Hypothalamic localization of the feeding effect of agouti-related peptide and alpha-melanocyte-stimulating hormone

The melanocortin-4 receptor (MC4R) in the hypothalamus is thought to be imp ortant in physiological regulation of food intake. We investigated which hy pothalamic areas known to express MC4R are involved in the regulation of fe eding by using alpha-melanocyte-stimulating hormone (alpha-MSH), an endogen ous MC4R agonist, and agouti-related peptide (Agrp), an endogenous MC4R ant agonist. Cannulae were inserted into the rat hypothalamic paraventricular ( PVN), arcuate (Arc), dorsomedial (DMN), and ventromedial (VMN) nuclei; the medial preoptic (MPO), anterior hypothalamic (AHA), and lateral hypothalami c (LHA) areas; and the extrahypothalamic central nucleus of the amygdala (C eA). Agrp (83-132) (0.1 nmol) and [Nle(4), D-Phe(7)]-alpha-MSH (NDP-MSH) (0 .1 nmol), a stable alpha-MSH analog, were administered to fed and fasted ra ts, respectively. The PVN, DMN, and MPO were the areas with the greatest re sponse to Agrp and NDP-MSH. At 8 h postinjection, Agrp increased feeding in the PVN by 218 +/- 23% (P < 0.005), in the DMN by 268 +/- 42% (P < 0.005), and in the MPO by 236 +/- 31% (P < 0.01) compared with a saline control gr oup for each nucleus. NDP-MSH decreased food intake in the PVN by 52 +/- 6% (P < 0.005), in the DMN by 44 +/- 6% (P < 0.0001), and in the MPO by 55 +/ - 6% (P < 0.0001) at 1 h postinjection. Injection into the AHA and CeA resu lted in smaller alterations in food intake. No changes in feeding were seen after the administration of Agrp into the Are, LHA, or VMN, but NDP-MSH su ppressed food intake in the Are and LHA. This study indicates that the hypo thalamic nuclei expressing MC4R vary in their sensitivity to Agrp and alpha -MSH with regard to their effect feeding.