Background:

Agouti-related protein is an endogenous antagonist of hypothalamic alpha-melanocortin receptors MC3R and MC4R with potent orexigenic activity. Although a complete deletion of the AgRP gene does not produce any significant metabolic phenotypes, reduction in AgRP expression by RNA interference is associated with increased metabolic rate along with reduced weight gain. In hypothalamus, it is produced by neurons in the medial portion of arcuate nucleus, which produce also the potent orexigenic peptide Neuropeptide Y (NP-Y). Another site of central AgRP production is the hypothalamic nucleus. Both AgRP and NP-Y expression was shown to be supressed by leptin. Central administration of AgRP induces hyperphagia and increased gain in body weight in rodents, but may also exert metabolic effects even when hyperphagia is prevented. In the absence of hyperphagia, intracerebralventricular administration of AgRP caused significant increases in plasma leptin and insulin concentrations (twofold and 1.5-fold, respectively) and fat pad mass. In the perifery, AgRP mRNA was found in adrenal glands, lung, testis, ovary, skeletal muscle and adipose tissue in humans or rodents. In the adrenals, it was shown that AgRP antagonizes glucosteroid production mediated by MC4R. AgRP could then modulate locally the functions of some peripheral tissues such as adrenals. In human and rat serum, detectable levels of AgRP-like activity were reported in the lower picogram range. The serum AgRP levels were elevated in obese humans compared to lean controls and increased with fasting in rats.