Obestatin is a recently discovered peptide encoded by the ghrelin gene. Obestatin was initially claimed to bind to the orphan receptor GPR39; however, this finding has been question and at present, obestatin receptor is still unknown. We have previously shown that obestatin exerts antiapoptotic effects in pancreatic β-cells and human pancreatic islets, through activation of survival pathways and interaction with the glucagon-like peptide 1 receptor (GLP-1R). Besides peripheral actions, obestatin displays central effects, such as regulation of sleep and mnemonic functions. Hippocampal neurogenesis, which is essential for mnemonic functions and learning, consists of progenitor cell proliferation and differentiation. Interestingly, both ghrelin and the synthetic peptidyl growth hormone secretagogue hexarelin have been previously shown to stimulate proliferation of adult rat hippocampal progenitor cells (AHPs). Here, we investigated obestatin effects on proliferation and apoptosis of AHPs and the underlying signalling pathways. Cell survival was assessed by MTT assay, cell proliferation by 5-bromo-2-deoxyuridine (BrdU) incorporation, and apoptosis through caspase-3 activity and Bcl-2 expression. Obestatin increased cell proliferation and survival and reduced apoptosis of AHPs that were cultured in growth factor-deprived medium. These effects involved increased activity of phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-related kinase (ERK1/2), Wnt/β-catenin and mammalian target of rapamycin (mTOR) signalling, as demonstrated by Western blot analysis and use of specific inhibitors. Furthermore, the specific antagonist of GLP-1R exendin-(9-39) abolished obestatin-induced proliferation and survival, suggesting GLP-1R-mediated signalling. These results indicate that obestatin promotes survival and proliferation and inhibits apoptosis of AHPs through activation of pathways which play a key role in neuroprotection. In addition, they suggest a possible role of obestatin in neuronal precursor cell protection and candidate this peptide as potential therapeutic molecule in conditions such as hippocampal damage.
OBESTATIN PROMOTES ADULT RAT HIPPOCAMPAL PROGENITOR CELL PROLIFERATION AND SURVIVAL THROUGH ACTIVATION OF PI3K/Akt, ERK1/2 and WNT/β-CATENIN SIGNALING
GRANATA, Riccarda;GARGANTINI, ELEONORA;BARAGLI, ALESSANDRA;SETTANNI, Fabio;GHIGO, Ezio
2012-01-01
Abstract
Obestatin is a recently discovered peptide encoded by the ghrelin gene. Obestatin was initially claimed to bind to the orphan receptor GPR39; however, this finding has been question and at present, obestatin receptor is still unknown. We have previously shown that obestatin exerts antiapoptotic effects in pancreatic β-cells and human pancreatic islets, through activation of survival pathways and interaction with the glucagon-like peptide 1 receptor (GLP-1R). Besides peripheral actions, obestatin displays central effects, such as regulation of sleep and mnemonic functions. Hippocampal neurogenesis, which is essential for mnemonic functions and learning, consists of progenitor cell proliferation and differentiation. Interestingly, both ghrelin and the synthetic peptidyl growth hormone secretagogue hexarelin have been previously shown to stimulate proliferation of adult rat hippocampal progenitor cells (AHPs). Here, we investigated obestatin effects on proliferation and apoptosis of AHPs and the underlying signalling pathways. Cell survival was assessed by MTT assay, cell proliferation by 5-bromo-2-deoxyuridine (BrdU) incorporation, and apoptosis through caspase-3 activity and Bcl-2 expression. Obestatin increased cell proliferation and survival and reduced apoptosis of AHPs that were cultured in growth factor-deprived medium. These effects involved increased activity of phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-related kinase (ERK1/2), Wnt/β-catenin and mammalian target of rapamycin (mTOR) signalling, as demonstrated by Western blot analysis and use of specific inhibitors. Furthermore, the specific antagonist of GLP-1R exendin-(9-39) abolished obestatin-induced proliferation and survival, suggesting GLP-1R-mediated signalling. These results indicate that obestatin promotes survival and proliferation and inhibits apoptosis of AHPs through activation of pathways which play a key role in neuroprotection. In addition, they suggest a possible role of obestatin in neuronal precursor cell protection and candidate this peptide as potential therapeutic molecule in conditions such as hippocampal damage.
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