Neuropeptide Y: Difference between revisions

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| image = Neuropeptide_Y.png
| image_source = Structure of Neuropeptide Y. From {{PDB|1ron}}.
| Name = Neuropeptide Y
| HGNCid = 7955
| Symbol = NPY
| AltSymbols =; PYY4
| OMIM = 162640
| ECnumber = 
| Homologene = 697
| MGIid = 97374
| GeneAtlas_image1 = PBB_GE_NPY_206001_at_tn.png
| Function = {{GNF_GO|id=GO:0001664 |text = G-protein-coupled receptor binding}} {{GNF_GO|id=GO:0004930 |text = G-protein coupled receptor activity}} {{GNF_GO|id=GO:0005184 |text = neuropeptide hormone activity}} {{GNF_GO|id=GO:0005246 |text = calcium channel regulator activity}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0005623 |text = cell}}
| Process = {{GNF_GO|id=GO:0006816 |text = calcium ion transport}} {{GNF_GO|id=GO:0006928 |text = cell motility}} {{GNF_GO|id=GO:0007187 |text = G-protein signaling, coupled to cyclic nucleotide second messenger}} {{GNF_GO|id=GO:0007218 |text = neuropeptide signaling pathway}} {{GNF_GO|id=GO:0007268 |text = synaptic transmission}} {{GNF_GO|id=GO:0007586 |text = digestion}} {{GNF_GO|id=GO:0008217 |text = blood pressure regulation}} {{GNF_GO|id=GO:0008283 |text = cell proliferation}} {{GNF_GO|id=GO:0008343 |text = adult feeding behavior}} {{GNF_GO|id=GO:0032100 |text = positive regulation of appetite}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 4852
    | Hs_Ensembl = ENSG00000122585
    | Hs_RefseqProtein = NP_000896
    | Hs_RefseqmRNA = NM_000905
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 7
    | Hs_GenLoc_start = 24290332
    | Hs_GenLoc_end = 24298002
    | Hs_Uniprot = P01303
    | Mm_EntrezGene = 109648
    | Mm_Ensembl = ENSMUSG00000029819
    | Mm_RefseqmRNA = NM_023456
    | Mm_RefseqProtein = NP_075945
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 6
    | Mm_GenLoc_start = 49753184
    | Mm_GenLoc_end = 49758913
    | Mm_Uniprot = P57774
  }}
}}
{{SI}}


