1. Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Showa-machi, Maebashi 371-8511, Japan
2. Department of Regulation Biology, Saitama University, Shimo-okubo, Saitama 378-8570, Japan
3. Pharmaceutical Discovery Research Laboratory, Teijin Pharma Limited, Asahigaoka, Hino 191-8512, Japan

Correspondence to: Masatomo Mori¹ Correspondence and requests for materials should be addressed to M.M. (Email: mmori@med.gunma-u.ac.jp).

Abstract

The brain hypothalamus contains certain secreted molecules that are important in regulating feeding behaviour^{1, 2, 3}. Here we show that nesfatin, corresponding to NEFA/nucleobindin2 (NUCB2), a secreted protein of unknown function, is expressed in the appetite-control hypothalamic nuclei in rats. Intracerebroventricular (i.c.v.) injection of NUCB2 reduces feeding. Rat cerebrospinal fluid contains nesfatin-1, an amino-terminal fragment derived from NUCB2, and its expression is decreased in the hypothalamic paraventricular nucleus under starved conditions. I.c.v. injection of nesfatin-1 decreases food intake in a dose-dependent manner, whereas injection of an antibody neutralizing nesfatin-1 stimulates appetite. In contrast, i.c.v. injection of other possible fragments processed from NUCB2 does not promote satiety, and conversion of NUCB2 to nesfatin-1 is necessary to induce feeding suppression. Chronic i.c.v. injection of nesfatin-1 reduces body weight, whereas rats gain body weight after chronic i.c.v. injection of antisense morpholino oligonucleotide against the gene encoding NUCB2. Nesfatin-1-induced anorexia occurs in Zucker rats with a leptin receptor mutation, and an anti-nesfatin-1 antibody does not block leptin-induced anorexia. In contrast, central injection of -melanocyte-stimulating hormone elevates NUCB2 gene expression in the paraventricular nucleus, and satiety by nesfatin-1 is abolished by an antagonist of the melanocortin-3/4 receptor. We identify nesfatin-1 as a satiety molecule that is associated with melanocortin signalling in the hypothalamus.

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