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Leptin But Not Ciliary Neurotrophic Factor (CNTF) Induces Phosphotyrosine Phosphatase-1B Expression in Human Neuronal Cells (SH-SY5Y): Putative Explanation of CNTF Efficacy in Leptin-Resistant State

Neuroendocrinologie Moléculaire de la Prise Alimentaire (Y.B., F.B., C.-M.V., V.B., J.D., M.T.), Unité Mixte de Recherche 1197, Université Paris-Sud 11/Institut National de la Recherche Agronomique, Orsay 91405, France; and Faculty of Agriculture, Food, and Environment Quality Sciences (A.G.), The Hebrew University of Jerusalem, Rehovot 76100, Israel

Address all correspondence and requests for reprints to: Professor Mohammed Taouis, Neuroendocrinologie Moléculaire de la Prise Alimentaire, Unité Mixte de Recherche 1197, Université Paris-Sud 11/Institut National de la Recherche Agronomique, Institut de Biologie Animale Intégrative et Cellulaire Bâtiment 447, Orsay 91405, France. E-mail: mohammed.taouis{at}u-psud.fr.

Growing evidences suggest that obesity is associated with hypothalamic leptin resistance, leading to the alteration of food intake control. Alternative treatment using ciliary neurotrophic factor (CNTF) has been suggested because CNTF exerts a leptin-like effect, even in leptin-resistant states, but the mechanisms by which CNTF maintains this effect are not yet understood. Both leptin and CNTF act in the hypothalamus through similar signaling pathways including janus kinase-2/signal transducer and activator of transcription (STAT)-3 pathway. To explore the differences and interactions between leptin and CNTF signaling pathways, differentiated human neuroblastoma cells (SH-SY5Y) were exposed to either leptin or CNTF and then challenged for each cytokine. Leptin pretreatment completely abolished leptin-dependent STAT-3 and ERK 1/2 phosphorylations without affecting CNTF action. The lack of cross-desensitization between leptin and CNTF signaling pathways occurred despite the induction of suppressor of cytokine signaling-3 in response to both cytokines. Interestingly, leptin as well as insulin induced the expression of phosphotyrosine phosphatase (PTP)-1B, whereas CNTF treatment did not affect its expression. In addition, acute leptin treatment but not CNTF induced PTP-1B expression in mouse hypothalamic arcuate nucleus. Furthermore, the overexpression of human PTP-1B in SH-SY5Y cells completely abolished leptin- and insulin-dependent janus kinase-2, STAT-3, and ERK 1/2 phosphorylations, but CNTF action was not altered. Collectively, our results suggest that PTP-1B constitutes a key divergent element between leptin/insulin and CNTF signaling pathways at the neuronal level, which may constitute a possible mechanism that explains the efficacy of CNTF in leptin-resistant states.