocrine-related cancers (see below).

Homology

The alignment of mature tetrapod NPY sequences reveals constant positions (91% identity) and only 4 positions are allowed to vary. In particular, amphibians sequences display an Arg-Lys replacement at position 19, porcine and bovine a Lys-Met replacement at position 17, ovine an Asp-Glu replacement at position 10, and chicken an Asn-Ser replacement at position 7. On the contrary, identical sequences of human mature NPY have been found in monkey, rat, rabbit, guinea pig, and alligator.

Mutations

Note

So far, in the literature there are many evidence which connect NPY and NPY receptors to a condition or disease, like hyperlipidemia, enhanced rate of atherosclerosis, increased body mass index (BMI), higher birth weigh, as well as alcohol dependence, depression and schizophrenia. To date there are reported only two non-synonymous sequence variants in the signal sequence part of NPY gene (p.L7P; 7th aa of the preproNPY, leucine, is changed to proline; rs16139) and c.64C>A (p.L22M; 22nd aa of the preproNPY, leucine, is changed to methionine; rs5571). The single nucleotide polymorphism (SNP) L7P was originally discovered in 1998 in Finnish and Dutch populations. It varies from 6% to 15% in the Caucasian populations and it seems to be totally absent or extremely low in oriental populations. L7P substitution is located in the signal peptide part of preproNPY and it is due to a single base substitution c.20T>C.

Implicated in

Entity name

Endocrine-related cancers

Note

Endocrine-related cancers are malignancies depending at least in part upon the trophic effect of specific hormones, and include breast, ovarian and prostate cancers, and to endocrine (pituitary tumors, adrenocortical lesions) and neuroendocrine (pheochromocytoma, neuroblastoma, gastroenteropancreatic tumors-PETs) tumors.

Oncogenesis

The involvement of NPY and NPY receptors (NPY-Rs) in the progression of endocrine-related cancers may be associated with: (a) expression of NPY-Rs in the context of the tumor, thus becoming a target of extratumorally secreted NPY proximal to the tumor. In this context, the presence of NPY-Rs may be targeted by specific drugs with either agonist or antagonist activity or by radiolabeled compounds (the universal ligand ¹²⁵I-labeled PYY, the selective Y1-R ¹²⁵I-labeled [Leu31, Pro34]-PYY and the selective Y2-R ¹²⁵I-labeled PYY3-36); (b) in situ production of NPY. Tumor-produced NPY may act locally in a paracrine fashion and/or reach the bloodstream and generate systemic effects. The measurement of NPY plasma levels may have the value of a diagnostic marker; (c) a combination of expression of NPY-Rs and local production of NPY by the tumor. NPY effects may result in either promotion or suppression of cancer growth through paracrine mechanisms.
NPY is then involved in specific steps of cancer progression, like cell proliferation, matrix invasion, metastatization, and angiogenesis. Proliferative or anti-proliferative effects of NPY have been shown in different cell systems and appear mediated mainly through the Y1-R, which has been involved in the control of the proliferation of vascular smooth muscle and endothelial cells and injured glial cells. NPY has also been found to modulate the proliferation of hepatic stellate cells and neural crest-derived tumors.
NPY significantly enhances also angiogenesis in various ex vivo and in vivo models of angiogenesis, such as aortic sprouting, Matrigel plug assay, and ischemic hind limb revascularization. NPY-driven angiogenesis has been proposed to be bimodal at least in vitro (at low and high concentration, 10^-12 and 10^-8 M, respectively) and through oligomerization of Y1-, Y2-, and Y5-R. These data might explain the in vivo NPY-induced angiogenesis both in tissues that contain low NPY concentrations, such as the nonsympathetically innervated aorta or growing organs lacking a mature NPY system and in tissues containing high NPY concentrations, such as the heart, mature vessels or muscles during high sympathetic activity induced by stress, ischemia, or injury. Nevertheless, by using an in vitro assay to test the multistage process of metastasis (cell attachment to extracellular matrix (ECM), enzymatic degradation of ECM, and migration to fibronectin) it has been demonstrated that NPY affects tumor matrix invasion. In particular, it inhibits the invasion of murine Colon 26-L5 adenocarcinoma cells through a reconstituted basement membrane, whereas on both the DU145 and PC-3 human androgen independent prostate cancer cells it was not. In none of the tumor cell lines considered, as neither on LNCaP human androgen dependent prostate cancer cells NPY enhanced the haptotactic migration.

