Neuropeptide Y
Neurotransmitters

Neuropeptide y (NPY) is a peptidic hormone that can be found in central, periferical and autonomic nervous system.
It is mainly secreted by NPY/AgRP cells of the paraventricular nucleus (PVN) and arcuate nucleus (ARC) of the hypothalamus, but also it is the neurotrasmettitor of many interneurons of mammals nervous system.
It has many elements and functions in common with YY peptide and pancreatic polypeptide and it is made by 34 amminoacids.

The effects of NPY are mediated by the linking to its receptors; there are 6 types of receptors (Y1-Y6), but Y1, Y2 and Y5 are the most studied. (1)
They are all coupled to Gi/0 proteins.

1. Role on NPY in obesity and metabolic syndrome

Npy has an important role in feeding because of its action on the center of feeding in the brain, by the linking to Y1 and Y5 receptors. The effects of NPYergic activity on food intake is also demonstrated by the blockade of Y1 and Y5 receptors (2;2010 Oct), which, as was expected, inhibited NPYergic activity and the food intake.
Moreover the food intake is regulated by Y2 receptors, that down-regulate the release of NPY after the binding of YY peptide, that inhibit its action.
The NPY gene transcription is activated by Ghrelin (by generation of ROS that act like transcription factors in NPY/AgRP cells) and glucocorticoid hormones (by the binding of II glucocorticoids receptors, which are activated only by relatively high levels of glucocorticoids) and inhibited by Leptin.
Hypothalamic NPY stimulates feeding, inhibits thermogenesis and increase the release of insulin and corticosteroid hormones (by CRH); it also stimulate the metabolism of cholesterol.
In obese people, NPY binds Y2 receptors on adipocytes and on endothelial cells of adipose blood vessels and stimulate the growth of abdominal adipocytes.
It has also discovered that abdominal adipocytes can produce NPY locally, in a positive-feedback loop. (3;2008 Jul)
It is also possible to say that stress stimulates the growth of fat tissue by production of high levels of glucocorticoids that stimulate the production of NPY.
Implications in metabolic syndrome is mediated by its role is the increase of blood insulin, in accelerating atherosclerosis, in vasoconstriction and in obesity. (2;2010 Oct)
Another point of view is about the structure of NPY, because a rare polymorphism (Leu7Pro;1998 Dec) of the gene is associated to high quantities of blood cholesterol and LDL.
In-spite of this, NPY has also a role in anorexia nervosa, maybe because of the strong limbic system inhibiting influence on the orexigenic effect of NPY and on food intake in some people.
Scientist are studying a method to treat obesity with Y2 receptor antagonist, because their blockage could prevent feeding. (4;2009 Oct)

2. Role in epilepsy [a;2003 Mar]

NPY gene is also expressed by ippocampal cells, amygdala and neocortical cells (in particular interneurons) that express g-aminobutirric acid (GABA).
NPY receptors are densely concentrated in the strata radiatum and oriens of Ammon's horn of rats and humans.
Epilepsy is a neurological disorder characterized by an imbalance between excitations (mediated by glutamatergic synapses) and inhibitions, that are mediated by GABA synapses.
Many studies demonstrated that NPY can inhibit excitatory inputs into pyramidal cell throughout Ammon's horn in the rat. (5;1997 Sep), (6;1993 Jan)
An example of this is the administration of kanic acid (it induces tonic–clonic seizures) after the injection of NPY into the lateral ventricle of epileptic patients, because after that epileptic seizures doesn’t occur any more. This effect is mediated by Y5-like receptors (Y5 receptors has been cloned in rats). NPY could be considered an endogenous anticonvulsant molecule, and NPY agonists acting on Y5-like receptors could become drugs in treatment of epilepsy. (7;1997)
Another point of view is the enhanced expression of NPY mRNA in many areas of brains of epileptic patients (like hippocampus, cerebral cortex and the amygdala) that mediates an endogenous anticonvulsant effect.
Moreover the expression of Y1 receptor is reduced and the number of Y2 is increased; stimulation of presynaptic Y2 receptors inhibits glutamate release (with a consequent anticonvulsant effect) and stimulation of Y1 receptors mediates a weak excitatory component of NPY action. This is considered an adaptive endogenous mechanism in order to reduce the hyperexcitability of cells during tonic–clonic seizures. (8;2004 Aug)
These events could be considered in treatment of epilepsy, in particular through gene therapy: the transduction of NPY gene results in an important decrease in the number if epileptic seizures. (9,2007 Feb)
Furthermore scientists studied the connection between epilepsy attacks and menstrual cycles in fertile women: they revealed that estradiol increase seizure susceptibility, but decrease seizure severity because of its capacity to increase the release of NPY. (10)

