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

Author:

Shimizu H.1,Oh-I S.1,Hashimoto K.1,Nakata M.2,Yamamoto S.2,Yoshida N.2,Eguchi H.3,Kato I.4,Inoue K.1,Satoh T.1,Okada S.1,Yamada M.1,Yada T.2,Mori M.1

Affiliation:

1. 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

2. Division of Integrative Physiology (M.N., S.Y., N.Y., T.Y.), Jichi Medical University School of Medicine, Tochigi 329-0498, Japan

3. Pharmaceutical Discovery Research Laboratory (H.E.), Teijin Pharma Limited, Hino 191-8512, Japan

4. Yanaihara Institute Inc. (I.K.), Shizuoka 418-0011, Japan

Abstract

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. Peripherally administered nesfatin-1 and its mid-segment suppress food intake in mice. The nicotinic cholinergic pathway to the nucleus tractus solitarius contributes to the anorexigenic action of the mid-segment.

Publisher

The Endocrine Society

Subject

Endocrinology

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