Entity name

Atherosclerosis

Note

In 1998 it has been reported that the P7 allele (p.P7) in the NPY signalling peptide could be a strongest genetic factor influencing serum cholesterol and low density lipo-protein (LDL) levels in obese subject. Two independent studies showed that: a) men with P7 substitution had a four-year increase in the mean and maximal common carotid intima-media thickness (IMT), b) increased carotid IMT in type 2 diabetes patients, c) obese subject with BMI> 30 Kg/m2 had increased serum total cholesterol and LDL cholesterol. On the contrary, in 443 children with a family history of cardiovascular disease (CVD) the Leu7Pro polymorphism was not associated with serum lipid values after adjustment for body weight in boys or girls, but may be associated with dietary response to LDL-cholesterol concentration in overweight boys with a family history of early-onset CVD.

Entity name

Obesity

Note

Although the role of NPY in the regulation of human feeding is not fully clear and there are several negative studies, in 2005 a study conducted on Dutch population of non-obese subjects, highlighted that both men and women, carried the L7P substitution, had higher mean BMI values. On the other hand, one conflicting study associated the p.L7P with lower BMI in premenopausal women.

Entity name

Diabetes

Note

The L7P polymorphism has been associated with onset of type 2 diabetes, impaired glucose tolerance and with a worse glycaemic balance in type 1 diabetic patients as measured by HbA1c levels. In addition, the preproNPY Pro7 carrier status, in middle-aged subjects, was a significant risk factor for type II diabetes and they were more insulin resistant and showed lower ghrelin levels compared to non-carriers. In general, healthy subjects with p.P7 allele have higher glucose, lower insulin and lower insulin/glucose ratio during rest, after meals, and during exercise.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
7529863	1995	Changes in plasma concentrations of vasoactive neuropeptides in patients with sepsis and septic shock.	Arnalich F et al
11207429	2000	Characterization of NPY mRNA-expressing cells in the human brain: co-localization with Y2 but not Y1 mRNA in the cerebral cortex, hippocampus, amygdala, and striatum.	Caberlotto L et al
12438144	2002	Catecholamine and neuropeptide Y secretion from human adrenal chromaffin cells: effect of nicotine and KCl.	Cavadas C et al
10949087	2000	Neuropeptide Y family of peptides: structure, anatomical expression, function, and molecular evolution.	Cerdá-Reverter JM et al
2417205	1985	Anatomy and physiology of the neuroendocrine arcuate nucleus.	Chronwall BM et al
9067840	1997	Laminar distribution of neuropeptide Y-immunoreactive neurons in human prefrontal cortex during development.	Delalle I et al
1312243	1992	Neuropeptide Y and neuropeptide Y receptor subtypes in brain and peripheral tissues.	Dumont Y et al
15337366	2004	Introduction to the reviews on neuropeptide Y.	Gehlert DR et al
7989494	1994	Angiotensin-II mediates norepinephrine and neuropeptide-Y secretion in a human pheochromocytoma.	Grouzmann E et al
10841982	2000	The leucine (7)-to-proline (7) polymorphism in the signal peptide of neuropeptide Y is not associated with Alzheimer's disease or the link apolipoprotein E.	Helisalmi S et al
11701704	2001	Enhanced exercise-induced GH secretion in subjects with Pro7 substitution in the prepro-NPY.	Kallio J et al
11689216	2001	Leucine7 to proline7 polymorphism in the preproneuropeptide Y is associated with the progression of carotid atherosclerosis, blood pressure and serum lipids in Finnish men.	Karvonen MK et al
3516312	1986	Effects of monosodium L-glutamate administration on neuropeptide Y-containing neurons in the rat hypothalamus.	Kerkérian L et al