Actions of neuropeptide Y (NPY) and a Y2 antagonist in rat hippocampal slices. A: effect of npy on the population excitatory postsynaptic potential (pEPSP) evoked by electrical stimulation of stratum radiatum in area CA2, recorded extracellularly in area CA1. Black trace, control response; red trace, response in the presence of 1 mM NPY; blue trace, response to NPY in the presence of the Y2-receptor antagonist, BIIE 0246 (100 NM). B: effect of NPY on primary afterdischarges (18 ADs) in the stimulus train–induced bursting (STIB) model in rat hippocampal slice. extracellular recording from area CA3 shows tonic–clonic 18 AD in control (left trace) in the presence of NPY (300 nm) (center trace), and in 300 nm NPY after pretreatment with BIIE 0246 (100 NM). C: time course of the inhibition of the 18 AD by NPY (300 nm) in the absence (red circles) and presence (blue triangles) of BIIE 0246 (100 nm). (B and C modified from ref. 53, with permission).

3. Role in depression [b]

As we said receptors of NPY are located three key locations in the brain that deal with stress: the amygdala, the hippocampus, and the locus coeruleus; in the amygdala, increased NPY levels may be associated with decreased feelings of anxiety.
Patients with PTSD show low concentration of neuropeptide y in cerebrospinal fluid (11;2009 Oct); this discovery demonstrated that it is implicated in many emotional processes like anxiety, depression and also in concentration.
The interaction with NPY and CRH (NPY antagonizes CRH) is the key event that can control the emotional state of the patient: CRH receptors are found throughout the brain, in areas specifically associated with stress reactions, such as the amygdala and the locus coeruleus.
On both of these brain structures, NPY and CRH have counterbalancing functional effects. In the amygdala, CRH can promote activation, resulting in stimulation and increased feelings of anxiety, while NPY results in decreased amygdala arousal and anti-anxiety feelings. (12;2011 Sep)
In locus coeruleus, CRH causes an increase in firing rate and in norepinephrine levels, while NPY has a counter effect, resulting in decreases in rate and level.
Moreover Y1 and Y2 receptors are also involved here: Y1 receptors can reduce the expression of conditioned fear, while Y2 receptor seem to have no important effects, but only a light synergistic role in fear acquisition and in fear extinction. (13)

4. Role in atherosclerosis and in vascular remodeling [c;2009 Jan]

NPY is also involved in pathogenesis of CAD , because of a linkage of the familiar type of the pathology and the genomic region of NPY. (14;2009 Jan)
Moreover the Leucine7 to Proline7 (Leu7Pro) polymorphism of the signal peptide of neuropeptide Y (NPY) increases risk for vascular complications in type 2 diabetes. (15;2010 Dec)
NPY is also a platelet-derived vasoconstrictor in some species, a vascular mitogen, via Y1 and Y5 receptors and an angiogenic factor via Y2 and Y5 receptors. (16;2007 Feb)
It can also modulate the expression of cytokines in atherosclerotic carotid plaques via Y2 receptors; their number is increased plaque cells stimulate with TNF-α, IL-12 or IFN-γ. (17;2011 Jun)

DPPIV is a Y2/Y5-selective agonist.

5. Role in cancer

Expression of NPY receptors (mainly Y1, Y2 and Y5) is enhanced in human breast carcinomas; Y5 receptor is involved in growth (via ERK pathway) and increased migration in human breast cancer cells.
Stress could be considered a cancer risk factor because of its induction of elevated levels of sympathetic neurotransmitters like norepinephrine and NPY. (18;2011 Aug)
Y1 receptors are also overexpressed in breast tumors, while Y2 receptors are only located in normal breast tissue. This can suggest that the neoplastic transformation can switch the expression of NPY receptors from Y2 to Y1. (19;2001 Apr)

6. Role in immunomodulation [d;2011 Dec]

NPY has also a role in modulating the immune system. In particular it can inhibit the production of IL-1β by microglial cells; this effect is exclusively mediated by the binding to Y1 receptors.
Microglial cells stimulated with LPS and ATP release high quantities of IL-1β, that can induce iNOS (inducible nitric oxide synthase) and consequently the production of NO. (20;2011 Dec)
The use of NPY can modulate inflammation responses associated with brain pathologies. (21;2010 Oct)
On the contrary NPY can also stimulate the production of TNF-α by macrophages in an autocrine manner; in-fact they have both Y1 receptors on their membrane and the ability to produce NPY under inflammatory stimulus like LPS. (22;2010 May)

