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Agouti-related peptide (AgRP) is a neuropeptide produced in the brain in the arcuate nucleus of the hypothalamus. It is an endogenous antagonist of melanocortin receptors (MC3-R and MC4-R) which plays a critical role in energy balance.

It was identified independently by two teams based on sequence similarity with Agouti signalling peptide, a protein synthesized in the skin that controls coat color1,2.

There are 3 synthetic AgRP fragments in humans, viz AgRP (25-51), AgRP (54-82) and AgRP (83-132). Amino-terminal fragments AgRP (25-51) and (54-82) were devoid of significant antagonist activity, whereas the amidated carboxyl-terminal AGRP fragment (83-132)-NH2 is potently active3.

Structural characteristics
The human AgRP is 132 amino acids in length, and is about 25 percent identical to agouti polypeptide. It contains 11 cysteines, the majority of which are located at the carboxyl terminal end of the polypeptide, and form 5 disulfide bridges4. The C-terminal portion of the peptide (87-132) is believed to be necessary for optimal binding and contains a five fingered spider-toxin motif with an eight amino acid portion mimicking alpha -MSH.

Mode of action
AgRP binds specifically to MC3-R and MC4-R as an inverse agonist. This inverse agonism antagonizes the action of alpha-MSH and also brings down the level of cAMP (secondary messenger) produced in the affected cells.

The major function of AgRP is to increase appetite and decrease metabolism. It is one of the most potent and longest appetite stimulator. It can used in treatment of obesity and is particularly beneficial in the prevention and treatment of type 2 diabetes5.