15753367	2005	Differential effects of neuropeptide Y on the growth and vascularization of neural crest-derived tumors.	Kitlinska J et al
8738876	1996	Evolution of neuropeptide Y, peptide YY and pancreatic polypeptide.	Larhammar D et al
12576090	2003	Impaired angiogenesis in neuropeptide Y (NPY)-Y2 receptor knockout mice.	Lee EW et al
9401585	1997	Time-dependent effects of ischaemia on neuropeptide Y mechanisms in pig renal vascular control in vivo.	Malmström RE et al
12187394	2002	Association analysis of genes involved in the leptin-signaling pathway with obesity in Brazil.	Mattevi VS et al
6589611	1984	Cloning, characterization, and DNA sequence of a human cDNA encoding neuropeptide tyrosine.	Minth CD et al
11240828	2001	Effect of prostatic neuropeptides on migration of prostate cancer cell lines.	Nagakawa O et al
7523222	1994	Neural sites of the human colon colocalize nitric oxide synthase-related NADPH diaphorase activity and neuropeptide Y.	Nichols K et al
15926114	2005	Leu7Pro polymorphism in the neuropeptide Y (NPY) gene is associated with impaired glucose tolerance and type 2 diabetes in Swedish men.	Nordman S et al
12678499	2003	Neuropeptide Y: the universal soldier.	Pedrazzini T et al
14747236	2004	Leucine 7 to proline 7 polymorphism in the preproneuropeptide Y is associated with proteinuria, coronary heart disease, and glycemic control in type 1 diabetic patients.	Pettersson-Fernholm K et al
17204352	2007	Role of neuropeptide Y and its receptors in the progression of endocrine-related cancer.	Ruscica M et al
18279562	2008	Leucine 7 to proline 7 polymorphism in the neuropeptide Y gene and changes in serum lipids during a family-based counselling intervention among school-aged children with a family history of CVD.	Salminen M et al
3840810	1985	Colocalization of neuropeptide Y immunoreactivity in brainstem catecholaminergic neurons that project to the paraventricular nucleus of the hypothalamus.	Sawchenko PE et al
2174222	1990	Signal epitopes in the three-dimensional structure of neuropeptide Y. Interaction with Y1, Y2, and pancreatic polypeptide receptors.	Schwartz TW et al
9243515	1997	Clonidine administration increases neuropeptide Y immunoreactivity and neuropeptide Y mRNA in the rat cerebral cortex neurons.	Smiałowska M et al
2475884	1989	Innervation of the thyroid. A study of the rat using retrograde tracing and immunocytochemistry.	Sundler F et al
6896083	1982	Neuropeptide Y--a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide.	Tatemoto K et al
14585600	2003	'Neuro'-peptides in glia: focus on NPY and galanin.	Ubink R et al
17268419	2007	Leu7Pro polymorphism of PreproNPY associated with an increased risk for type II diabetes in middle-aged subjects.	Ukkola O et al
2280235	1990	Elevation of plasma neuropeptide Y-like immunoreactivity and noradrenaline during myocardial ischaemia in man.	Ullman B et al
3351430	1988	Plasma levels of neuropeptide tyrosine Y (NPY) are increased in human sepsis but are unchanged during canine endotoxin shock despite raised catecholamine concentrations.	Watson JD et al
8472845	1993	Efficient amidation of C-peptide deleted NPY precursors by non-endocrine cells is affected by the presence of Lys-Arg at the C-terminus.	Wulff BS et al
10342879	1999	Daily changes in hypothalamic gene expression of neuropeptide Y, galanin, proopiomelanocortin, and adipocyte leptin gene expression and secretion: effects of food restriction.	Xu B et al
9686758	1998	Neuropeptide Y: a novel angiogenic factor from the sympathetic nerves and endothelium.	Zukowska-Grojec Z et al
16568137	2006	Polymorphisms in the NPY and AGRP genes and body fatness in Dutch adults.	van Rossum CT et al
12740814	2003	Semisynthesis and characterization of the first analogues of pro-neuropeptide y.	von Eggelkraut-Gottanka R et al

