Agouti-related peptide

Last updated
AGRP
1hyk.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases AGRP , agouti related neuropeptide, AGRT, ART, ASIP2, AgRP
External IDs OMIM: 602311; MGI: 892013; HomoloGene: 7184; GeneCards: AGRP; OMA:AGRP - orthologs
Orthologs
SpeciesHumanMouse
Entrez

181

11604

Ensembl

ENSG00000159723

ENSMUSG00000005705

UniProt

O00253

P56473

RefSeq (mRNA)

NM_001138

NM_001271806
NM_007427

RefSeq (protein)

NP_001129

NP_001258735
NP_031453

Location (UCSC) Chr 16: 67.48 – 67.48 Mb Chr 8: 106.29 – 106.36 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus. [5] AgRP is co-expressed with NPY and acts to increase appetite and decrease metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators. In humans, the agouti-related peptide is encoded by the AGRP gene. [6] [7]

Contents

Structure

AgRP is a paracrine signaling molecule made of 112 amino acids (the gene product of 132 amino acids is processed by removal of the N-terminal 20-residue signal peptide domain). It was independently identified by two teams in 1997 based on its sequence similarity with agouti signalling peptide (ASIP), a protein synthesized in the skin controlling coat colour. [6] [7] AgRP is approximately 25% identical to ASIP. The murine homologue of AgRP consists of 111 amino acids (precursor is 131 amino acids) and shares 81% amino acid identity with the human protein. Biochemical studies indicate AgRP to be very stable to thermal denaturation and acid degradation. Its secondary structure consists mainly of random coils and β-sheets [8] that fold into an inhibitor cystine knot motif. [9] AGRP maps to human chromosome 16q22 and Agrp to mouse chromosome 8D1-D2.

Function

Agouti-related protein is expressed primarily in the adrenal gland, subthalamic nucleus, and hypothalamus, with lower levels of expression in the testis, kidneys, and lungs. The appetite-stimulating effects of AgRP are inhibited by the hormone leptin and activated by the hormone ghrelin. Adipocytes secrete leptin in response to food intake. This hormone acts in the arcuate nucleus and inhibits the AgRP/NPY neuron from releasing orexigenic peptides. [10] Ghrelin has receptors on NPY/AgRP neurons that stimulate the secretion of NPY and AgRP to increase appetite. AgRP is stored in intracellular secretory granules and is secreted via a regulated pathway. [11] The transcriptional and secretory action of AgRP is regulated by inflammatory signals. [12] Levels of AgRP are increased during periods of fasting. It has been found that AgRP stimulates the hypothalamic-pituitary-adrenocortical axis to release ACTH, cortisol and prolactin. It also enhances the ACTH response to IL-1-beta, suggesting it may play a role in the modulation of neuroendocrine response to inflammation. [13] Conversely, AgRP-secreting neurons inhibit the release of TRH from the paraventricular nucleus (PVN), which may contribute to conservation of energy in starvation. [14] This pathway is part of a feedback loop, since TRH-secreting neurons from PVN stimulate AgRP neurons. [15]

Mechanism

AGRP has been demonstrated to be a competitive antagonist of melanocortin receptors, specifically MC3-R and MC4-R. The melanocortin receptors, MC3-R and MC4-R, are directly linked to metabolism and body weight control. These receptors are activated by the peptide hormone α-MSH (melanocyte-stimulating hormone) and antagonized by the agouti-related protein. [16] Whereas α-MSH acts broadly on most members of the MCR family (with the exception of MC2-R), AGRP is highly specific for only MC3-R and MC4-R. This inverse agonism not only antagonizes the action of melanocortin agonists such as α-MSH but also further decreases the cAMP produced by the affected cells. The exact mechanism by which AgRP inhibits melanocortin-receptor signalling is not completely clear. It has been suggested that Agouti-related protein binds MSH receptors and acts as a competitive antagonist of ligand binding. [17] Studies of Agouti protein in B16 melanoma cells supported this logic. The expression of AgRP in the adrenal gland is regulated by glucocorticoids. The protein blocks α-MSH-induced secretion of corticosterone. [18]

History

Orthologs of AgRP, ASIP, MCIR, and MC4R have been found in mammalian, teleost fish, and avian genomes. This suggests that the agouti-melanocortin system evolved by gene duplication from individual ligand and receptor genes in the last 500 million years. [16]

Role in obesity

AgRP induces obesity by chronic antagonism of the MC4-R. [19] Overexpression of AgRP in transgenic mice (or intracerebroventricular injection) causes hyperphagia and obesity, [20] whilst AgRP plasma levels have been found to be elevated in obese human males. [21] Understanding the role AgRP plays in weight gain may assist in developing pharmaceutical models for treating obesity. AgRP mRNA levels have been found to be down regulated following an acute stressful event. Studies suggest that systems involved in the regulation of stress response and of energy balance are highly integrated. Loss or gain of AgRP function may result in inadequate adaptive behavioural responses to environmental events, such as stress, and have potential to contribute to the development of eating disorders. It has been shown that polymorphisms in the AgRP gene have been linked with anorexia nervosa [22] as well as obesity. Some studies suggest that inadequate signalling of AgRP during stress may result in binge eating. Starvation-induced hypothalamic autophagy generates free fatty acids, which in turn regulate neuronal AgRP levels. [23]

