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

• Published in: Nature 2006-10, Vol.443 (7112), p.709-712
• Main Authors: Mori, Masatomo, Oh-I, Shinsuke, Shimizu, Hiroyuki, Satoh, Tetsurou, Okada, Shuichi, Adachi, Sachika, Inoue, Kinji, Eguchi, Hiroshi, Yamamoto, Masanori, Imaki, Toshihiro, Hashimoto, Koushi, Tsuchiya, Takafumi, Monden, Tsuyoshi, Horiguchi, Kazuhiko, Yamada, Masanobu
• Format: Article
• Language: English
• Subjects: alpha-MSH - metabolism; Animals; Anorexia - chemically induced; Anorexia - metabolism; Anorexia - prevention & control; Appetite Regulation - drug effects; Appetite Regulation - physiology; Biological and medical sciences; Body weight; Body Weight - drug effects; Brain; Calcium-Binding Proteins - administration & dosage; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - metabolism; Calcium-Binding Proteins - pharmacology; DNA-Binding Proteins - administration & dosage; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - pharmacology; Dose-Response Relationship, Drug; Eating disorders; Feeding behavior; Feeding Behavior - drug effects; Feeding Behavior - physiology; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; Hormones; Humanities and Social Sciences; Hypothalamus - metabolism; Injection; Injections, Intraventricular; Leptin - metabolism; Leptin - pharmacology; letter; Male; Mice; multidisciplinary; Mutation; Nerve Tissue Proteins - administration & dosage; Nerve Tissue Proteins - cerebrospinal fluid; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - pharmacology; Obesity - metabolism; Proteins; Rats; Rats, Wistar; Rats, Zucker; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, Leptin; Receptors, Melanocortin - metabolism; Rodents; Satiety Response - drug effects; Satiety Response - physiology; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature05162

The brain hypothalamus contains certain secreted molecules that are important in regulating feeding behaviour. 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 α-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.