Nesfatin-1/NUCB2 as a Potential New Element of Sleep Regulation in Rats

Szilvia Vas,Rege S Papp,György Bagdy,Miklós Palkovits,Csaba Ádori,Zita Kátai,Dorottya Pap,Katalin Könczöl,Zsuzsanna E Tóth,Gilberto Fisone

doi:10.1371/journal.pone.0059809

Szilvia Vas, Rege S Papp + Show 8 more

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https://doi.org/10.1371/journal.pone.0059809

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Abstract

Study ObjectivesMillions suffer from sleep disorders that often accompany severe illnesses such as major depression; a leading psychiatric disorder characterized by appetite and rapid eye movement sleep (REMS) abnormalities. Melanin-concentrating hormone (MCH) and nesfatin-1/NUCB2 (nesfatin) are strongly co - expressed in the hypothalamus and are involved both in food intake regulation and depression. Since MCH was recognized earlier as a hypnogenic factor, we analyzed the potential role of nesfatin on vigilance.DesignWe subjected rats to a 72 h-long REMS deprivation using the classic flower pot method, followed by a 3 h-long ‘rebound sleep’. Nesfatin mRNA and protein expressions as well as neuronal activity (Fos) were measured by quantitative in situ hybridization technique, ELISA and immunohistochemistry, respectively, in ‘deprived’ and ‘rebound’ groups, relative to controls sacrificed at the same time. We also analyzed electroencephalogram of rats treated by intracerebroventricularly administered nesfatin-1, or saline.ResultsREMS deprivation downregulated the expression of nesfatin (mRNA and protein), however, enhanced REMS during ‘rebound’ reversed this to control levels. Additionally, increased transcriptional activity (Fos) was demonstrated in nesfatin neurons during ‘rebound’. Centrally administered nesfatin-1 at light on reduced REMS and intermediate stage of sleep, while increased passive wake for several hours and also caused a short-term increase in light slow wave sleep.ConclusionsThe data designate nesfatin as a potential new factor in sleep regulation, which fact can also be relevant in the better understanding of the role of nesfatin in the pathomechanism of depression.

Highlights

Nesfatin-1, the N-terminal fragment of the nucleobindin2 protein (NUCB2) is a potent anorexigen decreasing nocturnal food intake in rodents in a dose-dependent manner [1]
rapid eye movement sleep (REMS) deprivation downregulated the expression of nesfatin, enhanced REMS during ‘rebound’ reversed this to control levels
The dorsolateral hypothalamus (DLH) with the zona incerta (ZI) hosts the most prominent nesfatin expressing cell population in the hypothalamus regarding the number of the cells and the expression level of the peptide (Fig. 1A)

Summary

Introduction

Nesfatin-1, the N-terminal fragment of the nucleobindin protein (NUCB2) is a potent anorexigen decreasing nocturnal food intake in rodents in a dose-dependent manner [1]. Higher plasma nesfatin-1/NUCB2 (nesfatin) levels in overweight patients point to its role in food intake regulation in humans [2]. A major cause of morbidity worldwide is characterized by marked alterations in emotional states and feeding, initial research on the role of nesfatin regarding this field may have high relevance. For plasma and cerebrospinal fluid nesfatin levels positively correlate, CNS problems related to alterations in nesfatin expression may underlie this elevation [2]. This is supported by the fact that nesfatin mRNA content is elevated in the Edinger-Westphal nucleus of depressed male suicide victims [6]. The existence of a relationship between nesfatin and sleep regulation can be assumed [10]

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