Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. It is secreted alongside other neurotransmitters such as GABA and

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

. In the autonomic system it is produced mainly by

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue. In the brain, it is produced in various locations including the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

, 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 A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., Endogeny (biology), endogenous) and responds to the env ...

, reducing voluntary alcohol intake, lowering blood pressure, and controlling epileptic seizures.

Function

Neuropeptide Y has been identified as being synthesized in GABAergic neurons and to act as a

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

during cellular communication. Neuropeptide Y is expressed in

interneuron Interneurons (also called internuncial neurons, association neurons, connector neurons, or intermediate neurons) are neurons that are not specifically motor neurons or sensory neurons. Interneurons are the central nodes of neural circuits, enab ...

s. NPY exerts most of its effects through Neuropeptide Y receptors, mainly Y1, Y2, Y4, and Y6. All receptors have been indicated as participants in post-synaptic transmission activity, but the Y2 receptor has also been found to be involved in pre-synaptic processing. The receptor protein that NPY operates on is a G protein-coupled receptor in the

rhodopsin Rhodopsin, also known as visual purple, is a protein encoded by the ''RHO'' gene and a G-protein-coupled receptor (GPCR). It is a light-sensitive receptor protein that triggers visual phototransduction in rod cells. Rhodopsin mediates dim ...

like 7-transmembrane GPCR family. Five subtypes of the NPY receptor have been identified in mammals, four of which are functional in humans. 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 Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...

receptors. High concentrations of neuropeptide Y synthesis and action have been found in the

and

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

, specifically in the arcuate nucleus (ARC) and dentate gyrus. The arcuate nucleus has been found to have one of the highest concentrations of NPY. This allows NPY to regulate

neuroendocrine Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules ( hormones) into the blood. In this way they b ...

release of various hypothalamic hormones such as luteinizing hormone. Neuropeptide Y1 receptors have been found in highest density in the dentate gyrus along with a variety of other brain areas. NPY is able to modulate the mitochondrial network by affecting the expression of many genes involved in mitochondrial functions and dynamics. It has been found that in breast muscle, ATP production genes (uncoupling protein, ''UCP''; nuclear factor erythroid 2 like 2, ''NFE2L2'') and a dynamics gene (mitofusin 1, ''MFN1'') were upregulated (''P'' < 0.05) at a low dose of NPY, while a high dose decreased (''P'' < 0.05) markers of mitochondrial dynamics (mitofusin 2, ''MFN2;'' OPA1 mitochondrial dynamin-like GTPase, ''OPA1'') and increased (''P'' < 0.05) genes involved in mitochondrial biogenesis (D-loop, peroxisome proliferator-activated receptor gamma, ''PPARG'').

Cell growth

Neuropeptide Y has been indicated as playing an important role in neurogenesis in various parts of the brain. Two particular brain areas where NPY affects neurogenesis are the sub-ventricular zone and the dentate gyrus of the

. These areas are where

cell growth Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...

and proliferation occur into adulthood.

Dentate gyrus

The dentate gyrus is significantly involved in cell proliferation, a process modulated by various internal factors including neuropeptide Y. Reduction or elimination of NPY released by

s decreased cell growth in this brain area. NPY affects neurogenesis by interacting with ERK kinase signaling pathways. Additionally, NPY acting on and stimulating Y1 receptors present on progenitor cell membranes in order to increase cell proliferation.

Sub-ventricular zone

Similar to the dentate gyrus, NPY has been found to increase cellular proliferation and differentiation in the sub-ventricular zone by specifically activating Y1 receptors in the ERK1/2 pathway. Additionally, NPY was found in neuronal fibers that pass through the sub-ventricular zone and extend to other brain areas. A variety of other effects and physiological processes involving NPY in the sub-ventricular zone have been discovered, many of which involve neuron migration patterns.

Olfactory bulb

It was found that after blocking NPY expression in mouse olfactory epithelium, the amount of olfactory precursor cells decreased by half. This in turn caused the mice to develop a lower amount of olfactory cells overall. This study exemplified NPY's influence on precursor cells.

