Agouti-related peptide

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

Structure
AgRP is a paracrine signalling molecule made up 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 is_associated_with::Agouti signalling peptide (ASIP), a protein synthesised in the skin that controls coat colour. AgRP is approximately 25% identical to ASIP. The is_associated_with::murine homologue of AgRP is made up of 111 amino acids (precursor is 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 that fold into an is_associated_with::inhibitor cystine knot motif. AgRP is mapped to human chromosome 16q22 and 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 is_associated_with::leptin and activated by the hormone is_associated_with::ghrelin. is_associated_with::Adipocytes secrete leptin in response to food intake. This hormone acts in the arcuate nucleus and inhibits the AgRP/NPY neuron from releasing is_associated_with::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 is_associated_with::hypothalamic-pituitary-adrenocortical axis to release is_associated_with::ACTH, is_associated_with::cortisol and is_associated_with::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 is_associated_with::melanocortin receptors, to be specific MC3-R and MC4-R. The melanocortin receptors, MC3-R and MC4-R, are directly linked to is_associated_with::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 is_associated_with::ligand binding. Studies of Agouti protein in B16 melanoma cells supported this logic. The expression of AgRP in the adrenal gland is regulated by is_associated_with::glucocorticoids. The protein blocks α-MSH-induced secretion of is_associated_with::corticosterone.

History
is_associated_with::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 is_associated_with::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 is_associated_with::transgenic mice (or intracerebroventricular injection) causes is_associated_with::hyperphagia and is_associated_with::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 is_associated_with::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 is_associated_with::eating disorders. It has been shown that polymorphisms in the AgRP gene have been linked with is_associated_with::anorexia nervosa as well as obesity. Some studies suggest that inadequate signalling of AgRP during stress may result in is_associated_with::binge eating. Recent studies have shown that is_associated_with::autophagy plays a key role in regulation of food intake and energy balance in maintaning neuronal AgRP levels.

Human proteins containing this domain
AGRP; ASIP