Neuropeptide Y
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'''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.
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>.
NPY also augments the vasoconstrictor effects of noradrenergic [[neurons]].
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==History==
Following the isolation of neuropeptide-y (NPY) from the [[hypothalamus]] of porcine in 1982, researchers began to speculate the involvement of NPY in hypothalamic-mediated functions. As more studies on the mysterious polypeptide began, the more of the big picture began to come into focus. Among these hallmark studies was a study done by Allen et al in 1983. One of the major findings in this study, appropriately entitled Neuropeptide Y distribution in the rat brain (1983), was the location of NPYergic axon terminals in the [[paraventricular nucleus]] (PVN) of the [[hypothalamus]]. Moreover, Allen et al discovered the highest levels of NPY immunoreactivity within the PVN of the hypothalamus.<ref>{{cite journal |last=Allen |first=YS |coauthors=Adrian TE, Allen JM, Tatemoto K, Crow TJ, Bloom SR, Polak JM. |year=1983 |title=Neuropeptide Y distribution in the rat brain |journal=Science |volume=221 |pages=877–879 |pmid=6136091 |doi=10.1126/science.6136091}}</ref>.
Six years later, in 1989, Morris et al honed 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>{{cite journal |last=Morris |first=BJ. |year=1989 |title=Neuronal localisation of neuropeptide Y gene expression in the rat brain |journal=J Comp Neurol |volume=290 |pages=358–368 |pmid=2592617 |doi=10.1002/cne.902900305}}</ref>.
However, just two years earlier, in 1987, Haas & George conducted a study that involved injecting NPY locally and discovered an interesting result. Haas & George found that following a 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 CRF.<ref>{{cite journal |last=Haas |first=DA |coauthors=George SR. |year=1989 |title=Neuropeptide Y-induced effects on hypothalamic corticotropin-releasing factor content and release are dependent on noradrenergic/adrenergic neurotransmission |journal=Brain Research |volume=498 |pages=333–338 |pmid=2551461 |doi=10.1016/0006-8993(89)91112-8}}</ref>.
The latter became major hallmark study in NPY studies, because a significant amount of work had already been done around CRH in the 1970s, and its involvement in stress and eating disorders such as [[obesity]]<ref>{{cite journal |last=Edwardson |first=JA |coauthors=Hough CA. |year=1975 |title=The pituitary-adrenal system of the genetically obese (ob/ob) mouse |journal=J Endocrinol |volume=65 |issue=1 |pages=99–107 |pmid=167093 }} </ref>.
These studies, collectively, marked the beginning of the role of NPY in orexigenesis or food intake.
==The role of NPY 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 NPYergic activity does indeed increase food intake. In these studies, exogenous NPY, <ref>{{cite journal |last=Hanson |first=ES |coauthors=Dallman MF |year=1995|title=Neuropeptide Y (NPY) may integrate responses of hypothalamic feeding systems and the hypothalamo-pituitary-adrenal axis |journal=J Neurorndocrinol |volume=7 |issue=4 |pages=273–279 |url=http://www.ncbi.nlm.nih.gov/pubmed/7647769?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum|doi=10.1111/j.1365-2826.1995.tb00757.x }} </ref> an NPY agonist such as dexamethasone <ref>{{cite journal |last=White |first=BD |coauthors=Dean RG, Edwards GL & Martin RJ|year=1995|title=Type II corticosteroids receptor stimulation increases NPY gene expression in the basomedial hypothalamus of rats |journal=Am J Physiol |volume=266 |issue=5 part 2 |pages=R1523–1529 |url=http://www.ncbi.nlm.nih.gov/pubmed/8203629?ordinalpos=39&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum }} </ref>, or N-acetyl [Leu 28, Leu31] NPY (24-36) <ref>{{cite journal |last=King |first=PJ |coauthors=Widdowson PS, Doods HN, Williams G.|year=1999|title=Regulation of neuropeptide Y release by neuropeptide Y receptor ligands and calcium channel antagonists in hypothalamic slices |journal=J Neurochem.