Neuropeptide Y

Neuropeptide Y (NPY) is a 36-is_associated_with::amino acid is_associated_with::neuropeptide that acts as a is_associated_with::neurotransmitter in the is_associated_with::brain and in the is_associated_with::autonomic nervous system of humans; slight variations of the peptide are found in many other animals. In the autonomic system it is produced mainly by is_associated_with::neurons of the is_associated_with::sympathetic nervous system and serves as a strong is_associated_with::vasoconstrictor and also causes growth of fat tissue. In the brain, it is produced in various locations including the is_associated_with::hypothalamus, 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 is_associated_with::circadian rhythm, reducing voluntary alcohol intake, lowering blood pressure, and controlling epileptic seizures.

Discovery
Following the isolation of neuropeptide-y (NPY) from the porcine is_associated_with::hypothalamus 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 is_associated_with::paraventricular nucleus (PVN) of the is_associated_with::hypothalamus, 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, is_associated_with::in situ hybridization results from the study showed the highest cellular levels of NPY is_associated_with::mRNA in the is_associated_with::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 is_associated_with::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 is_associated_with::obesity. These studies, collectively, marked the beginning of the role of NPY in orexigenesis or food intake.

The role of NPY in food intake
Behaviorial assays in orexigenic studies, in which is_associated_with::rats are the model organism, have been done collectively with is_associated_with::immunoassays and is_associated_with::in situ hybridization studies to confirm that elevating NPY-ergic activity does indeed increase food intake. In these studies, exogenous NPY, an NPY agonist such as is_associated_with::dexamethasone or N-acetyl [Leu 28, Leu31] NPY (24-36) are injected into the third ventricle or at the level of the hypothalamus with a is_associated_with::cannula.

Furthermore, these studies unanimously demonstrate that the stimulation of NPYergic activity via the administration of certain NPY is_associated_with::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.

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 is_associated_with::obesity. The study revealed four underlying factors that contributed to obesity in rats:
 * an increase in glucocorticosteroid concentrations in plasma;
 * insensitivity or resistance to is_associated_with::insulin;
 * is_associated_with::mutation of is_associated_with::leptin receptor; and
 * an increase in NPY mRNA and NPY release.

Furthermore, these factors correlate with each other. The sustained high levels of glucocorticosteroids stimulate is_associated_with::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 is_associated_with::glycogen in the tissues in the body. In the case of obesity, which researchers speculate to have a strong genetic and a dietary basis, is_associated_with::insulin resistance prevents high blood glucose regulation, resulting in morbid levels of glucose and is_associated_with::diabetes mellitus. 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 is_associated_with::corticotropin-releasing factor (CRF) on NPY synthesis and release. Meanwhile, obesity-induced insulin resistance and the mutation of the is_associated_with::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 is_associated_with::adrenalectomy or is_associated_with::hypophysectomy.

Correlation with stress and diet
Studies of mice and is_associated_with::monkeys show that repeated stress — and a high-is_associated_with::fat, high-is_associated_with::sugar diet — stimulate the release of neuropeptide Y, causing fat to build up in the is_associated_with::abdomen. 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.

Higher levels of NPY may be associated with resilience against and recovery from is_associated_with::posttraumatic stress disorder and with dampening the fear response, allowing individuals to perform better under extreme stress.

Alcoholism
Two results suggest that NPY might protect against is_associated_with::alcoholism:
 * is_associated_with::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 is_associated_with::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.

Receptors
The receptor protein that NPY operates on is a is_associated_with::G protein-coupled receptor in the is_associated_with::rhodopsin 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 receptors.