Discovery

Following the isolation of neuropeptide Y (NPY) from the porcine

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

, and the highest levels of NPY immunoreactivity was found within the PVN of the hypothalamus. 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 molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

in the arcuate nucleus (ARC) of the hypothalamus. 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. 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 Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

. These studies, collectively, marked the beginning for understanding the role of NPY in orexigenesis or food intake.

Connection to food intake

Behavioral 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, the

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...

dexamethasone (which activates NPY in the basomedial hypothalamus), or N-acetyl eu 28, Leu31NPY (24-36) are injected into the third ventricle or at the level of the hypothalamus with a

cannula A cannula (; Latin meaning 'little reed'; : cannulae or cannulas) is a tube that can be inserted into the body, often for the delivery or removal of fluid or for the gathering of samples. In simple terms, a cannula can surround the inner or out ...

. 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. 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.

Connection to obesity

A study in genetically obese rats demonstrated the role of NPY in

. Four underlying factors that contribute to obesity in rats are: * an increase in glucocorticosteroid concentrations in plasma; * insensitivity or resistance to

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

; *

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

leptin Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small"), also known as obese protein, is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long ...

receptor; and * an increase in NPY mRNA and NPY release. 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 hormonal derangement that increased 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 NPY concentration however is more difficult than rats. 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. 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 neurons 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. Furthermore, these factors correlate with each other. The sustained high levels of glucocorticosteroids stimulate

gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...

, 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 Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...

. 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 or hypophysectomy. A study showed that neuropeptide Y can be used as a biosensor in early detection of childhood obesity

Clinical significance

Alcoholism

The role of neuropeptide Y has gained substantial attention for its involvement with

alcoholism Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...

due to its diverse range of physiological effects. NPY neurons have been shown to interact with

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

reward and

emotion Emotions are physical and mental states brought on by neurophysiology, neurophysiological changes, variously associated with thoughts, feelings, behavior, behavioral responses, and a degree of pleasure or suffering, displeasure. There is ...

pathways in the nucleus accumbens and amygdala, respectively. NPY expression levels and

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

preference have been shown to exhibit an inverse relationship. Expression levels are dependent on the brain area of interest. This indicates that baseline NPY levels could possibly influence innate alcohol preferences. Previous studies have identified NPY's anxiolytic effects to a possible therapeutic drug target for alcoholism. As stated before, NPY levels and ethanol intake show an inverse relationship, therefore, increasing NPY availability could decrease alcohol intake. By creating a chemical

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

and stimulate Y1 receptors, alcohol consumption was successfully decreased in rats. Additionally, another similar study identified that NPY expression may be connected to behavioral regulation in relation to alcohol dependence. Administration of neuropeptide Y was found to reduce binge-drinking behavior. Although, it has been shown that NPY

gene expression Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...

, mRNA or neuropeptide levels are not influenced by long-term alcohol consumption, but changes do occur during withdrawal from alcohol. These findings show that neuropeptide Y has varying effects on alcohol consumption. Two results suggest that NPY might protect against

: * 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; * 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.

Stress and anxiety

Neuropeptide Y is considered to be an anxiolytic endogenous peptide and its levels can be modulated by stress. NPY has connections to the HPA axis and is believed to be necessary for stress modulation. It has been shown that higher levels of the Y1 and Y5 receptors in the amygdala result in reduced level of

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

. Additionally, the Y1 receptor has been linked to anxiolytic effects in the

forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain controls body temperature, reproductive functions, eating, sleeping, and the display of emotions. Ve ...

while Y2 has been associated with the pons. Conversely, higher levels of NPY may be associated with resilience against and recovery from posttraumatic stress disorder and with dampening the fear response, allowing individuals to perform better under extreme stress. Studies of

mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

and monkeys show that repeated stress—and a high- fat, high-

sugar Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecul ...

diet—stimulate the release of neuropeptide Y, causing fat to build up in the

abdomen The abdomen (colloquially called the gut, belly, tummy, midriff, tucky, or stomach) is the front part of the torso between the thorax (chest) and pelvis in humans and in other vertebrates. The area occupied by the abdomen is called the abdominal ...

. 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.

References

External links

EMBL receptor database entry
* {{Sigma receptor modulators Neuropeptides