Characterization of the neuroanatomical distribution of agouti-related protein immunoreactivity in the rhesus monkey and the rat

Agouti-related protein (AGRP) is a recently described homolog of the skin a gouti protein. AGRP is transcribed primarily in the adrenal and hypothalamu s and is a high affinity antagonist of the neural melanocortin-3 and melano cortin-4 receptors. The perikarya expressing AGRP messenger RNA are found i n the arcuate nucleus of the rat and rhesus monkey. Using a polyclonal anti body against the pharmacologically active domain of AGRP (amino acids 83-13 2), we have also characterized the distribution of AGRP-immunoreactive neur ons in both species. The major fiber tracts are conserved in both species, with dense projections originating in the arcuate nucleus and proceeding al ong the third ventricle. Dense fiber bundles are also visible in the parave ntricular, dorsomedial, and posterior nuclei in the hypothalamus, in the be d nucleus of the stria terminalis, and in the lateral septal nucleus of the septal region. hGRP-containing neurons are not visualized in a number of a reas, including portions of the amygdala, thalamus, and brain stem, that ex press MC3-R and MC4-R messenger RNA and receive innervation from POMC neuro ns that serve as the source of melanocortin agonists. Thus, AGRP is most li kely to be involved in modulating a conserved subset of the physiological f unctions of central melanocortin peptides. Based on the particular distribu tion of AGRP neurons, those functions are likely to include the central con trol of energy homeostasis.