Review article
A comparative account of nesfatin-1 in vertebrates

https://doi.org/10.1016/j.ygcen.2021.113874Get rights and content

Highlights

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    Nesfatin-1 is a pleiotropic hormone.

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    Nesfatin-1 regulates feeding, glucose homeostasis, reproduction and cardiovascular function.

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    Diverse pathways are employed by the peptide to carry out its pleiotropic functions.

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    Nesfatin-1 expression is regulated by several metabolic and reproductive hormones.

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    Nesfatin-1 is implicated in pathophysiology of several diseases.

Abstract

Nesfatin-1 was discovered as an anorexigenic peptide derived from proteolytic cleavage of the prepropeptide, nucleobindin 2 (NUCB2). It is widely expressed in central as well as peripheral tissues and is known to have pleiotropic effects such as regulation of feeding, reproduction, cardiovascular functions and maintenance of glucose homeostasis. In order to execute its multifaceted role, nesfatin-1 employs diverse signaling pathways though its receptor has not been identified till date. Further, nesfatin-1 is reported to be under the regulatory effect of feeding state, nutritional status as well as several metabolic and reproductive hormones. This peptide has also been associated with variety of human diseases, especially metabolic, reproductive, cardiovascular and mental disorders. The current review is aimed to present a consolidated picture and highlight lacunae for further investigation in order to develop a deeper comprehensive understanding on physiological significance of nesfatin-1 in vertebrates.

Introduction

Nesfatin-1 (Nucleobindin2-encoded satiety- and fat-influencing protein 1) was first identified in rat as a hypothalamic satiety-inducing peptide (Oh-I et al., 2006) and thereafter its presence has been demonstrated in several tissues of mammalian and non-mammalian vertebrates except reptiles (reviewed by Leung et al., 2019). It has been shown to regulate food intake, gastrointestinal activity, glucose homeostasis, cardiovascular functions, adipocyte growth and differentiation, reproduction and thermoregulation (reviewed by Feijóo-Bandín et al., 2016). In addition, nesfatin-1 has been implicated in several diseased conditions like obesity, polycystic ovarian syndrome, diabetes mellitus, depression, anxiety and epilepsy (reviewed by Dore et al., 2017). Diverse pathways of nesfatin-1 action have also been reported depending upon tissue and physiological functions (reviewed by Schalla and Stengel, 2018). Though limited, studies in non-mammalian vertebrates also present nesfatin-1 as a pleiotropic peptide (Fig. 1). Nonetheless, studies on role, mechanism of action and regulation of nesfatin-1 are fragmented and thereby, the current review aims to present a detailed account of the peptide in different vertebrates and also draw attention to the existing lacunas in our understanding of nesfatin-1.

Section snippets

Sequence characterization of nesfatin-1

Nesfatin-1 is an 82 amino acids long peptide derived from a parent protein, nucleobindin2 (NUCB2), as a result of proteolytic cleavage by prohormone convertase enzymes, PC1/3 and PC2 at conserved cleavage sites, Lys-Arg and Arg-Arg, respectively (Oh-I et al., 2006). In addition to nesfatin-1, nesfatin-2 and nesfatin-3 comprising of 79 and 231 amino acids are yielded from NUCB2 (Oh-I et al., 2006). This review is focused on nesfatin-1 which is reported to be conserved across vertebrates and is

Distribution of nesfatin-1

In this review, term NUCB2/nesfatin-1 is used in lieu of nesfatin-1 since antibodies raised against nesfatin-1 are reported to cross-react with NUCB2 and likewise, expression of nucb2 is estimated to analyse mRNA level of nesfatin-1 (reviewed by Aydin, 2013, Stengel et al., 2013, Prinz and Stengel, 2016). Studies on localization in brain (Tables 1A and 1B) are largely restricted to mammals (Oh-I et al., 2006, Foo et al., 2008, Goebel et al., 2009) with a few in fishes (Gonzalez et al., 2010,

