Nesfatin-1 Influences The Electric Activity Of Glucose Sensitive Neurones In The Nucleus Of Solitary Tract

Background:An anorexigenic peptide, nesfatin-1 was found by Mori.M(Japan) in rat PVN,SON of the hypothalamus, and NTS of the brain stem, the stomach and pancrea, and its expression in the paraventricular nucleus of the hypothalamus was reduced by starvation. Intracerebroventricular administration dose-dependently inhibited food intake for 6 h in male Wistar and leptin resistant, Zucker fatty rats. Intraperitoneal administration of nesfatin-1 and its mid-segment dosedependently inhibited food intake for 3 h. Mid-segment of nesfatin-1 decreased food intake under leptin-resistant animal models of obesity. Intraperitoneal administration of the mid-segment of nesfatin-1 increased proopiomelanocortin and cocain- and amphetamine-related peptide mRNA expression in the nucleus of the solitary tract, but not in arcuate nucleus of the hypothalamus. Now we know that 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. Ne(?)fatin-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 a-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.It is well established that the regulation of glucose is so important that the brain has glucose-sensing neurons located in key areas such as the hypothalamus, NTS, and amygdala which monitor glucose status in the body and initiate glucoprivic feeding, appropriate sympathoadrenal and neurohumoral responses to maintain homeostasis. Other works have shown that hindbrain catecholaminergic neurons are glucose responsive.glucose-excited neurons (glucose-EXC) increase and glucose-inhibited neurons (glucose-INH) decrease their firing rate when extracellular glucose concentration rises.Objective:To observe the effects of nesfatin-1 on the glucose sensitive neurons in the nucleus of solitary tract(NTS), explore the mechanism of NTS neurons involved in the suppressing of food intake.Methods:Whole-cell patch-clamp technique was used to record the discharges of 43 neurons in the NTS slice before and after the administration of glucose and nesfatin-1.Results:The 43 NTS neurons were tested with glucose, of which 20 were activated and identified as glucose-excited(G-EXC) neurons. The firing rate of G-EXC significantly increased after glucose administration(5mM). Of which 11 were depressed by glucose and identified as glucose-inhibited (G-INH) neurons; The firing rate of G-INH significantly reduced after glucose administration. Of which 12 failed to respond to glucose. 10min after returning to normal ACSF, of 20 G-EXC neurons examined for response to nesfatin-1(10nM),18 were activated, and 2 failed to respond to nesfatin-1.10 out of 11 G-INH neurons were suppressed by nesfatin-1, and 1 failed to respond to nesfatin-1.Conclusion:Our data clearly demonstrated that this newly-discovered peptide may exert at least a part of its physiological actions on the control of food intake as a direct result of its role in controlling the excitability of neurons in the NTS.