|volume=73 |issue=2 |pages=273–279 |url=http://www.ncbi.nlm.nih.gov/pubmed/10428060?ordinalpos=62&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum|doi=10.1046/j.1471-4159.1999.0730641.x }}</ref> are injected into the third ventricle <ref>{{cite journal |last=Hanson |first=ES |coauthors=Dallman MF |year=1995|title=Neuropeptide Y (NPY) may integrate responses of hypothalamic feeding systems and the hypothalamo-pituitary-adrenal axis |journal=J Neurorndocrinol |volume=7 |issue=4 |pages=273–279 |url=http://www.ncbi.nlm.nih.gov/pubmed/7647769?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum|doi=10.1111/j.1365-2826.1995.tb00757.x }} </ref> or at the level of the hypothalamus with a cannula <ref>{{cite journal |last=White |first=BD |coauthors=Dean RG, Edwards GL & Martin RJ|year=1995|title=Type II corticosteroids receptor stimulation increases NPY gene expression in the basomedial hypothalamus of rats |journal=Am J Physiol |volume=266 |issue=5 part 2 |pages=R1523–1529 |url=http://www.ncbi.nlm.nih.gov/pubmed/8203629?ordinalpos=39&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum }} </ref><ref>{{cite journal |last=Pomonis |first=JD |coauthors=Levine AS, Billington CJ|year=1997|title=TInteraction 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=J Neurosci. |volume=17 |issue=13 |pages=5175–1582 |url=http://www.ncbi.nlm.nih.gov/pubmed/9185555?ordinalpos=18&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum }} </ref>.
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 expectedly 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 |last=King |first=PJ |coauthors=Williams G, Doods H, Widdowson PS.|year=1999 |title=Effect of a selective neuropeptide Y Y(2) receptor antagonist, BIIE0246 on neuropeptide Y release |journal=Eur J Pharmacol. |volume=396 |issue=1 |pages=R1–3 |url=http://www.ncbi.nlm.nih.gov/pubmed/10822055?ordinalpos=59&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum |doi=10.1016/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>{{cite journal |last=Hanson |first=ES |coauthors=Dallman MF |year=1995|title=Neuropeptide Y (NPY) may integrate responses of hypothalamic feeding systems and the hypothalamo-pituitary-adrenal axis |journal=J Neurorndocrinol |volume=7 |issue=4 |pages=273–279 |url=http://www.ncbi.nlm.nih.gov/pubmed/7647769?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum|doi=10.1111/j.1365-2826.1995.tb00757.x }} </ref>.
==The role of NPY in obesity==
Dryden et al, conducted a study in 1995 using genetically obese rats to demonstrate the in role of NPY in eating disorders such as [[obesity]]. The study revealed four underlying factors that contributed to obesity in rats: 1.) an increase in [[glucocorticosteriod]] concentrations in [[plasma]]; 2.) insensitivity or resistance to [[insulin]]; 3.) [[mutation]] of [[leptin]] receptor; and, 4.) an increase in NPY mRNA and NPY release <ref>{{cite journal |last=Dryden |first=S |coauthors=Pickavance L, Frankish HM, Williams G|year=1995|title=Increased neuropeptide Y secretion in the hypothalamic paraventricular nucleus of obese (fa/fa) Zucker rats |journal=Brain Res|volume=690 |issue=2 |pages=185–188 |url=http://www.ncbi.nlm.nih.gov/pubmed/8535835?ordinalpos=314&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum|doi=10.1016/0006-8993(95)00628-4 }} </ref>. Furthermore, these factors are also correlates to each other. The sustained high levels of glucocorticosteriods stimulates [[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 various 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, [[diabetes mellitus]] <ref>{{cite journal |last=Wilcox |first=G |year=2005|title=Review Article: Insulin and Insulin Resistance |journal=Clin Biochem Rev |volume=26 |pages=19–39 |url=http://www.ncbi.nlm.nih.gov/pubmed/16278749?ordinalpos=14&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum }} </ref>. Furthermore, high levels of glucocorticosteriods causes an increase of NPY by directly activating type II glucocorticosteriods receptors (which are only activated by relatively high levels of glucocorticosteriods) and