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.

Abstract. Nesfatin/nucleobindin 2 (NuCB2) is expressed in the appetite-control hypothalamic nuclei and brainstem nuclei. Nesfatin/NuCB2 expression in the paraventricular nucleus of the hypothalamus was modulated by starvation and refeeding. intracerebroventricular administration of nesfatin-1 dose-dependently inhibited food intake for 6 hours in male Wistar and leptin resistant, zucker fatty rats. intraperitoneal administration of nesfatin-1 and its mid-segment (m30) dosedependently inhibited food intake for 3 hours in male iCr mice. intraperitoneal administration of m30 also decreased food intake in leptin-resistant, genetically obese (ob/ob), diabetic (db/db) mice and mice fed a 45% high fat diet for 28 days. intraperitoneal administration of m30 increased proopiomelanocortin and cocaine-and amphetamine-related peptide mRNA expression in the nucleus of the solitary tract of mice. In addition, intranasal administration of nesfatin-1 significantly inhibited food intake for 6 hours in male Wistar rats. We summarize recent observations about nesfatin-1, and attempt to present future direction of nesfatin-1 research for developing a new anti-obesity treatment.Key words: Nesfatin-1, Leptin, Food intake, Body weight, Obesity (Endocrine Journal 56: [537][538][539][540][541][542][543] 2009) We have proposed the concept of brain-adipose axis that endogenous molecule, expressed in both hypothalamus and adipose tissue, exists in the general circulation, and is involved in the regulation of both feeding behavior, and the determination of size and/ or number of adipocytes [1]. Troglitazone, peroxisome proliferator-activated receptor-γ (PPARγ) agonist, might modify the satiety in type 2 diabetic patients [2], and we attempted to identify a new protein regulated by PPARγ, which modulates feeding behavior. By using a subtraction-cloning assay, we found a new anorexigenic protein increased by troglitazone, and named it NEFa/nucleobindin 2 encoded satietyand fat-influencing protein (nesfatin), corresponding to NEFa/nucleobindin 2 (NuCB2), which had been reported to be a secreted protein of unknown function [3]. Nesfatin/NuCB2 is composed of a signal peptide of 24 amino acids and a protein structure containing 396 amino acids (Fig. 1). The homology of the amino acid sequence of nesfatin/NuCB2 is highly conserved in humans, mice and rats. in this review, we summarize recent observation about the physiological role of nesfatin-1, and discuss future direction for the research of this anorexigenic protein. Anorexigenic effect of nesfatin and its fragmentsNesfatin/NuCB2 is expressed in the appetite-control hypothalamic nuclei such as paraventricular nucleus (PVN), arcuate nucleus (ARC), supraoptic nucleus (SON) of hypothalamus, lateral hypothalamic area (LHa), and zona incerta in rats [3]. Nesfatin-1-immunoreactivity was also found in the brainstem nuclei such as nucleus of the solitary tract (NTS) and dorsal nucleus of vagus [3,4]. Selective reduction of nesfatin/NUCB2 mRNA expression in the PVN of rat was found under starved cond...

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OBJECTIVE: Leptin inhibits appetite and reduces body weight. However, subcutaneous leptin administration is not very effective on weight reduction. The present studies were undertaken to test the hypotheses that nasally administered leptin effectively accesses to the brain and inhibits appetite. METHODS: Recombinant leptin (0.5 mg/rat) was administered into the bilateral nasal spaces of rats (i.n.). Changes in serum immunoreactive leptin (IRL) and cerebrospinal fluid (CSF)-IRL concentrations after i.n. leptin administration were compared after intraperitoneal (i.p.) administration. The influence of 0.1 or 0.5% lysophosphatidylcholine (LPC) as an optimizer of leptin absorption was examined. The anorexic effects of i.n. leptin were compared with i.p. leptin in ad libitum fed rats. RESULTS: The i.n. leptin increased CSF-IRL concentrations, although serum IRL concentrations of rats administered leptin i.n. were lower than those administered i.p. The addition of 0.1 and 0.5% LPC dose-dependently increased serum IRL concentrations, but did not modify CSF-IRL concentrations in i.n. leptin-treated rats. The i.n. leptin inhibited dark-time food consumption at 0-1 h and 3-6 h in ad libitum fed rats. In contrast, i.p. leptin reduced food consumption only for an hour. Phosphorylated signal transducer and activator of transcription (STAT) 3 immunoreactive cells increased in the arcuate nucleus (ARC) of the hypothalamus at 3 h only following i.n. leptin. CONCLUSION: The present study demonstrated that i.n. leptin caused longer inhibition of appetite and phosphorylation of STAT3 in ARC. It is concluded that the trans-nasal route may be useful for the selective access of leptin to the brain in obese people.