Leptin restores adult hippocampal neurogenesis suppressed by chronic unpredictable stress and reverses glucocorticoid-induced inhibition of GSK3β/β-catenin signaling

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Abstract

Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease of neurogenesis. Our previous studies have shown leptin, an adipocyte-derived hormone with antidepressant-like properties ¹, promotes baseline neurogenesis in the adult hippocampus ². The present study aimed to determine whether leptin is able to restore stress-induced suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Chronic treatment with leptin reversed the CUS-induced reduction of hippocampal neurogenesis and depression-like behaviors. Leptin treatment elicited delayed long-lasting antidepressant-like effects in the behavioral despair test, and this effect was blocked by ablation of neurogenesis with X-irradiation. The functional isoform of the leptin receptor, LepRb, and the glucocorticoid receptor (GR) were colocalized in hippocampal neural stem/progenitor cells in vivo and in vitro. Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus. Further mechanistic analysis revealed that leptin and DEX converged on GSK3β and β-catenin. DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK3β, while leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK3 β and a key regulator in controlling neural progenitor proliferation, and reversed the inhibitory effects of DEX on β-catenin. Together, our results suggest that adult neurogenesis is involved in the delayed long-lasting antidepressant-like behavioral effects of leptin, and leptin treatment counteracts chronic stress and glucocorticoid-induced suppression of hippocampal neurogenesis via activating the GSK3β/β-catenin signaling pathway.

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Most cited references 141

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Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.

D. Cross, D Alessi, P. Cohen … (1995)

Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.

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Record: found
Abstract: found
Article: not found

More hippocampal neurons in adult mice living in an enriched environment.

G Kempermann, H Kuhn, F H Gage (1997)

Neurogenesis occurs in the dentate gyrus of the hippocampus throughout the life of a rodent, but the function of these new neurons and the mechanisms that regulate their birth are unknown. Here we show that significantly more new neurons exist in the dentate gyrus of mice exposed to an enriched environment compared with littermates housed in standard cages. We also show, using unbiased stereology, that the enriched mice have a larger hippocampal granule cell layer and 15 per cent more granule cell neurons in the dentate gyrus.

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Record: found
Abstract: found
Article: not found

Identification and expression cloning of a leptin receptor, OB-R.

Louis A Tartaglia, Marlene Dembski, Xun Weng … (1995)

The ob gene product, leptin, is an important circulating signal for the regulation of body weight. To identify high affinity leptin-binding sites, we generated a series of leptin-alkaline phosphatase (AP) fusion proteins as well as [125I]leptin. After a binding survey of cell lines and tissues, we identified leptin-binding sites in the mouse choroid plexus. A cDNA expression library was prepared from mouse choroid plexus and screened with a leptin-AP fusion protein to identify a leptin receptor (OB-R). OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor, the G-CSF receptor, and the LIF receptor. OB-R mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus. Genetic mapping of the gene encoding OB-R shows that it is within the 5.1 cM interval of mouse chromosome 4 that contains the db locus.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9607835

Journal ID (pubmed-jr-id): 20545

Journal ID (nlm-ta): Mol Psychiatry

Journal ID (iso-abbrev): Mol. Psychiatry

Title: Molecular Psychiatry

ISSN (Print): 1359-4184

ISSN (Electronic): 1476-5578

Publication date Nihms-submitted: 2 November 2011

Publication date (Electronic): 20 December 2011

Publication date (Print): July 2012

Publication date PMC-release: 01 January 2013

Volume: 17

Issue: 8

Pages: 790-808

Affiliations

[1 ]Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229

[2 ]Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229

Author notes

[* ]To whom correspondence should be addressed: Xin-Yun Lu, M.D., Ph.D., Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, Phone: 210-567-0803, Fax : 210-567-4303,: lux3@ 123456uthscsa.edu

Article

Manuscript ID: NIHMS334296

DOI: 10.1038/mp.2011.161

PMC ID: 3368076

PubMed ID: 22182938

SO-VID: 1cb981b0-a521-4d25-8c99-1c4a65f4678e

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