Agouti protein
1mr0.png
Identifiers
SymbolAgouti
Pfam PF05039
Pfam clan CL0083
InterPro IPR007733
PROSITE PDOC60024
SCOP2 1hyk / SCOPe / SUPFAM
OPM superfamily 112
OPM protein 1mr0
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Role in hunger circuitry

According to Mark L. Andermann and Bradford B. Lowell: "...AgRP neurons and the wiring diagram within which they operate can be viewed as the physical embodiment of the intervening variable, hunger." [24] Stimulation of neurons expressing AgRP can induce robust feeding behavior in mice that will trigger: increased food consumption, [25] increased willingness to work for food, [26] and increased investigation of food odors. [27]

Despite this, AgRP neurons are rapidly inhibited upon food presentation and the onset of eating. [28] One mechanism which may account for this discrepancy is the fact that AgRP neurons signal with Neuropeptide Y in order to allow for sustained feeding behavior that outlasts the activation of the neurons. [29]

AgRP neurons are also sensitive to satiety and hunger hormonal signals. One is an appetite stimulant, ghrelin which makes AgRP neurons more excitable through interactions with specialized ghrelin receptors. [30] Another is a satiety signal, leptin, which modulates AgRP activity through inwardly rectifying potassium channels, which alter the excitability of the neurons. [31] Leptin can also decrease the ability of AgRP neurons to carry out other physiological functions, such as triggering Long Term Potentiation of adjacent neurons. [32]

Although AgRP neurons can drive many different phases of feeding behavior, separate AgRP neurons project to different areas of the brain, demonstrating a parallel organizational structure. [33] This is evidenced by different projections of AgRP neurons to various areas of the brain driving different food related behaviors; for example, certain projections will promote increased food consumption, but not increased food odor investigation. [27]

Human proteins containing this domain

AGRP; ASIP

See also

Related Research Articles

<span class="mw-page-title-main">Proopiomelanocortin</span> Mammalian protein found in Homo sapiens

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.

<span class="mw-page-title-main">Leptin</span> Hormone that inhibits hunger

Leptin also obese protein is a protein hormone predominantly made by adipocytes. Its primary role is likely to regulate long-term energy balance.

<span class="mw-page-title-main">Arcuate nucleus</span>

The arcuate nucleus of the hypothalamus (ARH), or ARC, is also known as the infundibular nucleus to distinguish it from the arcuate nucleus of the medulla oblongata in the brainstem. The arcuate nucleus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.

<span class="mw-page-title-main">Ghrelin</span> Peptide hormone involved in appetite regulation

Ghrelin is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. Ghrelin may help prepare for food intake by increasing gastric motility and stimulating the secretion of gastric acid.

<span class="mw-page-title-main">Neuropeptide Y</span> Mammalian protein found in Homo sapiens

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. 

The melanocortins are a family of neuropeptide hormones which are the ligands of the melanocortin receptors. The melanocortin system consists of melanocortin receptors, ligands, and accessory proteins. The genes of the melanocortin system are found in chordates. Melanocortins were originally named so because their earliest known function was in melanogenesis. It is now known that the melanocortin system regulates diverse functions throughout the body, including inflammatory response, fibrosis, melanogenesis, steroidogenesis, energy homeostasis, sexual function, and exocrine gland function.

<span class="mw-page-title-main">Agouti-signaling protein</span> Protein-coding gene in the species Homo sapiens

Agouti-signaling protein is a protein that in humans is encoded by the ASIP gene. It is responsible for the distribution of melanin pigment in mammals. Agouti interacts with the melanocortin 1 receptor to determine whether the melanocyte produces phaeomelanin, or eumelanin. This interaction is responsible for making distinct light and dark bands in the hairs of animals such as the agouti, which the gene is named after. In other species such as horses, agouti signalling is responsible for determining which parts of the body will be red or black. Mice with wildtype agouti will be grey-brown, with each hair being partly yellow and partly black. Loss of function mutations in mice and other species cause black fur coloration, while mutations causing expression throughout the whole body in mice cause yellow fur and obesity.

<span class="mw-page-title-main">Peptide YY</span> Peptide released from cells in the ileum and colon in response to feeding

Peptide YY (PYY), also known as peptide tyrosine tyrosine, is a peptide that in humans is encoded by the PYY gene. Peptide YY is a short peptide released from cells in the ileum and colon in response to feeding. In the blood, gut, and other elements of periphery, PYY acts to reduce appetite; similarly, when injected directly into the central nervous system, PYY is also anorexigenic, i.e., it reduces appetite.

