Antiapoptotic Effects of Leptin in Human Neuroblastoma Cells

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 microm 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.

Leptin induces migration and invasion of glioma cells through MMP‐13 production

“…However, central regulation of leptin gene expression is different from that in the adipocytes. The co-localization of leptin and leptin receptors in multiple brain regions is consistent with reports that leptin regulates brain development, neuronal projections, and the expression of neuronal and glial proteins (Ahima et al 1999), and possesses both anti-apoptotic (Russo et al 2004) and neuroprotective properties (Dicou et al 2001). Leptin has also been shown to have mitogenic (Wolf et al 1999) and angiogenic activity (Sierra-Honigmann et al 1998) in a number of cell types.…”

Hypoxia-induced leptin production in human trophoblasts does not protect from apoptosis

“…In contrast, Fujita et al demonstrated that leptin in fasted mice is able to prevent the apoptotic reduction of lymphocyte numbers in steroid-injected mice via a bcl-xL-dependent mechanism (12). This anti-apoptotic effect of leptin is in line with evidence that the hormone protects SK-N-SH-SY5Y neuroblastoma cells from apoptosis in serum-free medium by a STAT/JAK-dependent down regulation of caspase-10 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (13). It is well known that leptin contributes to a physiological pregnancy by regulation of implantation, energy balance of placenta and conceptus, as well as an angiogenic factor (14 -16).…”

Serum leptin level and cognition in the elderly: Findings from the Health ABC Study

“…Indeed, leptin has been found to act as an anti-apoptotic hormone under stress conditions (Russo et al, 2004). A role for leptin in neurogenesis and neurodevelopment is strengthened by the observations of Udagaw and others (Udagawa et al, 2006) that leptin stimulates the proliferation of precursor cells committed to neuronal differentiation, and promotes neuronal terminal differentiation.…”