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The discovery of the peptide hormone ghrelin, an endogenous ligand for
the growth hormone secretagogue (GHS) receptor, yielded
the surprising result that the principal site of ghrelin synthesis
is the stomach and not the hypothalamus. Although ghrelin is likely to regulate
pituitary growth hormone (GH) secretion along with GH-releasing
hormone and somatostatin, GHS receptors have also been identified on hypothalamic
neurons and in the brainstem. Apart from potential
paracrine effects, ghrelin may thus offer an endocrine link between stomach,
hypothalamus and pituitary, suggesting an involvement in regulation of energy
balance. Here we show that peripheral daily administration of ghrelin caused
weight gain by reducing fat utilization in mice and rats. Intracerebroventricular
administration of ghrelin generated a dose-dependent increase in food intake
and body weight. Rat serum ghrelin concentrations were increased by fasting
and were reduced by re-feeding or oral glucose administration, but not by
water ingestion. We propose that ghrelin, in addition to its role in regulating
GH secretion, signals the hypothalamus when an increase in metabolic efficiency
is necessary.