Nesfatin-1: An Overview and Future Clinical Application

Abstract

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...

Nesfatin-1 exerts long-term effect on food intake and body temperature

“…Orexin initiates daytime food intake only, and NPY's action on body temperature is maintained for at least 24 h. 24,25 Earlier data showed that nesfatin-1 reduced nocturnal food intake in the first 6 h after icv injections or given intranasally at the beginning of the dark phase. 1,3 Report about longer than 24 h observations is not published so far. In our experiments, duration of food intake was also decreased in the first 6 h after injection of the drug at the beginning of the dark phase.…”

“…2 Moreover, fasting results in depletion of nesfatin-1 /NUCB2 mRNA and peptide in the supraoptic nucleus and in the PVN, whereas icv administration of an antisense oligonucleotide prepared against nesfatin-1 /NUCB2 induces an increase in food intake and body weight gain. 1,3 Localisation and wide distribution of nesfatin-1-producing neurons in the brain predispose its involvement in many other functions. As it has been already shown, nesfatin-1 decreases water intake, increases the mean arterial pressure, evokes anxietyrelated behaviour, and participates in the stress reaction.…”

Nesfatin Role as Possible New Anti Obesity Treatment

“…Nesfatin-1/NUCB-2 is colocalized with a number of hypothalamic peptides regulating food intake (Fort et al, 2008;Shimizu et al, 2009b;Maejima et al, 2009;Yoshida et al, 2010;Tan et al, 2011;Kerbel and Unniappan, 2012;GoebelStengel and Wang, 2013). Several interactions have been described to underlie the central anorexic effect of nesfatin-1 (Shimizu et al, 2009c). It has also been shown to play important roles in the control of cardiovascular function (Mimee et al, 2012).…”

“…In the light of this and the pre-clinical findings that central and peripheral injection of nesfatin-1 exerts its food reducing effects via a leptinindependent mechanism (Oh-I et al, 2006;Shimizu et al, 2009a), targeting nesfatin-1 may be a promising approach in the drug treatment of obesity and its complications. Ongoing pre-clinical data suggest the possible use of subcutaneous and intranasal routes of nesfatin-1 administration (Shimizu et al, 2009c), which needs to be further explored. Another important aspect to be unraveled is the weight loss upon chronic administration of nesfatin-1 (Li et al, 2010;Gonzalez et al, 2012;Li et al, 2013;Dong et al, 2013) and possible related changes in energy balance and/or basal metabolic rate (Foo et al, 2008;García-Galiano et al, 2010;Gonzales et al, 2011;Pałasz et al, 2012;Kerbel and Unniappan, 2012;García-Galiano et al, 2012;Ghanbari Niaki et al, 2013;Vas et al, 2013) for which studies so far are limited.…”

Possible Activation of the Immune System by Chronic Peripheral Nesfatin-1 Application at the Acute Phase of Ischemia/Reperfusion Injury

“…Recently, Oh-I et al (13) described a new anorexigenic protein which is derived from nucleobindin 2 (NUCB2) and named it NUCB2-encoded satiety and the fat-influencing protein-nesfatin- (14). Nesfatin produces three major peptide products such as nesfatin-1 (spanning residues 1-82), nesfatin-2 (residues 85-163), and named it NUCB2-encoded satiety and the fat-influencing protein as nesfatin (15).…”