Feeding behavior

The effect of nesfatin-1 on feeding was first demonstrated by Oh-I and group (2006) in rat wherein intracerebroventricular (ICV) injection of nesfatin-1 resulted in an appreciable decrease in food intake. This anorexigenic effect was reversed after injection of nesfatin-1 neutralizing antibody. Thereafter, satiety role of nesfatin-1 has been well demonstrated in mammals by administering nesfatin-1 in different regions of brain such as paraventricular nucleus (PVN), lateral parabranchial nucleus

Receptor downstream signaling

Although nesfatin-1 binding sites have been demonstrated in several tissues, including brain, pituitary, adipose tissue, liver, pancreas, lung, kidney, heart and gonads (Prinz et al., 2016), its specific receptor has not been identified so far. Nevertheless, diverse receptor downstream signaling mechanisms such as cyclic adenosine monophosphate-protein kinase A (cAMP-PKA), AMPK/AKT, mitogen-activated protein kinase (MAPK), ERK and voltage-gated ion channels have been reported to mediate

Regulation of NUCB2/nesfatin-1

Nutritional state emerges as one of the important regulators of NUCB2/nesfatin-1 expression in mammals as well as fishes. A decrease in Nucb2 expression during fasting is reported in hypothalamus (García-Galiano et al., 2010), gastric endocrine cells (Stengel et al., 2009b) and testes (García-Galiano et al., 2012) of rat and adipose tissue of mice (Ramanjaneya et al., 2010), whereas no change either in plasma nesfatin-1 or Nucb2 mRNA expression in gastric mucosa and gonadal fat could be seen in

Pathophysiological roles of nesfatin-1

Nesfatin-1 is shown to be associated with several disorders, importantly obesity, diabetes mellitus, polycystic ovarian syndrome (PCOS), anxiety and depression (Table 3). In general, serum nesfatin-1 level remains low in obese children and adults (Abaci et al., 2013, Lopez-Aguilar et al., 2018, de Dios et al., 2019, Kim et al., 2019). Since this is a satiety-inducing peptide, obesity might have resulted due to hyperphagia. This idea is strengthened by several studies wherein a negative

Nesfatin-1-like peptide

Recently, a nesfatin-1-like peptide (NLP) consisting of seventy-seven amino acids derived from the proteolytic cleavage of NUCB1 has been discovered in mice. Like nesfatin-1, sequence analysis of NLP shows conservation of its putative bioactive core (21–49 amino acids) among vertebrates (Ramesh et al., 2015b). Limited functional studies on NLP in rodents and fishes report similar pleiotropic roles that are attributed to nesfatin-1. An inhibition of food intake has been observed upon

Conclusion

Nesfatin-1 is shown to be a pleiotropic peptide involved in regulation of several physiological functions like feeding behavior, metabolism, steroidogenesis, gestation, puberty and cardioprotection. Due to diverse functions, mechanism of action as well as regulation of nesfatin-1 is multifaceted. Although nesfatin-1 receptor has not been identified till date, implications of different tissue- and function-dependent downstream effectors are proposed to translate its action. The production of

Future perspective

Despite the fact that nesfatin-1 is a recently discovered peptide, numerous studies have been carried out demonstrating its pleiotropic physiological role in mammals while it remains meagrely explored in non-mammalian vertebrates. Nevertheless, to demonstrate species- and tissue-specific precise action of nesfatin-1, efforts have to be made to identify its specific receptor in vertebrates. Curiously, evidence suggesting the involvement of nesfatin-1 in disease pathogenesis are contradictory.

CRediT authorship contribution statement

Krittika Dotania: Writing - original draft. Mamta Tripathy: Writing - review & editing. Umesh Rai: Supervision, Conceptualization, Writing - review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

The first author is thankful to University Grant Commission, New Delhi, India for financial assistance as Junior Research Fellowship.

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