Nesfatin-1 Receptor: Distribution, Signaling and Increasing Evidence for a G Protein-Coupled Receptor – A Systematic Review

Abstract

BackgroundNesfatin-1 is an 82-amino acid polypeptide, cleaved from the 396-amino acid precursor protein nucleobindin-2 (NUCB2) and discovered in 2006 in the rat hypothalamus. In contrast to the growing body of evidence for the pleiotropic effects of the peptide, the receptor mediating these effects and the exact signaling cascades remain still unknown.MethodsThis systematic review was conducted using a search in the Embase, PubMed, and Web of Science databases. The keywords “nesfatin-1” combined with “receptor”, “signaling”, “distribution”, “pathway”, g- protein coupled receptor”, and “binding” were used to identify all relevant articles reporting about potential nesfatin-1 signaling and the assumed mediation via a Gi protein-coupled receptor.ResultsFinally, 1,147 articles were found, of which 1,077 were excluded in several steps of screening, 70 articles were included in this systematic review. Inclusion criteria were studies investigating nesfatin-1’s putative receptor or signaling cascade, observational preclinical and clinical studies, experimental studies, registry-based studies, cohort studies, population-based studies, and studies in English language. After screening for eligibility, the studies were assigned to the following subtopics and discussed regarding intracellular signaling of nesfatin-1 including the potential receptor mediating these effects and downstream signaling of the peptide.ConclusionThe present review sheds light on the various effects of nesfatin-1 by influencing several intracellular signaling pathways and downstream cascades, including the peptide’s influence on various hormones and their receptors. These data point towards mediation via a Gi protein-coupled receptor. Nonetheless, the identification of the nesfatin-1 receptor will enable us to better investigate the exact mediating mechanisms underlying the different effects of the peptide along with the development of agonists and antagonists.

Nesfatin-1 protects against diabetic cardiomyopathy in the streptozotocin-induced diabetic mouse model via the p38-MAPK pathway

“…Nesfatin-1 regulates multiple hormones and their receptors. The specific receptors in heart tissue remain largely unknown [ 33 ]. Future identification of the tissue-specific receptors will be critical to understanding the physiology of nesfatin-1.…”

The Actions of Centrally Administered Nesfatin-1 on Emesis, Feeding, and Locomotor Activity in Suncus murinus (House Musk Shrew)

“…The former explanation may be more likely, as in streptozotocin-induced type 2 diabetic mice, a low dose of nesfatin-1 activates the AMPK-ACC pathway more effectively than a higher dose ( Dong et al, 2013 ). Other studies have suggested that the nesfatin-1 singling pathway is via a G i protein-coupled receptor ( Rupp et al, 2021 ) which can be desensitized following activation by regulatory peptides, such as ghrelin ( Camina et al, 2004 ) and substance P ( Holland et al, 1993 ).…”

Premetazoan Origin of Neuropeptide Signaling

“…Different functions of nesfatin-1 have been reported in vertebrates, including the regulation of glucose metabolism, reproduction, anxiety, and responses to stress ( Schalla and Stengel 2018 ; Friedrich and Stengel 2021 ). Its role as a satiety-inducing factor has been widely reported in mammals and fish ( Ayada et al 2015 ; Sundarrajan et al 2016 ; Rupp et al 2021 ). NUCB precursors encoding the nesfatin-1 peptide region are also present in invertebrates, including ophiuroid echinoderms and the fruit fly Drosophila melanogaster ( Otte et al 1999 ; Zandawala et al 2017 ).…”

“…NUCB precursors encoding the nesfatin-1 peptide region are also present in invertebrates, including ophiuroid echinoderms and the fruit fly Drosophila melanogaster ( Otte et al 1999 ; Zandawala et al 2017 ). So far, no receptor has been identified for the nesfatin-1 peptide ( Rupp et al 2021 ).…”