'''Neuropeptide Y''' ('''NPY''') is a 36-[[amino acid]] [[neuropeptide]] that acts as a [[neurotransmitter]] in the [[brain]] and in the [[autonomic nervous system]] of humans; slight variations of the peptide are found in many other animals.<ref name=tatemoto>{{cite book | author = Tatemoto K | chapter = Neuropeptide Y: History and Overview <!--| title=Neuropeptide Y and Related Peptides--> | volume = 162 | title = Handbook of Experimental Pharmacology | publisher = Springer | year = 2004 | editor = Michel MC |pages=2–15|url=https://books.google.com/books?id=LkfD192yqogC&lpg=PP1&pg=PA1#v=onepage&q&f=false}}</ref> In the autonomic system it is produced mainly by [[neuron]]s of the [[sympathetic nervous system]] and serves as a strong [[vasoconstrictor]] and also causes growth of fat tissue.<ref name=kuo/> In the brain, it is produced in various locations including the [[hypothalamus]], and is thought to have several functions, including: increasing food intake and storage of energy as fat, reducing anxiety and stress, reducing pain perception, affecting the [[circadian rhythm]], reducing voluntary alcohol intake, lowering blood pressure, and controlling epileptic seizures.<ref name=tatemoto/><ref name="Colmers">{{cite journal | vauthors = Colmers WF, El Bahh B | title = Neuropeptide Y and Epilepsy | journal = Epilepsy Currents | volume = 3 | issue = 2 | pages = 53–58 | date = March 2003 | pmid = 15309085 | pmc = 321170 | doi = 10.1046/j.1535-7597.2003.03208.x }}</ref>
==Discovery==
Following the isolation of neuropeptide-y (NPY) from the [[Domestic pig|porcine]] [[hypothalamus]] in 1982, researchers began to speculate about the involvement of NPY in hypothalamic-mediated functions. In a 1983 study, NPY-ergic axon terminals were located in the [[paraventricular nucleus]] (PVN) of the [[hypothalamus]], and the highest levels of NPY immunoreactivity was found within the PVN of the hypothalamus.<ref name=allen_et_al83>{{cite journal | vauthors = Allen YS, Adrian TE, Allen JM, Tatemoto K, Crow TJ, Bloom SR, Polak JM | title = Neuropeptide Y distribution in the rat brain | journal = Science | volume = 221 | issue = 4613 | pages = 877–9 | date = August 1983 | pmid = 6136091 | doi = 10.1126/science.6136091 }}</ref>
Six years later, in 1989, Morris et al. homed in on the location of NPYergic nuclei in the brain. Furthermore, [[in situ hybridization]] results from the study showed the highest cellular levels of NPY [[mRNA]] in the [[arcuate nucleus]] (ARC) of the hypothalamus.<ref name="pmid2592617">{{cite journal | vauthors = Morris BJ | title = Neuronal localisation of neuropeptide Y gene expression in rat brain | journal = The Journal of Comparative Neurology | volume = 290 | issue = 3 | pages = 358–68 | date = December 1989 | pmid = 2592617 | doi = 10.1002/cne.902900305 }}</ref>
In 1989, Haas & George reported that local injection of NPY into the PVN resulted in an acute release of [[corticotropin-releasing hormone]] (CRH) in the rat brain, proving that NPYergic activity directly stimulates the release and synthesis of CRH.<ref name="pmid2551461">{{cite journal | vauthors = Haas DA, George SR | title = Neuropeptide Y-induced effects on hypothalamic corticotropin-releasing factor content and release are dependent on noradrenergic/adrenergic neurotransmission | journal = Brain Research | volume = 498 | issue = 2 | pages = 333–8 | date = October 1989 | pmid = 2551461 | doi = 10.1016/0006-8993(89)91112-8 }}</ref>
The latter became a hallmark paper in NPY studies. A significant amount of work had already been done in the 1970s on CRH and its involvement in stress and eating disorders such as [[obesity]].<ref name="pmid167093">{{cite journal | vauthors = Edwardson JA, Hough CA | title = The pituitary-adrenal system of the genetically obese (ob/ob) mouse | journal = The Journal of Endocrinology | volume = 65 | issue = 1 | pages = 99–107 | date = April 1975 | pmid = 167093 | doi = 10.1677/joe.0.0650099 }}</ref> These studies, collectively, marked the beginning of the role of NPY in [[orexigenic|orexigenesis]] or food intake.
==Role in food intake==
Behaviorial assays in orexigenic studies, in which [[rat]]s are the model organism, have been done collectively with [[immunoassay]]s and [[in situ hybridization]] studies to confirm that elevating NPY-ergic activity does indeed increase food intake. In these studies, exogenous NPY,<ref name="Hanson ES, Dallman MF 1995 273–9">{{cite journal | vauthors = Hanson ES, Dallman MF | title = Neuropeptide Y (NPY) may integrate responses of hypothalamic feeding systems and the hypothalamo-pituitary-adrenal axis | journal = Journal of Neuroendocrinology | volume = 7 | issue = 4 | pages = 273–9 | date = April 1995 | pmid = 7647769 | doi = 10.1111/j.1365-2826.1995.tb00757.x }}</ref> an NPY agonist such as [[dexamethasone]]<ref name="White1994">{{cite journal | vauthors = White BD, Dean RG, Edwards GL, Martin RJ | title = Type II corticosteroid receptor stimulation increases NPY gene expression in basomedial hypothalamus of rats | journal = The American Journal of Physiology | volume = 266 | issue = 5 Pt 2 | pages = R1523-9 | date = May 1994 | pmid = 8203629 | url = http://ajpregu.physiology.org/cgi/pmidlookup?view=reprint&pmid=8203629 }}</ref> or N-acetyl [Leu 28, Leu31] NPY (24-36)<ref>{{cite journal | vauthors = King PJ, Widdowson PS, Doods HN, Williams G | title = Regulation of neuropeptide Y release by neuropeptide Y receptor ligands and calcium channel antagonists in hypothalamic slices | journal = Journal of Neurochemistry | volume = 73 | issue = 2 | pages = 641–6 | date = August 1999 | pmid = 10428060 | doi = 10.1046/j.1471-4159.1999.0730641.x }}</ref> are injected into the third ventricle<ref name="Hanson ES, Dallman MF 1995 273–9"/> or at the level of the hypothalamus with a [[cannula]].<ref name="White1994" /><ref>{{cite journal | vauthors = Pomonis JD, Levine AS, Billington CJ | title = Interaction of the hypothalamic paraventricular nucleus and central nucleus of the amygdala in naloxone blockade of neuropeptide Y-induced feeding revealed by c-fos expression | journal = The Journal of Neuroscience | volume = 17 | issue = 13 | pages = 5175–82 | date = July 1997 | pmid = 9185555 | url = http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=9185555 }}</ref>


