Abstract
Studies of nesfatin-1 in glucose metabolism have become a topic of interest recently, however, the specific receptor for nesfatin-1 has not yet been identified. Some studies hinted at a connection between nesfatin-1 and the ghrelin receptor, growth hormone secretagogue receptor. Therefore, we aimed to study the role of GHSR in the glycemic effects of nesfatin-1 as well as its downstream pathways. We employed C57/BL6 mice (wild type and GHSR knockout mice) eating a normal chow diet and a high fat diet in this study, and the experimental technique included western blot, real-time PCR, immunofluorescence and ELISA. We found that in mice fed a normal chow diet (NCD), nesfatin-1 improved glucose tolerance, up-regulated AKT kinase (AKT) mRNA levels and phosphorylation and GLUT4 membrane translocation in skeletal muscle. These effects were blocked by co-injection of GHSR antagonist [D-Lys3]-GHRP-6 and were attenuated in GHSR knockout mice. In mice fed high-fat diet (HFD), nesfatin-1 not only exerted the effects observed in NCD mice, but also suppressed appetite and raised AKT levels in liver tissues that also required GHSR. Peripheral nesfatin-1 suppressed c-fos expression of GHSR immunoreactive neurons induced by fasting in hypothalamic nuclei, indicating that nesfatin-1 inhibited the activation of central GHSR. We concluded that the effects of nesfatin-1 on food intake and glucose metabolism were GHSR-dependent, and that the glycemic effect was associated with AKT and GLUT4. This study should stimulate further exploration of the nesfatin-1 receptor.
Highlights
Nesfatin-1 is an anorexic peptide discovered in 2006 [1]
Nesfatin-1 was found interacting with a G protein-coupled receptor in the rat brain [3], and its peripheral and central localization was described by 125I-nesfatin-1 autoradiography in 2016 [40]
A recent article suggested that nesfatin-1 might have anti-inflammatory effects acting through Growth hormone secretagogue receptor (GHSR) [41], confirming our findings regarding the relationship between nesfatin-1 and GHSR
Summary
Nesfatin-1 is an anorexic peptide discovered in 2006 [1]. Protein nucleobindin-2 (NUCB2), its precursor, was found to be related to severe obesity in human children [2]. It has been shown to inhibit food intake and reduce body weight both centrally [1, 11] and peripherally [12], suggesting a potential therapeutic role in obesity. Continuous subcutaneous administration of nesfatin-1 diminishes blood glucose levels during the oral glucose tolerance test (OGTT), while intracerebroventricular (ICV) injection of nesfatin-1 did not reduce blood glucose levels [13], suggesting that the glycemic effect of nesfatin-1 may be peripheral. Another study found that the effect of peripheral nesfatin-1 on reducing blood glucose was mediated in a glucose- and insulin-dependent manner [14]. Nesfatin-1 decreased blood glucose indirectly in other organs: co-injection of insulin and nesfatin-1 increased phosphorylation levels of AKT kinase (AKT) in liver, skeletal muscle, and adipose tissue, and improved GLUT4 levels to increase glucose uptake [13]
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