Journal Article

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

Inoue, Kinji, Yamamoto, Masanori, Adachi, Sachika, Horiguchi, Kazuhiko, Monden, Tsuyoshi, Yamada, Masanobu, Tsuchiya, Takafumi, Shimizu, Hiroyuki, Mori, Masatomo, Hashimoto, Koushi, Okada, Shuichi, Imaki, Toshihiro, Satoh, Tetsurou, Oh-I, Shinsuke, Eguchi, Hiroshi

2006

Overview

Enough is enough Appetite is regulated — at least in part — in the hypothalamus, the brain region that links the nervous and endocrine systems. A screen for appetite-regulating molecules has now identified a fragment of the protein nucleobindin 2, dubbed nesfatin-1, as a satiety molecule produced in the hypothalamus. When nesfatin-1 is injected into the brain, rats eat less and lose weight. When nesfatin-1 is blocked, animals eat more. Nesfatin-1 is therefore a possible target for antiobesity drugs. A secreted protein, nesfatin-1, is expressed in the hypothalamus and induces the feeling of being full. In rats, its injection into the brain decreases food intake, but blocking its action stimulates appetite. 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 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: 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