==Overview==
Furthermore, these studies unanimously demonstrate that the stimulation of NPYergic activity via the administration of certain NPY [[agonists]] increases food intake compared to baseline data in rats. The effects of NPYergic activity on food intake is also demonstrated by the blockade of certain NPY receptors (Y1 and Y5 receptors), which, as was expected, inhibited NPYergic activity; thus, decreases food intake. However, a 1999 study by King et al. demonstrated the effects of the activation of the NPY autoreceptor Y2, which has been shown to inhibit the release of NPY and thus acts to regulate food intake upon its activation.<ref>{{cite journal | vauthors = King PJ, Williams G, Doods H, Widdowson PS | title = Effect of a selective neuropeptide Y Y(2) receptor antagonist, BIIE0246 on neuropeptide Y release | journal = European Journal of Pharmacology | volume = 396 | issue = 1 | pages = R1-3 | date = May 2000 | pmid = 10822055 | doi = 10.1016/S0014-2999(00)00230-2 | url = http://linkinghub.elsevier.com/retrieve/pii/S0014-2999(00)00230-2 }}</ref> In this study a highly selective Y2 antagonist, BIIE0246  was administered locally into the ARC. Radioimmunoassay data, following the injection of BIIE0246, shows a significant  increase in NPY release compared to the control group. Though the pharmacological half-life of exogenous NPY, other agonists, and antagonist is still obscure, the effects are not long lasting and the rat body employs an excellent ability to regulate and normalize abnormal NPY levels and therefore food consumption.<ref name="Hanson ES, Dallman MF 1995 273–9"/>
'''Neuropeptide Y''' (NPY) is a 36 [[amino acid]] peptide [[neurotransmitter]] found in the [[brain]] and [[autonomic nervous system]].  


NPY has been associated with a number of physiologic processes in the brain, including the regulation of energy balance, memory and learning, and epilepsy.<ref name="Colmers">{{cite journal | author=Colmers WF, El Bahn B | title=Neuropeptide Y and Epilepsy | journal=Epilepsy Currents/American Epilepsy Society | year=2003 | pages=53-8 | volume=2 | issue=3 | pmid=15309085}}</ref> The main effect is increased food intake and decreased physical activity.
==Role in obesity==


NPY is secreted by the [[hypothalamus]], and in addition to increasing food intake, it increases the proportion of energy stored as fat and blocks [[Nociception|nociceptive]] signals to the brain<ref> [http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/G/GutHormones.html#neuropeptideY users.rcn.com - Hormones of the Gut]</ref>.
Dryden et al., conducted a study in 1995 using genetically obese rats to demonstrate the role of NPY in eating disorders such as [[obesity]]. The study revealed four underlying factors that contributed to obesity in rats:
* an increase in [[corticosteroid|glucocorticosteroid]] concentrations in [[Blood plasma|plasma]];
* insensitivity or resistance to [[insulin]];
* [[mutation]] of [[leptin]] receptor; and
* an increase in NPY mRNA and NPY release.<ref>{{cite journal | vauthors = Dryden S, Pickavance L, Frankish HM, Williams G | title = Increased neuropeptide Y secretion in the hypothalamic paraventricular nucleus of obese (fa/fa) Zucker rats | journal = Brain Research | volume = 690 | issue = 2 | pages = 185–8 | date = September 1995 | pmid = 8535835 | doi = 10.1016/0006-8993(95)00628-4 }}</ref>


NPY also augments the vasoconstrictor effects of noradrenergic [[neurons]].
In obesity chronically elevated levels of NPY can be seen, this has been seen in rats fed on a high fat diet for 22 weeks and resulted in a genetic mutation increasing NPY release due to a defective leptin signal compared to control rats. In humans increased levels of free NPY were found in obese women and not in their leaner counterparts, analysing human hypothalamus' for NYP concentration however is more difficult than rats.<ref name="Minor_2008">{{cite journal | vauthors = Minor RK, Chang JW, de Cabo R | title = Hungry for life: How the arcuate nucleus and neuropeptide Y may play a critical role in mediating the benefits of calorie restriction | journal = Molecular and Cellular Endocrinology | volume = 299 | issue = 1 | pages = 79–88 | date = February 2009 | pmid = 19041366 | pmc = 2668104 | doi = 10.1016/j.mce.2008.10.044 }}</ref> During weaning in rats there is an early expression of gene mutations that increase hypothalamic release of NPY in rats, however in humans multiple genes are commonly associated with the results of obesity and metabolic syndrome.<ref name="Minor_2008"/> In most obesity cases the increased secretion of  NPY is a central / hypothalamic resistance to energy excess hormone signals such as leptin, that can be a result of a variety of reasons in the CNS. In rodents resistant to obesity when fed on an obesogenic diet they had a significantly lower amount of NPY receptor in the hypothalamus suggesting an increased activity of NPY neurones in obese rats meaning that the reduction in the release of NPY may be beneficial to the reduction of obesity incidence alongside the consumption of a healthy diet and exercise. This would need to be seen in human research before looking at  this avenue of weight loss although currently there is some evidence that suggests NPY is a significant predictor in weight regain after weight loss to maintain old levels of energy storage.<ref name="Minor_2008" />