NPY inhibits nuclear translocation of NF-κB after IL-1β challenge. A, confocal microscopy photomicrographs of microglial cells treated with 1 μm NPY and 1.5 ng/ml IL-1β for 15 min were taken to assess the role of NPY and IL-1β in the NF-κB signaling pathway. Cells were stained for NF-κB (in green), for CD11b (in red), and with Hoechst 33342 (nuclei in blue). Nuclear translocation of NF-κB was promoted by IL-1β and inhibited when cells were treated with NPY. Orthogonal sections show nuclear localization of NF-κB (in green). Scale bar, 10 μm. B, Western blotting analysis was performed to study the inhibitory effect of NPY on NF-κB (65 kDa) nuclear translocation upon IL-1β stimulation. After IL-1β challenge, a significant increase in NF-κB protein levels was observed. When cells were treated with NPY, the amount NF-κB was reduced to values comparable with control. A representative blot is shown below the graph. Data are expressed as mean ± S.E. (n = 3) and as a percentage of control (*, p < 0.05, using Bonferroni's multiple comparison test).

7. Role in pain modulation [e;2006 Sep]

Dorsal roots neurons produce NPY in response to inflammation (inflammatory pain) and after a nervous damage (neuropathic pain).
It is a powerful pain modulator; in particular it can inhibit the transition from acute to chronic pain in an endogenous way. (23;2011 Apr)
This effect is exerted by Y1 receptors, in particular located on a group of glutamatergic interneurons in the superficial dorsal horn laminae and by the Y2-mediated inhibition of Ca2+ channel currents in dorsal root ganglion neurons.
In-spite of that, NPY can also have a pro-nociceptive action depending on the differential distribution of receptor. (24;2007 Feb)
Y2 receptors seem to be responsible for the increase of the hyperalgesic response in neuropatic pain; to characterize NPY action, specific Y1 and Y2 antagonists were also delivered directly into dorsal root ganglion, which revealed that behavioral actions of NPY were abolished by Y2 receptor antagonist. (25;2011 May)

8. Role in sympathetic activity [f;2011 Mar] and in hypertension

NPY has been founded in many sympathetic ganglion neurons, in a high number of neurons of parasympathetic cranial ganglia and in cells of intramural ganglia of the enteric nervous system.
Action of NPY on peripheral organs-targets is predominantly realized through postsynaptic receptors Y1, Y3 Y5, presynaptic receptors of the Y2 type and is independent from alpha-receptors. (26)
It is present in large electron-dense vesicles and is released at high-frequency stimulation.
NPY affects not only vascular tone, frequency and strength of heart contractions, motorics and secretion of the gastrointestinal tract, but also has trophic effect and produces proliferation of cells of organs-targets, specifically of vessels, myocardium, and adipose tissue.
Moreover both NPY and a-MSH appears to be implicated in the hypothalamic regulation of sympathetic nervous system (SNS) activity. (27;2008 Sep), (28;2011 May)
In cardiac desease (induced by hypertension) NPY was recognized as an important mediator released from sympathetic nerves in the heart, affecting coronary artery constriction and myocardial contraction, via Y1, Y2 and Y5 receptors. Its levels in plasma become elevated due to the increased sympathetic activation present in stress-related cardiac conditions.
Moreover many NPY and Y receptor polymorphisms may predispose individuals to increased risk of hypertension and cardiac complications. (29;2007)

Neuropeptide Y co-exists and co-operates with noradrenaline in perivascular nerve fibers.

CONCLUSIONS

NPY is involved in many physiological and pathological functions and it can be used as a marker in serum to make diagnoses.
High or low levels of NPY in blood can be linked to many pathological states, because its systemic effects.
Stress-conditions are very dangerous also because of high levels of NPY that can lead to obesity, type 2 diabetes, systemic high blood pressure, immune weakness and cardiac disorders and because its antagonist action against CRH.
Someone call NPY "molecule of pessimism" because low levels in the blood can make people more likely to be depressed and pessimist, because of high activation of prefrontal-cortex and, moreover, susceptible to tensive muscle headache. (30;1994 Jan)
Another interesting thing is the link between tryptophan and NPY: synthesis of NPY needs that aminoacid.

byIvan Oppedisano