J. Kamegai et al., Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and agouti-related protein mRNA levels and body weight in rats, DIABETES, 50(11), 2001, pp. 2438-2443
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.