==Role in regulation of feeding==
Furthermore, these factors correlate with each other. The sustained high levels of glucocorticosteroids stimulate [[gluconeogenesis]], which subsequently causes an increase of blood glucose that activates the release of insulin to regulate glucose levels by causing its reuptake and storage as [[glycogen]] in the tissues in the body. In the case of obesity, which researchers speculate to have a strong genetic and a dietary basis, [[insulin resistance]] prevents high blood glucose regulation, resulting in morbid levels of glucose and [[diabetes mellitus]].<ref>{{cite journal | vauthors = Wilcox G | title = Insulin and insulin resistance | journal = The Clinical Biochemist. Reviews | volume = 26 | issue = 2 | pages = 19–39 | date = May 2005 | pmid = 16278749 | pmc = 1204764 }}</ref> In addition, high levels of glucocorticosteroids causes an increase of NPY by directly activating type II glucocorticosteroids receptors (which are activated only by relatively high levels of glucocorticosteroids) and, indirectly, by abolishing the negative feedback of [[corticotropin-releasing factor]] (CRF) on NPY synthesis and release. Meanwhile, obesity-induced insulin resistance and the mutation of the [[leptin receptor]] (ObRb) results in the abolition of inhibition of NPYergic activity and ultimately food intake via other negative feedback mechanisms to regulate them. Obesity in rats was significantly reduced by [[adrenalectomy]]<ref>{{cite journal | vauthors = Yukimura Y, Bray GA | title = Effects of adrenalectomy on body weight and the size and number of fat cells in the Zucker (fatty) rat | journal = Endocrine Research Communications | volume = 5 | issue = 3 | pages = 189–98 | year = 1978 | pmid = 747998 | doi = 10.1080/07435807809083752 }}</ref> or [[hypophysectomy]].<ref>{{cite journal | vauthors = Powley TL, Morton SA | title = Hypophysectomy and regulation of body weight in the genetically obese Zucker rat | journal = The American Journal of Physiology | volume = 230 | issue = 4 | pages = 982–7 | date = April 1976 | pmid = 1267030 | url = http://ajplegacy.physiology.org/cgi/content/abstract/230/4/982 }}</ref>
NPY's role in regulating energy balance is well known. It forms part of the "lipostat" system along with [[leptin]] and [[corticotropin-releasing hormone]] (CRH). High NPY levels in the [[cerebrospinal fluid]] are associated with high food intake and decreased physical activity. Leptin, produced by [[adipocyte]]s in response to high fat levels, is detected by the [[arcuate nucleus]] in the hypothalamus. Increased arcuate nucleus activity acts on the [[paraventricular nucleus]] to inhibit the production of NPY at that site, thus reducing feeding behaviour. Arcuate nucleus activity also stimulates the release of CRH which further decreases feeding and increases energy expenditure.


==Correlation with stress and diet==
==Correlation with stress and diet==
Studies of mice and monkeys show that repeated [[Stress (medicine)|stress]]— and a high-[[fat]], high-[[sugar]] diet— stimulate the release of neuropeptide Y, causing fat to build up in the [[abdomen]]. Researchers believe that by manipulating levels of the appetite hormone, they could make fat melt from areas where it was not desired and accumulate at sites where it is needed.<ref>{{cite news|url=http://www.chicagotribune.com/news/nationworld/chi-fat_02jul02,1,5760439.story?coll=chi-newsnationworld-hed |title=Research points to way to eliminate belly fat|author=Thomas H. Maugh II|date=July 2, 2007|publisher=Chicago Tribune}}</ref><ref>{{cite journal |last=Kuo |first=LE |coauthors=Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, Lee EW, Burnett MS, Fricke ST, Kvetnansky R, Herzog H, Zukowska Z. |year=2007 |month=July |title=Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome |journal=Nature Medicine |volume=13 |issue=7 |pages=803-811 |url=http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17603492&ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum }}</ref>