Other Information

Locus ID:

NCBI: 4852
MIM: 162640
HGNC: 7955
Ensembl: ENSG00000122585

Variants:

dbSNP: 4852
ClinVar: 4852
TCGA: ENSG00000122585
COSMIC: NPY

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000122585	ENST00000242152	P01303
ENSG00000122585	ENST00000242152	A4D158
ENSG00000122585	ENST00000405982	P01303
ENSG00000122585	ENST00000405982	A4D158
ENSG00000122585	ENST00000407573	P01303
ENSG00000122585	ENST00000407573	A4D158

Expression (GTEx)

100

150

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Adipocytokine signaling pathway	KEGG	ko04920
Adipocytokine signaling pathway	KEGG	hsa04920
Alcoholism	KEGG	hsa05034
Alcoholism	KEGG	ko05034
cAMP signaling pathway	KEGG	hsa04024
cAMP signaling pathway	KEGG	ko04024
Regulation of lipolysis in adipocytes	KEGG	hsa04923
Signal Transduction	REACTOME	R-HSA-162582
Signaling by GPCR	REACTOME	R-HSA-372790
GPCR ligand binding	REACTOME	R-HSA-500792
Class A/1 (Rhodopsin-like receptors)	REACTOME	R-HSA-373076
Peptide ligand-binding receptors	REACTOME	R-HSA-375276
GPCR downstream signaling	REACTOME	R-HSA-388396
G alpha (i) signalling events	REACTOME	R-HSA-418594

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PMIDs
PA128406954	Weight gain	Disease	MultilinkAnnotation	associated	24279860
PA258	NPY1R	Gene	Pathway	associated
PA31741	NPY2R	Gene	Pathway	associated

References

Pubmed ID	Year	Title	Citations
37013432	2024	Alpha Calcitonin Gene-related Peptide, Neuropeptide Y, and Substance P as Biomarkers for Diagnosis and Disease Activity and Severity in Multiple Sclerosis.	0
37070394	2024	Neuropeptide Y gene variants and Agreeableness: interaction effect with the birth cohort and the serotonin transporter promoter polymorphism.	1
37889542	2024	Neuropeptide Y gene polymorphisms and chronic kidney disease progression.	1
37931511	2024	Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons.	2
37937329	2024	Neuropeptide Y is elevated in heart failure and is an independent predictor of outcomes.	1
38387703	2024	Npy transcription is regulated by noncanonical STAT3 signaling in hypothalamic neurons: Implication with lipotoxicity and obesity.	1
37013432	2024	Alpha Calcitonin Gene-related Peptide, Neuropeptide Y, and Substance P as Biomarkers for Diagnosis and Disease Activity and Severity in Multiple Sclerosis.	0
37070394	2024	Neuropeptide Y gene variants and Agreeableness: interaction effect with the birth cohort and the serotonin transporter promoter polymorphism.	1
37889542	2024	Neuropeptide Y gene polymorphisms and chronic kidney disease progression.	1
37931511	2024	Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons.	2
37937329	2024	Neuropeptide Y is elevated in heart failure and is an independent predictor of outcomes.	1
38387703	2024	Npy transcription is regulated by noncanonical STAT3 signaling in hypothalamic neurons: Implication with lipotoxicity and obesity.	1
35728621	2023	Neuropeptide Y and measures of stress in a longitudinal study of women with the fibromyalgia syndrome.	0
36525977	2023	Structural basis for Y2 receptor-mediated neuropeptide Y and peptide YY signaling.	4
36768369	2023	Sympathetic System in Wound Healing: Multistage Control in Normal and Diabetic Skin.	4

Citation

Massimiliano Ruscica ; Elena Dozio ; Paolo Magni

NPY (neuropeptide Y)

Atlas Genet Cytogenet Oncol Haematol. 2009-05-01

Online version: http://atlasgeneticsoncology.org/gene/44438