indirectly, by abolishing the negative feedback of CRF on NPY synthesis and release. Meanwhile, obesity-induced insulin resistance and the mutation of the leptin receptor (ObRb) results in the abolishment of other negative feedback mechanisms to regulate NPYergic activity and ultimately food intake. Furthermore, obesity in rats was significantly reduced by adrenalectomy <ref>{{cite journal |last=Yukimura |first=Y |coauthors= Bray GA |year=1978|title=Effects of adrenalectomy on body weight and the size and number of fat cells in Zucker (fatty) rat |journal=Endocr Res Commun. |volume=5|pages=189–198 |url=http://www.ncbi.nlm.nih.gov/pubmed/747998?ordinalpos=105&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum }}</ref> and a hypophysectomy <ref>{{cite journal |last=Powley|first=T |coauthors= Morton SA |year=1976 |title=Hypophysectomy and regulation of body weight in the genetically obese Zucker rat |journal=Amer. J Physiol. |volume=230 |issue=4 |pages=982–987 |url=http://www.ncbi.nlm.nih.gov/pubmed/1267030?ordinalpos=101&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum }}</ref>
==The role of NPY in anorexia nervosa==
Kaye et al conducted a study in 1990 to demonstrate the role of NPY in [[anorexia nervosa]]. In this [[post mortem]] study, high levels of NPY were found in the [[cerebrospinal fluid]] of patients with anorexia nervosa. Subsequently, high concentrations of [[adrenacorticotropin hormone]] (ACTH) and cortisol in the plasma were also found in patients with anorexia nervosa <ref>{{cite journal |last=Kaye |first=WH |coauthors= Berrettini W, Gwirtsman H & George DT |year=1990|title=Altered cerebrospinal fluid neuropeptide Y and peptide YY immunoreactivity in anorexia and bulimia nervosa |journal=Arch Gen Psychiatry. |volume=47|pages=548–556 |url=http://www.ncbi.nlm.nih.gov/pubmed/2350207?ordinalpos=144&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum }}</ref>. Another study conducted seven years later revealed low levels of leptin, the hormone that inhibits NPY release at relatively high levels, were found to correlate with the extremely low levels of adipocytes in these patients; hence, the anxeriogenic nature of [[leptin]]<ref>{{cite journal |last=Rohner-Jeanrenuad |first=E |coauthors= Jeanrenuad B |year=1997 |title=Central nervous system and body weight regulation |journal=Ann Endocrinol (Paris). |volume=58 |pages=548–556 |url=http://www.ncbi.nlm.nih.gov/pubmed/9239233?ordinalpos=46&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum }}</ref>. Furthermore, while the high levels of NPY increased food intake or hunger in patients with anorexia nervosa, the emotional discomfort associated with eating may explain the resistance to the orexigenic effects of NPY—suggesting a strong [[limbic system]] influence on food intake in eating disorder such as anorexia nervosa and [[bulimia nervosa]] <ref>{{cite journal |last=Kaye |first=WH |coauthors= Berrettini W, Gwirtsman H & George DT |year=1990|title=Altered cerebrospinal fluid neuropeptide Y and peptide YY immunoreactivity in anorexia and bulimia nervosa |journal=Arch Gen Psychiatry. |volume=47|pages=548–556 |url=http://www.ncbi.nlm.nih.gov/pubmed/2350207?ordinalpos=144&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum }}</ref>.
==Correlation with stress and diet==
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 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 |doi=10.1038/nm1611 }}</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 |doi=10.1016/j.biopsych.2005.08.027 }}</ref>
==Receptors==
{{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.<!--
--><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==
* [[Antianalgesia]]
* [[Neuropeptide]]
*[[Obesity]]
*[[Anorexia nervosa]]
==References==
{{reflist}}
==External links==
* [http://www.ebi.ac.uk/interpro/IEntry?ac=IPR000611 EMBL receptor database entry]
* {{MeshName|Neuropeptide+Y}}
{{Neuropeptides}}
[[Category:Neuropeptides]]
[[de:Neuropeptid Y]]
[[ja:神経ペプチドY]]
[[nl:Neuropeptide Y]]
[[pl:Neuropeptyd Y]]
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