Higher levels of NPY may be associated with [[Psychological_resilience|resilience]] against and recovery from [[posttraumatic stress disorder]].<ref>{{cite journal |last=Yehuda |first=Rachel |coauthors=Brand, Sarah; Yang, Ren-Kui |year=2006 |month=April |title=Plasma Neuropeptide Y Concentrations in Combat Exposed Veterans: Relationship to Trauma Exposure, Recovery from PTSD, and Coping |journal=Biological Psychiatry |volume=59 |issue=7 |pages=660-663 |issn=0006-3223 |url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T4S-4HPD3X4-6&_user=10&_coverDate=04%2F01%2F2006&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=e5d9bbeed6bc927c33abc2e4463e13c3 |accessdate= 2007-08-23 }}</ref>
Studies of [[mouse|mice]] and [[monkey]]s show that repeated [[Stress (medicine)|stress]]—and a high-[[fat]], high-[[sugar]] diet—stimulate the release of neuropeptide Y, causing fat to build up in the [[abdomen]]. Researchers believe that by manipulating levels of NPY, they could eliminate fat from areas where it was not desired and accumulate at sites where it is needed.<ref name=kuo>{{cite journal | vauthors = Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, Lee EW, Burnett MS, Fricke ST, Kvetnansky R, Herzog H, Zukowska Z | title = Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome | journal = Nature Medicine | volume = 13 | issue = 7 | pages = 803–11 | date = July 2007 | pmid = 17603492 | doi = 10.1038/nm1611 }}</ref><ref>{{cite news | url = http://www.chicagotribune.com/news/nationworld/chi-fat_02jul02,1,5760439.story?coll=chi-newsnationworld-hed | title = Research points to way to eliminate belly fat | first = Thomas H. | last = Maugh | name-list-format = vanc | date = July 2, 2007 | work = [[Chicago Tribune]] }}</ref>
 
Conversely, higher levels of NPY may be associated with [[Psychological resilience|resilience]] against and recovery from [[posttraumatic stress disorder]]<ref name="pmid16325152">{{cite journal | vauthors = Yehuda R, Brand S, Yang RK | title = Plasma neuropeptide Y concentrations in combat exposed veterans: relationship to trauma exposure, recovery from PTSD, and coping | journal = Biological Psychiatry | volume = 59 | issue = 7 | pages = 660–3 | date = April 2006 | pmid = 16325152 | doi = 10.1016/j.biopsych.2005.08.027 }}</ref> and with dampening the fear response, allowing individuals to perform better under extreme stress.<ref>{{cite news|url=http://www.newsdaily.com/stories/tre51f02b-us-stress-soldiers/ |title=Research shows why some soldiers are cool under fire|author=Julie Steenhuysen|date=February 16, 2009}}</ref>
 
==Alcoholism==
Two results suggest that NPY might protect against [[alcoholism]]:
* [[knock-out mice]] in which a type of NPY receptor has been removed show a higher voluntary intake of alcohol and a higher resistance to alcohol's sedating effects, compared to normal mice;<ref name="pmid11826154">{{cite journal | vauthors = Thiele TE, Koh MT, Pedrazzini T | title = Voluntary alcohol consumption is controlled via the neuropeptide Y Y1 receptor | journal = The Journal of Neuroscience | volume = 22 | issue = 3 | pages = RC208 | date = February 2002 | pmid = 11826154 | doi = }}</ref>
* the [[Drosophila melanogaster|common fruit fly]] has a neuropeptide that is similar to NPY, known as [[neuropeptide F]]. The levels of neuropeptide F are lowered in sexually frustrated male flies, and this causes the flies to increase their voluntary intake of alcohol.<ref>{{cite web|title=Deprived of Sex, Jilted Flies Drink More Alcohol|date=March 15, 2012|work=UCSF News Center|url=http://www.ucsf.edu/news/2012/03/11662/deprived-sex-jilted-flies-drink-more-alcohol}}</ref>


==Receptors==
==Receptors==
{{Main|Neuropeptide Y receptor}}
{{Main|Neuropeptide Y receptor}}
The receptor protein that NPY operates on is a [[G-protein coupled receptor]] in the [[rhodopsin]] like GPCR family. These receptors are [[metabotropic]], causing metabolic changes in the target cell rather than directly opening ion channels. The protein contains seven membrane spanning domains and five subtypes have been identified in mammals, four of which are functional in humans.<!--
The receptor protein that NPY operates on is a [[G protein-coupled receptor]] in the [[rhodopsin]] like 7-transmembrane GPCR family. Five subtypes of the NPY receptor have been identified in mammals, four of which are functional in humans.<ref name="Michel">{{cite journal | vauthors = Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D, Quirion R, Schwartz T, Westfall T | title = XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors | journal = Pharmacological Reviews | volume = 50 | issue = 1 | pages = 143–50 | date = March 1998 | pmid = 9549761 }}</ref> Subtypes Y1 and Y5 have known roles in the stimulation of feeding while Y2 and Y4 seem to have roles in appetite inhibition (satiety). Some of these receptors are among the most highly conserved neuropeptide receptors.
  --><ref name="Michel">{{cite journal | author=Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D, Quirion R, Schwartz T, Westfall T | title=XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors | journal=Pharmacological Reviews | year=1998 | pages=143-50 | volume=50 | issue=1 | pmid=9549761}}</ref> Subtypes Y1 and Y5 have known roles in the stimulation of feeding while Y2 and Y4 seem to have roles in appetite inhibition (satiety). Some of these receptors are among the most highly conserved neuropeptide receptors.


