Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and agouti-related protein mRNA levels and body weight in rats

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), was originally purified from the rat stomach. Like the synthetic g rowth hormone secretagogues (GHSs), ghrelin specifically releases growth ho rmone (GH) after intravenous administration. Also consistent with the centr al actions of GHSs, ghrelin-immunoreactive cells were shown to be located i n the hypothalamic arcuate nucleus as well as the stomach. Recently, we sho wed that a single central administration of ghrelin increased food intake a nd hypothalamic agouti-related protein (AGRP) gene expression in rodents, a nd the orexigenic effect of this peptide seems to be independent of its GH- releasing activity. However, the effect of chronic infusion of ghrelin on f ood consumption and body weight and their possible mechanisms have not been elucidated. In this study, we determined the effects of chronic intracereb roventricular treatment with ghrelin on metabolic factors and on neuropepti de genes that are expressed in hypothalamic neurons that have been previous ly shown to express the GHS-R and to regulate food consumption. Chronic cen tral administration of rat ghrelin (1 mug/rat every 12 h for 72 h) signific antly increased food intake and body weight. However, it did not affect pla sma insulin, glucose, leptin, or GH concentrations. We also found that chro nic central administration of ghrelin increased both neuropeptide Y (NPY) m RNA levels (151.0 +/- 10.1% of saline-treated controls; P < 0.05) and AGRP mRNA levels (160.0 +/- 22.5% of saline-treated controls; P < 0.05) in the a rcuate nucleus. Thus, the primary hypothalamic targets of ghrelin are NPY/A GRP-containing neurons, and ghrelin is a newly discovered orexigenic peptid e in the brain and stomach.