Abstract
Leptin, an adipose-derived hormone, has been implicated in several physiological processes involving the hippocampus. However, the role of leptin in adult hippocampal neurogenesis remains unknown. Here we show that leptin regulates neurogenesis in the dentate gyrus of adult mice as well as in cultured adult hippocampal progenitor cells. Chronic administration of leptin to adult mice increased cell proliferation without significant effects on the differentiation and the survival of newly proliferated cells in the dentate gyrus. The expression of the long form leptin receptor, LepRb, was detected in hippocampal progenitor cells by reverse transcription-PCR and immunohistochemistry. Leptin treatment also increased proliferation of cultured adult hippocampal progenitor cells. Analysis of signal transduction pathways revealed that leptin stimulated phosphorylation of Akt and STAT3 but not ERK1/2. Furthermore, pre-treating the cells with specific inhibitors of Akt or STAT3 attenuated leptin-induced cell proliferation in a dose-dependent manner. Taken together, our results support a role for leptin in adult hippocampal neurogenesis and suggest the involvement of the Akt and STAT3 signaling pathways in mediating the actions of leptin on neurogenesis.
Highlights
Leptin is an adipocyte-derived cytokine encoded by the obese gene
Adult Mice—The time course effect of leptin on adult hippocampal cell proliferation was determined in mice at a dose (1 mg/kg body weight) that has been shown to be effective in inducing antidepressant-like effects [21, 29]
Phosphorylated ERK1/2 was not significantly altered after leptin treatment at either dose (Fig. 7, E and F). These results suggest the phosphatidylinositol 3-kinase (PI3K)/Akt and Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (STAT3) signaling pathways are recruited by leptin in adult hippocampal progenitor cells
Summary
Leptin is an adipocyte-derived cytokine encoded by the obese (ob) gene. It circulates as a 16-kDa peptide and is transported into the brain via a saturable transport system (9 –11). 18238 JOURNAL OF BIOLOGICAL CHEMISTRY (LepRb), a Type I cytokine receptor, which results in Janus kinase 2 (Jak2)-mediated phosphorylation of two tyrosine residues (Tyr985 and Tyr1138) in the cytoplasmic tail of the receptor [12]. Phosphorylated Tyr985 of LepRb recruits SH2-containing protein-tyrosine phosphatase-2, leading to activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) pathway [13, 14]. We characterized the possible signaling mechanisms by which leptin exerts its effects on neurogenesis in cultured adult hippocampal stem/progenitor cells
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