==See also==
== See also ==
* [[Anorexia nervosa]]
* [[Antianalgesia]]
* [[Antianalgesia]]
* [[Neuropeptide]]
* [[Neuropeptide]]
* [[Obesity]]


==References==
== References ==
{{reflist|2}}
{{Reflist|33em}}


==External links==
== External links ==
* [http://www.ebi.ac.uk/interpro/IEntry?ac=IPR000611 EMBL receptor database entry]
* [http://www.ebi.ac.uk/interpro/IEntry?ac=IPR000611 EMBL receptor database entry]
* {{MeshName|Neuropeptide+Y}}
* {{MeshName|Neuropeptide+Y|3=Neuropeptide Y}}


{{PDB_Gallery|geneid=4852}}
{{Neuropeptides}}
{{Neuropeptides}}
{{Orexigenics}}
{{Signaling peptide/protein receptor modulators}}
{{Sigma receptor modulators}}
[[Category:Neuropeptides]]
[[Category:Neuropeptides]]
[[ja:神経ペプチドY]]
[[pl:Neuropeptyd Y]]
{{WH}}
{{WikiDoc Sources}}

Revision as of 14:05, 20 August 2017

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Neuropeptide Y
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Chemical and physical data
FormulaC190H287N55O57
Molar mass4253.7 g/mol
 ☒N☑Y (what is this?)  (verify)

Neuropeptide Y (NPY) is a 36-amino acid neuropeptide that acts as a neurotransmitter in the brain and in the autonomic nervous system of humans; slight variations of the peptide are found in many other animals.[1] In the autonomic system it is produced mainly by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue.[2] In the brain, it is produced in various locations including the hypothalamus, and is thought to have several functions, including: increasing food intake and storage of energy as fat, reducing anxiety and stress, reducing pain perception, affecting the circadian rhythm, reducing voluntary alcohol intake, lowering blood pressure, and controlling epileptic seizures.[1][3]

Discovery

Following the isolation of neuropeptide-y (NPY) from the porcine hypothalamus in 1982, researchers began to speculate about the involvement of NPY in hypothalamic-mediated functions. In a 1983 study, NPY-ergic axon terminals were located in the paraventricular nucleus (PVN) of the hypothalamus, and the highest levels of NPY immunoreactivity was found within the PVN of the hypothalamus.[4]

Six years later, in 1989, Morris et al. homed in on the location of NPYergic nuclei in the brain. Furthermore, in situ hybridization results from the study showed the highest cellular levels of NPY mRNA in the arcuate nucleus (ARC) of the hypothalamus.[5]

In 1989, Haas & George reported that local injection of NPY into the PVN resulted in an acute release of corticotropin-releasing hormone (CRH) in the rat brain, proving that NPYergic activity directly stimulates the release and synthesis of CRH.[6]

The latter became a hallmark paper in NPY studies. A significant amount of work had already been done in the 1970s on CRH and its involvement in stress and eating disorders such as obesity.[7] These studies, collectively, marked the beginning of the role of NPY in orexigenesis or food intake.

Role in food intake

Behaviorial assays in orexigenic studies, in which rats are the model organism, have been done collectively with immunoassays and in situ hybridization studies to confirm that elevating NPY-ergic activity does indeed increase food intake. In these studies, exogenous NPY,[8] an NPY agonist such as dexamethasone[9] or N-acetyl [Leu 28, Leu31] NPY (24-36)[10] are injected into the third ventricle[8] or at the level of the hypothalamus with a cannula.[9][11]

Furthermore, these studies unanimously demonstrate that the stimulation of NPYergic activity via the administration of certain NPY agonists increases food intake compared to baseline data in rats. The effects of NPYergic activity on food intake is also demonstrated by the blockade of certain NPY receptors (Y1 and Y5 receptors), which, as was expected, inhibited NPYergic activity; thus, decreases food intake. However, a 1999 study by King et al. demonstrated the effects of the activation of the NPY autoreceptor Y2, which has been shown to inhibit the release of NPY and thus acts to regulate food intake upon its activation.[12] In this study a highly selective Y2 antagonist, BIIE0246 was administered locally into the ARC. Radioimmunoassay data, following the injection of BIIE0246, shows a significant increase in NPY release compared to the control group. Though the pharmacological half-life of exogenous NPY, other agonists, and antagonist is still obscure, the effects are not long lasting and the rat body employs an excellent ability to regulate and normalize abnormal NPY levels and therefore food consumption.[8]

Role in obesity

Dryden et al., conducted a study in 1995 using genetically obese rats to demonstrate the role of NPY in eating disorders such as obesity. The study revealed four underlying factors that contributed to obesity in rats:

