title: Leptin-dependent neurotoxicity via induction of apoptosis in adult rat neurogenic cells.
abstract: Adipocyte-derived hormone leptin has been recently implicated in the control of neuronal plasticity. To explore whether modulation of adult neurogenesis may contribute to leptin control of neuronal plasticity, we used the neurosphere assay of neural stem cells derived from the adult rat subventricular zone (SVZ). Endogenous expression of specific leptin receptor (ObRb) transcripts, as revealed by RT-PCR, is associated with activation of both ERK and STAT-3 pathways via phosphorylation of the critical ERK/STAT-3 amino acid residues upon addition of leptin to neurospheres. Furthermore, leptin triggered withdrawal of neural stem cells from the cell cycle as monitored by Ki67 labeling. This effect was blocked by pharmacological inhibition of ERK activation thus demonstrating that ERK mediates leptin effects on neural stem cell expansion. Leptin-dependent withdrawal of neural stem cells from the cell cycle was associated with increased apoptosis, as detected by TUNEL, which was preceded by cyclin D1 induction. Cyclin D1 was indeed extensively colocalized with TUNEL-positive, apoptotic nuclei. Cyclin-D1 silencing by specific shRNA prevented leptin-induced decrease of the cell number per neurosphere thus pointing to the causal relationship between leptin actions on apoptosis and cyclin D1 induction. Leptin target cells in SVZ neurospheres were identified by double TUNEL/phenotypic marker immunocytofluorescence as differentiating neurons mostly. The inhibition of neural stem cell expansion via ERK/cyclin D1-triggered apoptosis defines novel biological action of leptin which may be involved in adiposity-dependent neurotoxicity.
authors.affiliation: Physiologie de la Reproduction et des Comportements, UMR 85 Institut National de la Recherche Agronomique, Centre INRA de Tours, Université François Rabelais de Tours Nouzilly, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Segura
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 901, Institut de Neurobiologie de la Méditerranée, Parc Scientifique de Luminy, Aix-Marseille Université Marseille, France.
authors.forename: Laurie
authors.initials: L
authors.lastname: Efthimiadi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 901, Institut de Neurobiologie de la Méditerranée, Parc Scientifique de Luminy, Aix-Marseille Université Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Porcher
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 901, Institut de Neurobiologie de la Méditerranée, Parc Scientifique de Luminy, Aix-Marseille Université Marseille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Courtes
authors.affiliation: Signalisation et Transports Ioniques Membranaires, ERL 7368 Centre National de la Recherche Scientifique, Université de Poitiers Poitiers, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Coronas
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 901, Institut de Neurobiologie de la Méditerranée, Parc Scientifique de Luminy, Aix-Marseille Université Marseille, France ; Centre de Recherche des Cordeliers, UMR_S 1138 INSERM, Paris Descartes University, Sorbonne Paris Cité, Pierre and Marie Curie University Paris, France.
authors.forename: Slavica
authors.initials: S
authors.lastname: Krantic
authors.affiliation: Physiologie de la Reproduction et des Comportements, UMR 85 Institut National de la Recherche Agronomique, Centre INRA de Tours, Université François Rabelais de Tours Nouzilly, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Moyse
keywords: ERK; STAT3; adult neural stem cells; leptin; neuronal death; neurospheres; proliferation; rat