Agouti-related peptide

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agouti related protein homolog (mouse)
Available structures PDB 1hyk, 2iqv, 1mr0
Identifiers
Symbols	AGRP; AGRT; ASIP2; MGC118963; ART
External IDs	OMIM: 602311 MGI: 892013 HomoloGene: 7184 GeneCards: AGRP Gene
Gene Ontology Molecular function • receptor binding • neuropeptide hormone activity Cellular component • extracellular region Biological process • adult feeding behavior • neuropeptide signaling pathway • hormone-mediated signaling Sources: Amigo / EGO
Orthologs
Species	Human	Mouse
Entrez	181	11604
Ensembl	ENSG00000159723	ENSMUSG00000005705
UniProt	O00253	P56473
RefSeq (mRNA)	NM_007316	NM_007427
RefSeq (protein)	NP_001129	NP_031453
Location (UCSC)	Chr 16: 66.07 - 66.08 Mb	Chr 8: 108.09 - 108.09 Mb
PubMed search	[1]	[2]

Agouti protein
180px
Identifiers
Symbol	Agouti
Pfam	PF05039
Pfam clan	CL0083
InterPro	IPR007733
PROSITE	PDOC60024
SCOP	1hyk
OPM protein	1mr0
Available PDB structures: 1hykA:87-122 1mr0A:87-120 1y7jA:80-128 1y7kA:80-128

Agouti-related protein also called Agouti-related peptide (AgRP) is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is only synthesised in NPY containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus. AgRP is co-expressed with Neuropeptide Y and works by increasing appetite and decreasing 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.

Structure

AgRP is a paracrine signalling molecule made up of 132 amino acids. It was independently identified by two teams in 1997 based on its sequence similarity with Agouti signalling peptide (ASIP), a protein synthesised in the skin that controls coat colour. AgRP is approximately 25% identical to ASIP. The murine homologue of AgRP is made up of 131 amino acids and shares 81% amino acid identity with the human protein. Biochemical studies indicate AgRP is very stable to thermal denaturation and acid degradation. Its secondary structure consists mainly of random coils and β-sheets. AgRP is mapped to human chromosome 16q22 and mouse chromosome 8D1-D2.

Function

Agouti-related protein is primarily expressed 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. 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. The transcriptional and secretory action of AgRP is regulated by inflammatory signals. 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.

Mechanism

AGRP has been demonstrated to be an inverse agonist 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. 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. 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.

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.

Role in Obesity

AgRP induces obesity by chronic antagonism of the MC4-R. Overexpression of AgRP in transgenic mice (or intracerebroventricular injection) causes hyperphagia and obesity, whilst AgRP plasma levels have been found to be elevated in obese human males. 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 may potentially contribute to the development of eating disorders. It has been shown that polymorphisms in the AgRP gene have been linked with anorexia nervosa as well as obesity. Some studies suggest that inadequate signalling of AgRP during stress may result in binge eating.

Human proteins containing this domain

AGRP; ASIP

See also

• Agouti

Further reading

• http://zootekni.comu.edu.tr/a_kadro/yayin/pala/agouti%20pakistan.pdf
• http://www.endotext.org/obesity/obesity5/obesity5.htm

External links

• MeSH agouti-related+protein
• Agouti domain in PROSITE

nl:Agouti-related peptide