In obesity chronically elevated levels of NPY can be seen, this has been seen in rats fed on a high fat diet for 22 weeks and resulted in a genetic mutation increasing NPY release due to a defective leptin signal compared to control rats. In humans increased levels of free NPY were found in obese women and not in their leaner counterparts, analysing human hypothalamus' for NYP concentration however is more difficult than rats.[14] During weaning in rats there is an early expression of gene mutations that increase hypothalamic release of NPY in rats, however in humans multiple genes are commonly associated with the results of obesity and metabolic syndrome.[14] In most obesity cases the increased secretion of NPY is a central / hypothalamic resistance to energy excess hormone signals such as leptin, that can be a result of a variety of reasons in the CNS. In rodents resistant to obesity when fed on an obesogenic diet they had a significantly lower amount of NPY receptor in the hypothalamus suggesting an increased activity of NPY neurones in obese rats meaning that the reduction in the release of NPY may be beneficial to the reduction of obesity incidence alongside the consumption of a healthy diet and exercise. This would need to be seen in human research before looking at this avenue of weight loss although currently there is some evidence that suggests NPY is a significant predictor in weight regain after weight loss to maintain old levels of energy storage.[14]

Furthermore, these factors correlate with each other. The sustained high levels of glucocorticosteroids stimulate gluconeogenesis, which subsequently causes an increase of blood glucose that activates the release of insulin to regulate glucose levels by causing its reuptake and storage as glycogen in the tissues in the body. In the case of obesity, which researchers speculate to have a strong genetic and a dietary basis, insulin resistance prevents high blood glucose regulation, resulting in morbid levels of glucose and diabetes mellitus.[15] In addition, high levels of glucocorticosteroids causes an increase of NPY by directly activating type II glucocorticosteroids receptors (which are activated only by relatively high levels of glucocorticosteroids) and, indirectly, by abolishing the negative feedback of corticotropin-releasing factor (CRF) on NPY synthesis and release. Meanwhile, obesity-induced insulin resistance and the mutation of the leptin receptor (ObRb) results in the abolition of inhibition of NPYergic activity and ultimately food intake via other negative feedback mechanisms to regulate them. Obesity in rats was significantly reduced by adrenalectomy[16] or hypophysectomy.[17]

Correlation with stress and diet

Studies of mice and monkeys show that repeated stress—and a high-fat, high-sugar diet—stimulate the release of neuropeptide Y, causing fat to build up in the abdomen. Researchers believe that by manipulating levels of NPY, they could eliminate fat from areas where it was not desired and accumulate at sites where it is needed.[2][18]

Conversely, higher levels of NPY may be associated with resilience against and recovery from posttraumatic stress disorder[19] and with dampening the fear response, allowing individuals to perform better under extreme stress.[20]

Alcoholism

Two results suggest that NPY might protect against alcoholism:

  • knock-out mice in which a type of NPY receptor has been removed show a higher voluntary intake of alcohol and a higher resistance to alcohol's sedating effects, compared to normal mice;[21]
  • the common fruit fly has a neuropeptide that is similar to NPY, known as neuropeptide F. The levels of neuropeptide F are lowered in sexually frustrated male flies, and this causes the flies to increase their voluntary intake of alcohol.[22]

Receptors

Main article: Neuropeptide Y receptor

The receptor protein that NPY operates on is a G protein-coupled receptor in the rhodopsin like 7-transmembrane GPCR family. Five subtypes of the NPY receptor have been identified in mammals, four of which are functional in humans.[23] Subtypes Y1 and Y5 have known roles in the stimulation of feeding while Y2 and Y4 seem to have roles in appetite inhibition (satiety). Some of these receptors are among the most highly conserved neuropeptide receptors.

