Neuropeptide Y
Encyclopedia
Neuropeptide Y is a 36-amino acid
peptide neurotransmitter
found in the brain
and autonomic nervous system
.
"NPY has been associated with a number of physiologic processes in the brain, including the 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 blocks nociceptive
signals to the brain. NPY also augments the vasoconstrictor effects of noradrenergic neurons.
in 1982, researchers began to speculate about the involvement of NPY in hypothalamic-mediated functions. 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 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 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 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
.
These studies, collectively, marked the beginning of the role of NPY in orexigenesis or food intake.
are the model organism, have been done collectively with immunoassay
s and in situ hybridization
studies to confirm that NPYergic activity does indeed increase food intake. In these studies, exogenous NPY, an NPY agonist such as 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 cannula.
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.
. 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 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 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 by adrenalectomy
or hypophysectomy
.
. In this post mortem study, high levels of NPY were found in the cerebrospinal fluid
of patients with anorexia nervosa. Subsequently, high concentrations of adrenocorticotropic hormone
(ACTH) and cortisol in 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, 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 NPY—suggesting a strong limbic system
influence on food intake in eating disorder such as anorexia nervosa and bulimia nervosa
.
and monkey
s 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 not desired and accumulate at sites where it is needed.
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.
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 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.
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
peptide neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
found in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
.
"NPY has been associated with a number of physiologic processes in the brain, including the 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
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
, and, in addition to increasing food intake, it increases the proportion of energy stored as fat and blocks nociceptive
Nociception
Nociception is defined as "the neural processes of encoding and processing noxious stimuli." It is the afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue...
signals to the brain. NPY also augments the vasoconstrictor effects of noradrenergic neurons.
Discovery
Following the isolation of neuropeptide-y (NPY) from the porcine hypothalamusHypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
in 1982, researchers began to speculate about the involvement of NPY in hypothalamic-mediated functions. 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
Paraventricular nucleus
The paraventricular nucleus is a neuronal nucleus in the hypothalamus. It contains multiple subpopulations of neurons that are activated by a variety of stressful and/or physiological changes. Many PVN neurons project directly to the posterior pituitary where they release oxytocin or vasopressin...
(PVN) of the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
. Moreover, Allen et al. discovered the highest levels of NPY 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
In situ hybridization
In situ hybridization is a type of hybridization that uses a labeled complementary DNA or RNA strand to localize a specific DNA or RNA sequence in a portion or section of tissue , or, if the tissue is small enough , in the entire tissue...
results from the study showed the highest cellular levels of NPY mRNA in the arcuate nucleus
Arcuate nucleus
The arcuate nucleus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence...
(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
Corticotropin-releasing hormone
Corticotropin-releasing hormone , originally named corticotropin-releasing factor , and also called corticoliberin, is a polypeptide hormone and neurotransmitter involved in the stress response...
(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
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
.
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 ratsRATS
RATS may refer to:* RATS , Regression Analysis of Time Series, a statistical package* Rough Auditing Tool for Security, a computer program...
are the model organism, have been done collectively with immunoassay
Immunoassay
An immunoassay is a biochemical test that measures the presence or concentration of a substance in solutions that frequently contain a complex mixture of substances. Analytes in biological liquids such as serum or urine are frequently assayed using immunoassay methods...
s and in situ hybridization
In situ hybridization
In situ hybridization is a type of hybridization that uses a labeled complementary DNA or RNA strand to localize a specific DNA or RNA sequence in a portion or section of tissue , or, if the tissue is small enough , in the entire tissue...
studies to confirm that NPYergic activity does indeed increase food intake. In these studies, exogenous NPY, an NPY agonist such as 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 cannula.
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.
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 obesityObesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
. The study revealed four underlying factors that contributed to obesity in rats: (1) an increase in glucocorticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
concentrations in plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
; (2) insensitivity or resistance to insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
; (3) mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
of leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
receptor; and (4) an increase in NPY mRNA and NPY release. Furthermore, these factors also correlate with each other. The sustained high levels of glucocorticosteroids stimulate gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
, 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
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
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 regulation, resulting in morbid levels of glucose and diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
. 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
Leptin receptor
Leptin receptor also known as LEP-R is a protein that in humans is encoded by the LEPR gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin...
(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 by adrenalectomy
Adrenalectomy
Adrenalectomy is the surgical removal of one or both adrenal glands. It is usually advised for patients with tumors of the adrenal glands. The procedure can be performed using an open incision or laparoscopic technique....
or hypophysectomy
Hypophysectomy
Hypophysectomy is the surgical removal of the hypophysis . It is most commonly performed to treat tumors, especially craniopharyngioma tumors. Sometimes it is used to treat Cushing's syndrome due to pituitary adenoma...
.
The role of NPY in anorexia nervosa
Kaye et al. conducted a study in 1990 to demonstrate the role of NPY in anorexia nervosaAnorexia nervosa
Anorexia nervosa is an eating disorder characterized by refusal to maintain a healthy body weight and an obsessive fear of gaining weight. Although commonly called "anorexia", that term on its own denotes any symptomatic loss of appetite and is not strictly accurate...
. In this post mortem study, high levels of NPY were found in the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
of patients with anorexia nervosa. Subsequently, high concentrations of adrenocorticotropic hormone
Adrenocorticotropic hormone
Adrenocorticotropic hormone , also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological...
(ACTH) and cortisol in 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, the anorexigenic nature of leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
. 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 NPY—suggesting a strong limbic system
Limbic system
The limbic system is a set of brain structures including the hippocampus, amygdala, anterior thalamic nuclei, septum, limbic cortex and fornix, which seemingly support a variety of functions including emotion, behavior, long term memory, and olfaction. The term "limbic" comes from the Latin...
influence on food intake in eating disorder such as anorexia nervosa and bulimia nervosa
Bulimia nervosa
Bulimia nervosa is an eating disorder characterized by binge eating and purging or consuming a large amount of food in a short amount of time, followed by an attempt to rid oneself of the food consumed, usually by purging and/or by laxative, diuretics or excessive exercise. Bulimia nervosa is...
.
Correlation with stress and diet
Studies of miceMouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
and monkey
Monkey
A monkey is a primate, either an Old World monkey or a New World monkey. There are about 260 known living species of monkey. Many are arboreal, although there are species that live primarily on the ground, such as baboons. Monkeys are generally considered to be intelligent. Unlike apes, monkeys...
s show that repeated stress
Stress (medicine)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
— and a high-fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
, high-sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
diet — stimulate the release of neuropeptide Y, causing fat to build up in the abdomen
Abdomen
In vertebrates such as mammals the abdomen constitutes the part of the body between the thorax and pelvis. The region enclosed by the abdomen is termed the abdominal cavity...
. Researchers believe that by manipulating levels of the appetite hormone, they could make fat melt from areas where it was not desired and accumulate at sites where it is needed.
Higher levels of NPY may be associated with resilience
Psychological resilience
Resilience in psychology refers to the idea of an individual's tendency to cope with stress and adversity. This coping may result in the individual “bouncing back” to a previous state of normal functioning, or using the experience of exposure to adversity to produce a “steeling effect” and function...
against and recovery from posttraumatic stress disorder and with dampening the fear response, allowing individuals to perform better under extreme stress.
Receptors
The receptor protein that NPY operates on is a G protein-coupled receptorG protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
in the rhodopsin
Rhodopsin
Rhodopsin, also known as visual purple, is a biological pigment of the retina that is responsible for both the formation of the photoreceptor cells and the first events in the perception of light. Rhodopsins belong to the G-protein coupled receptor family and are extremely sensitive to light,...
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 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.