Rapid Publication 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 sec-retagogue (GHS) receptor originally isolated from the stomach, occurs in the hypothalamic arcuate nucleus and may play a role in energy homeostasis. Synthetic GHSs have activated the hypothalamic arcuate neurons containing neuropeptide Y (NPY), suggesting 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 intracerebroven-tricular (ICV) injection of ghrelin (5–5,000 ng/rat) caused a significant and dose-related increase in cumulative food intake in rats. Ghrelin (500 ng/rat) was also effective in growth hormone–deficient spontaneous dwarf rats. Hypothalamic NPY mRNA expression was increased in rats that received a single ICV injection of ghrelin (500 ng/rat) (~160% of that in vehicle-treated groups, P < 0.05). The ghrelin's orexigenic effect was abolished dose-dependently by ICV co-injection of NPY Y1 receptor antagonist (10–30 µg/rat). The leptin-induced inhibition of food intake was reversed by ICV co-injection of ghrelin in a dose-dependent manner (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 antagonizes leptin action through the activation of hypothalamic NPY/Y1 receptor pathway. G rowth hormone secretagogues (GHSs) are synthetic compounds that cause the release of growth hormone (GH) from the pituitary (1). They act through the GHS receptor (GHS-R) (2), a previously orphaned G-protein–coupled receptor that is expressed in the hypothalamus, pituitary, pancreas, etc. (2–4). GHSs stimulate GH release by a direct pituitary action (5,6), but several lines of evidence have suggested that it does so via a hypothalamic mechanism as well (7,8). Clinically, GHSs alone or in combination with growth hormone–releas-ing hormone (GHRH) have been used for diagnosis and treatment of various forms of GH deficiency (1,9,10). Using cells expressing GHS-R as assay systems, Kojima et al. (11) have recently isolated from the rat stomach a novel GH-releasing acylated peptide of 28 amino acids. Termed ghrelin, it can specifically stimulate GH release in vivo and in vitro. Previous studies have demonstrated that central as well as peripheral administration of GHS increases food intake and body weight in rats (12–16). Furthermore, GHS administration induces c-fos mRNA expression in the hypothalamic arcuate neurons containing neuropeptide Y (NPY), a potent stimula-tor of food intake (17). Indeed, GHS-R is colocalized with NPY in the rat hypothalamic arcuate nucleus (18). …