Affiliation:
1. Centre for Hormone Research, Murdoch Childrens Research Institute, Department of Paediatrics University of Melbourne, Royal Children’s Hospital, Parkville 3052, Victoria, Australia
Abstract
Abstract
Many factors regulate nervous system development, including complex cross-talk between local neuroendocrine systems. The adipocyte-secreted hormone leptin, mainly known for its key roles in nutrition and reproductive balance, may also be involved in neuroanatomical organization, myelination processes, and neuronal/glia maturation. SK-N-SH-SY5Y neuroblastoma cells were employed as an in vitro model of human neuronal cells to determine whether leptin exerts neuroprotective activities. We show that SH-SY5Y cells express leptin, the long and short isoforms of the leptin receptor (ObRl, ObRs). In SH-SY5Y cells, leptin induced signal transducer and activator of transcription (STAT)-3 phosphorylation and suppressor of cytokine signaling-3 mRNA expression. Leptin dose-dependently increased cell number (up to 200% at 1 μm by 48 h, P < 0.01), and at 24–48 h, leptin at 100 nm increased SH-SY5Y cell number by 30–50%, respectively. SH-SY5Y cell viability was reduced in serum-free conditions at 24 h, and addition of leptin at 100 nm significantly reduced apoptosis by approximately 20% (P < 0.001). Leptin’s antiapoptotic activity required Janus kinase/STAT, MAPK, and phosphatidylinositol-3-kinase activation because the antiapoptotic effects of leptin were abolished, and caspase-3 immunoreactivity increased in the presence of the specific blockers AG490, U0126, or LY294002. Gene array demonstrated that leptin inhibits apoptosis via potent down-regulation of caspase-10 and TNF-related apoptosis-inducing ligand. Our data thus demonstrate, for the first time, that leptin stimulates, in a time- and dose-dependent manner, neuroblastoma cell proliferation and that the underlying mechanisms involve suppression of apoptosis via the Janus kinase-STAT, phosphatidylinositol-3 kinase, and MAPK pathways that culminate altogether in the down-regulation of the apoptotic factors caspase-10 and TNF-related apoptosis-inducing ligand.
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122 articles.
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