Nature 443, 709-712 (12 October 2006) | doi:10.1038/nature05162; Received 8 June 2006; Accepted 11 August 2006; Published online 1 October 2006

Identification of nesfatin-1 as a satiety molecule in the hypothalamus

Shinsuke Oh-I1, Hiroyuki Shimizu1, Tetsurou Satoh1, Shuichi Okada1, Sachika Adachi2, Kinji Inoue2, Hiroshi Eguchi3, Masanori Yamamoto3, Toshihiro Imaki1, Koushi Hashimoto1, Takafumi Tsuchiya1, Tsuyoshi Monden1, Kazuhiko Horiguchi1, Masanobu Yamada1 and Masatomo Mori1

The brain hypothalamus contains certain secreted molecules that are important in regulating feeding behaviour1, 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 alpha-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.

  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).


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