Multiple signaling pathways mediate ghrelin-induced proliferation of hippocampal neural stem cells

Abstract

Ghrelin, an endogenous ligand for the GH secretagogue receptor (GHS-R) receptor 1a (GHS-R1a), has been implicated in several physiologic processes involving the hippocampus. The aim of this study was to investigate the molecular mechanisms of ghrelin-stimulated neurogenesis using cultured adult rat hippocampal neural stem cells (NSCs). The expression of GHS-R1a was detected in hippocampal NSCs, as assessed by western blot analysis and immunocytochemistry. Ghrelin treatment increased the proliferation of cultured hippocampal NSCs assessed by BrdU incorporation. The exposure of cells to the receptor-specific antagonist D-Lys-3-GHRP-6 abolished the proliferative effect of ghrelin. By contrast, ghrelin showed no significant effect on cell differentiation. The expression of GHS-R1a was significantly increased by ghrelin treatment. The analysis of signaling pathways showed that ghrelin caused rapid activation of ERK1/2 and Akt, which were blocked by the GHS-R1a antagonist. In addition, ghrelin stimulated the phosphorylation of Akt downstream effectors, such as glycogen synthase kinase (GSK)-3b, mammalian target of rapamycin (mTOR), and p70 S6K. The activation of STAT3 was also caused by ghrelin treatment. Furthermore, pretreatment of cells with specific inhibitors of MEK/ERK1/2, phosphatidylinositol-3-kinase (PI3K)/Akt, mTOR, and Jak2/STAT3 attenuated ghrelin-induced cell proliferation. Taken together, our results support a role for ghrelin in adult hippocampal neurogenesis and suggest the involvement of the ERK1/2, PI3K/Akt, and STAT3 signaling pathways in the mediation of the actions of ghrelin on neurogenesis. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3b and activation of mTOR/p70 S6K contribute to the proliferative effect of ghrelin.

Evaluation of mTOR signaling pathway proteins in rat gastric mucosa exposed to sulfite and ghrelin

“…That effect might be due to suppression of mTOR pathway, modulated by sulfite via tuberin activation, by ghrelin, which also supports the increase of cell proliferation by ghrelin administration in our previous study (24). Similarly, a study reported that mTOR/P70S6k signaling pathway mediated ghrelin-induced proliferation of neural stem cells (39).…”

Ghrelin is required for dietary restriction-induced enhancement of hippocampal neurogenesis: lessons from ghrelin knockout mice

“…Additionally, in our recent report [7], we found that mice with targeted disruption of the ghrelin gene showed a decreased number of progenitor cells in the dentate gyrus (DG) of the hippocampus, while ghrelin replacement restored progenitor cell numbers to those of wild-type (WT) controls. Proliferative effect of ghrelin on hippocampal progenitor cells seems to be mediated through the activation of its receptor because GHS-R1a antagonist completely blocked the effect of ghrelin in vitro [8]. Collectively, these findings suggest that ghrelin may play an important role in adult hippocampal neurogenesis.…”

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

“…Since ghrelin leads to neuropeptide Y and GABA release in the hypothalamus, it may have a similar action in the hippocampus [214]. Another possibility is that ghrelin induces the proliferation of hippocampal neural stem cells [222]. Alternatively, it acts as an anti-inflammatory agent, as demonstrated in the periphery [223].…”