Many molecules compose the brain-adipose axis that controls appetite. Using a subtraction cloning assay, we searched genes which were activated by a PPAR-gamma activator and identified nesfatin, a secreted protein of unknown function, which was expressed in the appetite-control hypothalamic nuclei and adipose in rats. Intracerebroventricular (icv) injection of nesfatin caused a dose-dependent decrease in food intake, and icv injection of its antibody stimulated feeding. The structure of nesfatin possesses several cleavage sites that may undergo processing by prohormone convertase (PC), and nesfatin was co-localized with PC-2 and PC-3. Western blot analysis demonstrated the presence of nesfatin-1 in the hypothalamic extract. Icv injection of nesfatin-1, but not nesfatin-2 or -3, produced satiety, and injection of an antibody neutralizing nesfatin-1 stimulated feeding. Chronic icv injection of nesfatin-1 reduced body weight, and rats gained body weight after chronic icv administration of an antisense morpholino-oligonucleotide against the nesfatin gene. The present data provide evidence that nesfatin is a novel, secreted anorexigenic molecule in the hypothalamus. [J Physiol Sci. 2006;56 Suppl:S56]
