Neuropeptide Y

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Neuropeptide Y
Structure of Neuropeptide Y. From PDB 1ron.
Available structures: 1f8p, 1fvn, 1icy, 1ron
Identifiers
Symbol(s)	NPY; PYY4
External IDs	OMIM: 162640 MGI: 97374 HomoloGene: 697
Gene ontology Molecular Function: • G-protein-coupled receptor binding • G-protein coupled receptor activity • neuropeptide hormone activity • calcium channel regulator activity Cellular Component: • extracellular region • extracellular space • cell Biological Process: • calcium ion transport • cell motility • G-protein signaling, coupled to cyclic nucleotide second messenger • neuropeptide signaling pathway • synaptic transmission • digestion • blood pressure regulation • cell proliferation • adult feeding behavior • positive regulation of appetite
RNA expression pattern
More reference expression data
Orthologs
	Human	Mouse
Entrez	4852	109648
Ensembl	ENSG00000122585	ENSMUSG00000029819
Uniprot	P01303	P57774
Refseq	NM_000905 (mRNA) NP_000896 (protein)	NM_023456 (mRNA) NP_075945 (protein)
Location	Chr 7: 24.29 - 24.3 Mb	Chr 6: 49.75 - 49.76 Mb
Pubmed search	[1]	[2]

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.^[1] 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 nociceptive signals to the brain^[2].

NPY also augments the vasoconstrictor effects of noradrenergic neurons.

Contents 1 History 2 The role of NPY in food intake 3 The role of NPY in obesity 4 The role of NPY in anorexia nervosa 5 Correlation with stress and diet 6 Receptors 7 See also 8 References 9 External links

[edit] 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.^[3].

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.^[4].

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.^[5].

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^[6]. These studies, collectively, marked the beginning of the role of NPY in orexigenesis or food intake.

[edit] 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, ^[7] an NPY agonist such as dexamethasone ^[8], or N-acetyl [Leu 28, Leu31] NPY (24-36) ^[9] are injected into the third ventricle ^[10] or at the level of the hypothalamus with a cannula ^[11][12].

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 ^[13]. 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 ^[14].

[edit] 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 ^[15]. 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 ^[16]. 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 ^[17] and a hypophysectomy ^[18]

[edit] 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 ^[19]. 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^[20]. 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 ^[21].

[edit] 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 the appetite hormone, they could make fat melt from areas where it was not desired and accumulate at sites where it is needed.^[22][23]

Higher levels of NPY may be associated with resilience against and recovery from posttraumatic stress disorder.^[24]

[edit] Receptors

Main article: 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.^[25] 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.

[edit] See also

• Antianalgesia
• Neuropeptide
• Obesity
• Anorexia nervosa

[edit] References

[edit] External links

• EMBL receptor database entry
• MeSH Neuropeptide+Y

v • d • e Peptides: neuropeptides Hypothalamic Somatostatin - CRH - GnRH - GHRH - Orexins - TRH - POMC (ACTH, MSH, Lipotropin) Gastrointestinal hormones Cholecystokinin - Gastric inhibitory polypeptide - Gastrin - Motilin - Secretin - Vasoactive intestinal peptide Other hormones Vasopressin - Calcitonin - Other Angiotensin - Bombesin/Neuromedin B - Calcitonin gene-related peptide - Carnosine - Delta sleep-inducing peptide - FMRFamide - Galanin - Gastrin releasing peptide - Kinins (Bradykinin, Tachykinins ) - Neuromedin (B, N, U) - Neuropeptide Y - Neurophysins - Neurotensin - Opioid peptide - Pancreatic polypeptide - Pituitary adenylate cyclase activating peptide