See also

References

  1. ↑ 1.0 1.1 Tatemoto K (2004). "Neuropeptide Y: History and Overview". In Michel MC. Handbook of Experimental Pharmacology. 162. Springer. pp. 2–15.
  2. ↑ 2.0 2.1 Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, Lee EW, Burnett MS, Fricke ST, Kvetnansky R, Herzog H, Zukowska Z (July 2007). "Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome". Nature Medicine. 13 (7): 803–11. doi:10.1038/nm1611. PMID 17603492.
  3. ↑ Colmers WF, El Bahh B (March 2003). "Neuropeptide Y and Epilepsy". Epilepsy Currents. 3 (2): 53–58. doi:10.1046/j.1535-7597.2003.03208.x. PMC 321170. PMID 15309085.
  4. ↑ Allen YS, Adrian TE, Allen JM, Tatemoto K, Crow TJ, Bloom SR, Polak JM (August 1983). "Neuropeptide Y distribution in the rat brain". Science. 221 (4613): 877–9. doi:10.1126/science.6136091. PMID 6136091.
  5. ↑ Morris BJ (December 1989). "Neuronal localisation of neuropeptide Y gene expression in rat brain". The Journal of Comparative Neurology. 290 (3): 358–68. doi:10.1002/cne.902900305. PMID 2592617.
  6. ↑ Haas DA, George SR (October 1989). "Neuropeptide Y-induced effects on hypothalamic corticotropin-releasing factor content and release are dependent on noradrenergic/adrenergic neurotransmission". Brain Research. 498 (2): 333–8. doi:10.1016/0006-8993(89)91112-8. PMID 2551461.
  7. ↑ Edwardson JA, Hough CA (April 1975). "The pituitary-adrenal system of the genetically obese (ob/ob) mouse". The Journal of Endocrinology. 65 (1): 99–107. doi:10.1677/joe.0.0650099. PMID 167093.
  8. ↑ 8.0 8.1 8.2 Hanson ES, Dallman MF (April 1995). "Neuropeptide Y (NPY) may integrate responses of hypothalamic feeding systems and the hypothalamo-pituitary-adrenal axis". Journal of Neuroendocrinology. 7 (4): 273–9. doi:10.1111/j.1365-2826.1995.tb00757.x. PMID 7647769.
  9. ↑ 9.0 9.1 White BD, Dean RG, Edwards GL, Martin RJ (May 1994). "Type II corticosteroid receptor stimulation increases NPY gene expression in basomedial hypothalamus of rats". The American Journal of Physiology. 266 (5 Pt 2): R1523–9. PMID 8203629.
  10. ↑ King PJ, Widdowson PS, Doods HN, Williams G (August 1999). "Regulation of neuropeptide Y release by neuropeptide Y receptor ligands and calcium channel antagonists in hypothalamic slices". Journal of Neurochemistry. 73 (2): 641–6. doi:10.1046/j.1471-4159.1999.0730641.x. PMID 10428060.
  11. ↑ Pomonis JD, Levine AS, Billington CJ (July 1997). "Interaction of the hypothalamic paraventricular nucleus and central nucleus of the amygdala in naloxone blockade of neuropeptide Y-induced feeding revealed by c-fos expression". The Journal of Neuroscience. 17 (13): 5175–82. PMID 9185555.
  12. ↑ King PJ, Williams G, Doods H, Widdowson PS (May 2000). "Effect of a selective neuropeptide Y Y(2) receptor antagonist, BIIE0246 on neuropeptide Y release". European Journal of Pharmacology. 396 (1): R1–3. doi:10.1016/S0014-2999(00)00230-2. PMID 10822055.
  13. ↑ Dryden S, Pickavance L, Frankish HM, Williams G (September 1995). "Increased neuropeptide Y secretion in the hypothalamic paraventricular nucleus of obese (fa/fa) Zucker rats". Brain Research. 690 (2): 185–8. doi:10.1016/0006-8993(95)00628-4. PMID 8535835.
  14. ↑ 14.0 14.1 14.2 Minor RK, Chang JW, de Cabo R (February 2009). "Hungry for life: How the arcuate nucleus and neuropeptide Y may play a critical role in mediating the benefits of calorie restriction". Molecular and Cellular Endocrinology. 299 (1): 79–88. doi:10.1016/j.mce.2008.10.044. PMC 2668104. PMID 19041366.
  15. ↑ Wilcox G (May 2005). "Insulin and insulin resistance". The Clinical Biochemist. Reviews. 26 (2): 19–39. PMC 1204764. PMID 16278749.
  16. ↑ Yukimura Y, Bray GA (1978). "Effects of adrenalectomy on body weight and the size and number of fat cells in the Zucker (fatty) rat". Endocrine Research Communications. 5 (3): 189–98. doi:10.1080/07435807809083752. PMID 747998.
  17. ↑ Powley TL, Morton SA (April 1976). "Hypophysectomy and regulation of body weight in the genetically obese Zucker rat". The American Journal of Physiology. 230 (4): 982–7. PMID 1267030.
  18. ↑ Maugh TH (July 2, 2007). "Research points to way to eliminate belly fat". Chicago Tribune.
  19. ↑ Yehuda R, Brand S, Yang RK (April 2006). "Plasma neuropeptide Y concentrations in combat exposed veterans: relationship to trauma exposure, recovery from PTSD, and coping". Biological Psychiatry. 59 (7): 660–3. doi:10.1016/j.biopsych.2005.08.027. PMID 16325152.
  20. ↑ Julie Steenhuysen (February 16, 2009). "Research shows why some soldiers are cool under fire".
  21. ↑ Thiele TE, Koh MT, Pedrazzini T (February 2002). "Voluntary alcohol consumption is controlled via the neuropeptide Y Y1 receptor". The Journal of Neuroscience. 22 (3): RC208. PMID 11826154.
  22. ↑ "Deprived of Sex, Jilted Flies Drink More Alcohol". UCSF News Center. March 15, 2012.
  23. ↑ Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D, Quirion R, Schwartz T, Westfall T (March 1998). "XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors". Pharmacological Reviews. 50 (1): 143–50. PMID 9549761.

External links

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