Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway

Ghrelin, an endogenous ligand for growth hormone secretagogue (GBS) recepto r originally isolated from the stomach, occurs in the hypothalamic arcuate nucleus and may piety a role in energy homeostasis. Synthetic GHSs have act ivated the hypothalamic arcuate neurons containing neuropeptide Y (NPY), su ggesting the involvement of NPY in some of ghrelin actions. This study was designed to elucidate the role of ghrelin in the regulation of food intake. A single intracerebroventricular (ICV) injection of ghrelin (5-5,000 ng/ra t) caused a significant and dose-related increase in cumulative food intake in rats. Ghrelin (500 ng/rat) was also effective in growth hormone-deficie nt spontaneous dwarf rats. Hypothalamic NPY mRNA expression was increased i n rats that received a single ICV injection of ghrelin (500 ng/rat) (simila r to 160% of that in vehicle-treated groups, P < 0.05). The ghrelin's orexi genic effect was abolished dose-dependently by ICV co-injection of NPY Y1 r eceptor antagonist (10-30 <mu>g/rat). The leptin-induced inhibition of food intake was reversed by ICV co-injection of ghrelin in a dose-dependent man ner (5-500 ng/rat). Leptin reduced hypothalamic NPY mRNA expression by 35% (P < 0.05), which was abolished by ICV co-injection of ghrelin (500 ng/rat) . This study provides evidence that ghrelin is an orexigenic peptide that a ntagonizes leptin action through the activation of hypothalamic NPY/Y1 rece ptor pathway.