<span class="mw-page-title-main">Enterostatin</span> Chemical compound

Enterostatin is a pentapeptide derived from a proenzyme in the gastrointestinal tract called procolipase. It reduces food intake, in particular fat intake, when given peripherally or into the brain.

Nesfatin-1 is a neuropeptide produced in the hypothalamus of mammals. It participates in the regulation of hunger and fat storage. Increased nesfatin-1 in the hypothalamus contributes to diminished hunger, a 'sense of fullness', and a potential loss of body fat and weight.

<span class="mw-page-title-main">Growth hormone secretagogue receptor</span> Protein-coding gene in the species Homo sapiens

Growth hormone secretagogue receptor(GHS-R), also known as ghrelin receptor, is a G protein-coupled receptor that binds growth hormone secretagogues (GHSs), such as ghrelin, the "hunger hormone". The role of GHS-R is thought to be in regulating energy homeostasis and body weight. In the brain, they are most highly expressed in the hypothalamus, specifically the ventromedial nucleus and arcuate nucleus. GSH-Rs are also expressed in other areas of the brain, including the ventral tegmental area, hippocampus, and substantia nigra. Outside the central nervous system, too, GSH-Rs are also found in the liver, in skeletal muscle, and even in the heart.

<span class="mw-page-title-main">KiSS1-derived peptide receptor</span> Mammalian protein found in Homo sapiens

The KiSS1-derived peptide receptor is a G protein-coupled receptor which binds the peptide hormone kisspeptin (metastin). Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues. Activation of the kisspeptin receptor is linked to the phospholipase C and inositol trisphosphate second messenger cascades inside the cell.

<span class="mw-page-title-main">Melanocortin 4 receptor</span> Mammalian protein found in Homo sapiens

Melanocortin 4 receptor (MC4R) is a melanocortin receptor that in humans is encoded by the MC4R gene. It encodes the MC4R protein, a G protein-coupled receptor (GPCR) that binds α-melanocyte stimulating hormone (α-MSH). In mouse models, MC4 receptors have been found to be involved in feeding behaviour, the regulation of metabolism, sexual behaviour, and male erectile function.

<span class="mw-page-title-main">Melanocortin 3 receptor</span> Mammalian protein found in Homo sapiens

Melanocortin 3 receptor (MC3R) is a protein that in humans is encoded by the MC3R gene.

<span class="mw-page-title-main">Pancreatic polypeptide receptor 1</span> Protein-coding gene in the species Homo sapiens

Pancreatic polypeptide receptor 1, also known as Neuropeptide Y receptor type 4, is a protein that in humans is encoded by the PPYR1 gene.

<span class="mw-page-title-main">Central melanocortin system</span> System involved in the regulation of weight and peripheral tissue such as hair and skin

The central melanocortin system is defined anatomically as a collection of central nervous system circuits which include:

<span class="mw-page-title-main">Teleost leptins</span>

Teleost leptins are a family of peptide hormones found in fish (teleostei) that are orthologs of the mammalian hormone leptin. The teleost and mammalian leptins appear to have similar functions, namely, regulation of energy intake and expenditure.

<span class="mw-page-title-main">MRAP2</span> Protein

Melanocortin 2 receptor accessory protein 2 is a protein that in humans is encoded by the MRAP2 gene. MRAP2 is a transmembrane accessory protein to a family of five receptors called the melanocortin receptors (MC1-5). Human genome sequencing analysis led to the discovery of MRAP2, Human MRAP2 gene is located in chromosome 6q14.3, a different chromosomal location from that of human MRAP which is a paralogy to MRAP2. MRAP2 is thought to be involved in regulating the expression of the melanocortin (MC1-5) and some non-melanocortin receptors such as ghrelin receptor (GHSR-1a), orexin (OX1R) receptor and prokineticin receptor (PKR-1).

<span class="mw-page-title-main">Pathophysiology of obesity</span> Physiological processes in obese people

Pathophysiology of obesity is the study of disordered physiological processes that cause, result from, or are otherwise associated with obesity. A number of possible pathophysiological mechanisms have been identified which may contribute in the development and maintenance of obesity.

The food-entrainable oscillator (FEO) is a circadian clock that can be entrained by varying the time of food presentation. It was discovered when a rhythm was found in rat activity. This was called food anticipatory activity (FAA), and this is when the wheel-running activity of mice decreases after feeding, and then rapidly increases in the hours leading up to feeding. FAA appears to be present in non-mammals (pigeons/fish), but research heavily focuses on its presence in mammals. This rhythmic activity does not require the suprachiasmatic nucleus (SCN), the central circadian oscillator in mammals, implying the existence of an oscillator, the FEO, outside of the SCN, but the mechanism and location of the FEO is not yet known. There is ongoing research to investigate if the FEO is the only non-light entrainable oscillator in the body.

References

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