Neuropeptide Y
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Location (UCSC) | Chr 7: 24.28 – 24.29 Mb | Chr 6: 49.8 – 49.81 Mb | |||||||
PubMed search | [3] | [4] |
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Chemical and physical data | |
Formula | C190H287N55O57 |
Molar mass | 4253.714 g·mol−1 |
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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
In the autonomic system it is produced mainly by
Function
Neuropeptide Y has been identified as being synthesized in
The receptor protein that NPY operates on is a
High concentrations of neuropeptide Y synthesis and action have been found in the hypothalamus and hippocampus, 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 release of various hypothalamic hormones such as luteinizing hormone.[13] Neuropeptide Y1 receptors have been found in highest density in the dentate gyrus along with a variety of other brain areas.[14]
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).[15]
Cell growth
Neuropeptide Y has been indicated as playing an important role in
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 interneurons decreased cell growth in this brain area. NPY affects neurogenesis by interacting with ERK kinase signaling pathways.[17] Additionally, NPY acting on and stimulating Y1 receptors present on progenitor cell membranes in order to increase cell proliferation.[16]
Sub-ventricular zone
Similar to the dentate gyrus, NPY has been found to increase cellular proliferation and
Olfactory bulb
It was found that after blocking NPY expression in mouse
Discovery
Following the isolation of neuropeptide Y (NPY) from the
Six years later, in 1989, Morris et al. homed in on the location of NPYergic nuclei in the brain. Furthermore,
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.[22]
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
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,[24] the glucocorticoid dexamethasone (which activates NPY in the basomedial hypothalamus),[25] or N-acetyl [Leu 28, Leu31] NPY (24-36)[26] are injected into the third ventricle[24] or at the level of the hypothalamus with a cannula.[25][27]
Furthermore, these studies unanimously demonstrate that the stimulation of NPYergic activity via the administration of certain NPY
Connection to obesity
A study in genetically obese rats demonstrated the role of NPY in obesity.[29] Four underlying factors that contribute to obesity in rats are:
- an increase in glucocorticosteroid concentrations in plasma;
- insensitivity or resistance to insulin;
- mutation of leptin receptor; and
- an increase in NPY mRNA and NPY release.[30]
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.[31] 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.[31] 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.[31]
Furthermore, these factors correlate with each other. The sustained high levels of glucocorticosteroids stimulate
A study showed that neuropeptide Y can be used as a biosensor in early detection of childhood obesity[35]
Clinical significance
Alcoholism
The role of neuropeptide Y has gained substantial attention for its involvement with
Previous studies have identified NPY's anxiolytic effects to a possible therapeutic drug target for alcoholism.[37] 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 for a Y2 receptor that would indirectly act as an agonist and stimulate Y1 receptors, alcohol consumption was successfully decreased in rats.[36] 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.[38] Although, it has been shown that NPY gene expression, 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.[36]
Two results suggest that NPY might protect against alcoholism:
- 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;[39]
- 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.[40]
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.[41] It has been shown that higher levels of the Y1 and Y5 receptors in the amygdala result in reduced level of anxiety.[42] Additionally, the Y1 receptor has been linked to anxiolytic effects in the forebrain while Y2 has been associated with the pons.[11]
Conversely, higher levels of NPY may be associated with
Studies of
See also
References
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029819 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ "Deprived of Sex, Jilted Flies Drink More Alcohol". UCSF News Center. March 15, 2012.
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- ^ Steenhuysen J (February 16, 2009). "Research shows why some soldiers are cool under fire". Archived from the original on February 19, 2009. Retrieved February 17, 2009.
- ^ Maugh TH (July 2, 2007). "Research points to way to eliminate belly fat". Chicago Tribune.
External links
- EMBL receptor database entry
- Neuropeptide Y at the U.S. National Library of Medicine Medical Subject Headings (MeSH)