Neuropeptide Y (NPY) is a 36-amino acid peptide neurotransmitter found in the brain and autonomic nervous system.

Neuropeptide Y

Clinical data

Pregnancy cat.

Legal status

Identifiers

ATC code

ChEMBL

CHEMBL267633

Chemical data

Formula

C190 H287 N55 O57

Mol. mass

4253.6

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"NPY has been associated with a number of physiologic processes in the brain, including the [1] regulation of energy balance, memory and learning, and epilepsy." 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 [2] blocks nociceptive signals to the brain. NPY also augments the vasoconstrictor effects of noradrenergic neurons.
Contents
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1 Discovery 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]Discovery Following the isolation of neuropeptide-y (NPY) from the porcine hypothalamus in 1982, researchers [citation began to speculate about the involvement of NPY in hypothalamic-mediated functions. needed] [3] Among these hallmark studies was a study done by Allen et al. in 1983. One of the major findings in this study 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 [3] immunoreactivity 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 [4] NPY mRNA in the arcuate nucleus (ARC) of the hypothalamus. However, just two years earlier, in 1987, Haas & George conducted a study that involved injecting NPY locally and discovered an interesting result: 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 [5] 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 [6] as obesity. 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 [7] indeed increase food intake. In these studies, exogenous NPY, an NPY agonist such as [8] [9] [7] dexamethasone or N-acetyl [Leu 28, Leu31] NPY (24-36) are injected into the third ventricle or at [8][10] the level of the hypothalamus with a cannula. Furthermore, these studies unanimously demonstrate that the stimulation of NPYergic activity via the administration of certain NPY agonistsincreases 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 [11] 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 [7] NPY levels and therefore food consumption.

[edit]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: (1) an increase in glucocorticosteroid concentrations in plasma; (2) insensitivity or resistance to insulin; (3) mutation of leptin receptor; and (4) an increase in NPY mRNA and NPY [12] release. Furthermore, these factors also 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 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 [13] regulation, resulting in morbid levels of glucose and diabetes mellitus. Furthermore, high levels of glucocorticosteriods causes an increase of NPY by directly activating type II glucocorticosteriods receptors (which are activated only by relatively high levels of glucocorticosteriods) 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 other negative feedback mechanisms to regulate NPYergic activity and ultimately food intake. Furthermore, obesity in rats was significantly reduced [14] [15] by adrenalectomy or hypophysectomy. [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 thecerebrospinal fluid of patients with anorexia nervosa. Subsequently, high concentrations of adrenocorticotropic hormone (ACTH) and cortisol in [16] the plasma were also found in patients with anorexia nervosa. 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, [17] the anorexigenic nature of leptin. 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 NPYsuggesting a strong limbic system influence [16] on food intake in eating disorder such as anorexia nervosa and bulimia nervosa. [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 [18][19] not desired and accumulate at sites where it is needed. Higher levels of NPY may be associated with resilience against and recovery from posttraumatic [20] stress disorder and with dampening the fear response, allowing individuals to perform better under [21] extreme stress. [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 [22] subtypes 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 receptors.