Neuropeptide Y

NPY
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
Aliases NPY, PYY4, Neuropeptid Y gene, neuropeptide Y
External IDs OMIM: 162640 MGI: 97374 HomoloGene: 697 GeneCards: NPY
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez

4852

109648

Ensembl

ENSG00000122585

ENSMUSG00000029819

UniProt

P01303

P57774

RefSeq (mRNA)

NM_000905

NM_023456

RefSeq (protein)

NP_000896.1

NP_075945.1

Location (UCSC) Chr 7: 24.28 – 24.29 Mb Chr 6: 49.82 – 49.83 Mb
PubMed search [1] [2]
Wikidata
View/Edit HumanView/Edit Mouse
Neuropeptide Y
Identifiers
CAS Number 82785-45-3 N
ChemSpider none
ChEMBL CHEMBL267633 N
Chemical and physical data
Formula C190H287N55O57
Molar mass 4253.7 g/mol
 NYesY (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.[3] 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.[4] 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.[3][5]

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.[6]

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.[7]

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.[8]

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.[9] 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 elevating NPY-ergic activity does indeed increase food intake. In these studies, exogenous NPY,[10] an NPY agonist such as dexamethasone[11] or N-acetyl [Leu 28, Leu31] NPY (24-36)[12] are injected into the third ventricle[10] or at the level of the hypothalamus with a cannula.[11][13]

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.[14] 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.[10]

The role of NPY 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.[16] 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.[16] 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.[17]

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.[18] 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[19] or hypophysectomy.[20]

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.[4][21]

Conversely, higher levels of NPY may be associated with resilience against and recovery from posttraumatic stress disorder[22] and with dampening the fear response, allowing individuals to perform better under extreme stress.[23]

Alcoholism

Two results suggest that NPY might protect against alcoholism:

Receptors

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.[26] 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. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. 1 2 Tatemoto K (2004). "Neuropeptide Y: History and Overview". In Michel MC. Handbook of Experimental Pharmacology. 162. Springer. pp. 2–15.
  4. 1 2 Kuo LE, Kitlinska JB, Tilan JU, et al. (July 2007). "Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome". Nat. Med. 13 (7): 803–11. doi:10.1038/nm1611. PMID 17603492.
  5. ↑ Colmers WF, El Bahn B (2003). "Neuropeptide Y and Epilepsy". Epilepsy Currents/American Epilepsy Society. 2 (3): 53–8. doi:10.1046/j.1535-7597.2003.03208.x. PMC 321170Freely accessible. PMID 15309085.
  6. ↑ 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.
  7. ↑ Morris BJ (December 1989). "Neuronal localisation of neuropeptide Y gene expression in rat brain". J. Comp. Neurol. 290 (3): 358–68. doi:10.1002/cne.902900305. PMID 2592617.
  8. ↑ 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 Res. 498 (2): 333–8. doi:10.1016/0006-8993(89)91112-8. PMID 2551461.
  9. ↑ Edwardson JA, Hough CA (April 1975). "The pituitary-adrenal system of the genetically obese (ob/ob) mouse". J. Endocrinol. 65 (1): 99–107. doi:10.1677/joe.0.0650099. PMID 167093.
  10. 1 2 3 Hanson ES, Dallman MF (April 1995). "Neuropeptide Y (NPY) may integrate responses of hypothalamic feeding systems and the hypothalamo-pituitary-adrenal axis". J. Neuroendocrinol. 7 (4): 273–9. doi:10.1111/j.1365-2826.1995.tb00757.x. PMID 7647769.
  11. 1 2 White BD, Dean RG, Edwards GL, Martin RJ (May 1994). "Type II corticosteroid receptor stimulation increases NPY gene expression in basomedial hypothalamus of rats". Am. J. Physiol. 266 (5 Pt 2): R1523–9. PMID 8203629.
  12. ↑ 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". J. Neurochem. 73 (2): 641–6. doi:10.1046/j.1471-4159.1999.0730641.x. PMID 10428060.
  13. ↑ Pomonis JD, Levine AS, Billington CJ (1 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". J. Neurosci. 17 (13): 5175–82. PMID 9185555.
  14. ↑ 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". Eur. J. Pharmacol. 396 (1): R1–3. doi:10.1016/S0014-2999(00)00230-2. PMID 10822055.
  15. ↑ 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 Res. 690 (2): 185–8. doi:10.1016/0006-8993(95)00628-4. PMID 8535835.
  16. 1 2 Minor, Robin (2008). "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: 79–88. doi:10.1016/j.mce.2008.10.044.
  17. ↑ Minor, Robin (2008). "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: 79–88. doi:10.1016/j.mce.2008.10.044.
  18. ↑ Wilcox G (May 2005). "Insulin and insulin resistance". Clin Biochem Rev. 26 (2): 19–39. PMC 1204764Freely accessible. PMID 16278749.
  19. ↑ Yukimura Y, Bray GA (1978). "Effects of adrenalectomy on body weight and the size and number of fat cells in the Zucker (fatty) rat". Endocr Res Commun. 5 (3): 189–98. doi:10.1080/07435807809083752. PMID 747998.
  20. ↑ Powley TL, Morton SA (1 April 1976). "Hypophysectomy and regulation of body weight in the genetically obese Zucker rat". Am. J. Physiol. 230 (4): 982–7. PMID 1267030.
  21. ↑ Thomas H. Maugh II (July 2, 2007). "Research points to way to eliminate belly fat". Chicago Tribune.
  22. ↑ 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". Biol. Psychiatry. 59 (7): 660–3. doi:10.1016/j.biopsych.2005.08.027. PMID 16325152.
  23. ↑ Julie Steenhuysen (February 16, 2009). "Research shows why some soldiers are cool under fire".
  24. ↑ Thiele TE, Koh MT, Pedrazzini T (February 2002). "Voluntary alcohol consumption is controlled via the neuropeptide Y Y1 receptor". J. Neurosci. 22 (3): RC208. PMID 11826154.
  25. ↑ "Deprived of Sex, Jilted Flies Drink More Alcohol". UCSF News Center. March 15, 2012.
  26. ↑ Michel MC, Beck-Sickinger A, Cox H, Doods HN, Herzog H, Larhammar D, Quirion R, Schwartz T, Westfall T (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.
This article is issued from Wikipedia - version of the 10/23/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.