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Peripheral Administration of Nesfatin-1 Reduces Food Intake in Mice: The Leptin-Independent Mechanism

Department of Medicine and Molecular Science (H.S., S.O.-I., K.H., K.I., T.S., S.O., M.Y., M.M.), Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; Division of Integrative Physiology (M.N., S.Y., N.Y., T.Y.), Jichi Medical University School of Medicine, Tochigi 329-0498, Japan; Pharmaceutical Discovery Research Laboratory (H.E.), Teijin Pharma Limited, Hino 191-8512, Japan; and Yanaihara Institute Inc. (I.K.), Shizuoka 418-0011, Japan

Address all correspondence and requests for reprints to: H. Shimizu, Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan. E-mail: hshimizu{at}showa.gunma-u.ac.jp.

Nesfatin-1 is a novel satiety molecule in the hypothalamus and is also present in peripheral tissues. Here we sought to identify the active segment of nesfatin-1 and to determine the mechanisms of its action after peripheral administration in mice. Intraperitoneal injection of nesfatin-1 suppressed food intake in a dose-dependent manner. Nesfatin-1 has three distinct segments; we tested the effect of each segment on food intake. Injection of the midsegment decreased food intake under leptin-resistant conditions such as db/db mice and mice fed a high-fat diet. After injection of the midsegment, expression of c-Fos was significantly activated in the brainstem nucleus tractus solitarius (NTS) but not in the hypothalamic arcuate nucleus; the nicotinic cholinergic pathway to the NTS contributed to midsegment-induced anorexia. Midsegment injection significantly increased expression of proopiomelanocortin and cocaine- and amphetamine-regulated transcript genes in the NTS but not in the arcuate nucleus. Investigation of mutant midsegments demonstrated that a region with amino acid sequence similarity to the active site of agouti-related peptide was indispensable for anorexigenic induction. Our findings indicate that the midsegment of nesfatin-1 causes anorexia, possibly by activating POMC and CART neurons in the NTS via a leptin-independent mechanism after peripheral stimulation.

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