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Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3β/β-catenin signaling.

Garza JC, Guo M, Zhang W, Lu XY - Mol. Psychiatry (2011)

Bottom Line: Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis.Leptin treatment elicited a delayed long-lasting antidepressant-like effect in the forced swim behavioral despair test, and this effect was blocked by ablation of neurogenesis with X-irradiation.Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

ABSTRACT
Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis. Our previous studies have shown that leptin, an adipocyte-derived hormone with antidepressant-like properties, promotes baseline neurogenesis in the adult hippocampus. This study aimed to determine whether leptin is able to restore 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 a delayed long-lasting antidepressant-like effect in the forced swim 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 glycogen synthase kinase-3β (GSK-3β) and β-catenin. While DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK-3β, leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK-3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK-3β and a key regulator in controlling hippocampal neural progenitor cell proliferation, and reversed the inhibitory effects of DEX on β-catenin. Taken 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 GSK-3β/β-catenin signaling pathway.

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Effects of leptin and dexamethasone on phosphorylation of GSK3β and nuclear translocation of β-catenin. A. Hippocampal neural stem/progenitor cells were treated with dexamethasone (DEX, 10 μM), leptin (1 nM), or a combination of leptin and DEX for 20 min. Phosphorylation of GSK3β at Ser9 (left panel) and Tyr216 (right panel) was determined using Western blot. B. Representative confocal images demonstrating immunohistochemical staining of β-catenin in cultured hippocampal neural stem/progenitor cells treated with DEX (10 μM), leptin (1 nM), or a combination of both for 48 h. Scale bar = 10 μm. C and D. Western blot showing levels of β-catenin form total cell extracts (C) and nuclear extracts (D) of hippocampal neural stem/progenitor cells treated with DEX (10 μM), leptin (1 nM), or a combination of both for 48 h. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 compared to vehicle/vehicle treatment.
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Figure 5: Effects of leptin and dexamethasone on phosphorylation of GSK3β and nuclear translocation of β-catenin. A. Hippocampal neural stem/progenitor cells were treated with dexamethasone (DEX, 10 μM), leptin (1 nM), or a combination of leptin and DEX for 20 min. Phosphorylation of GSK3β at Ser9 (left panel) and Tyr216 (right panel) was determined using Western blot. B. Representative confocal images demonstrating immunohistochemical staining of β-catenin in cultured hippocampal neural stem/progenitor cells treated with DEX (10 μM), leptin (1 nM), or a combination of both for 48 h. Scale bar = 10 μm. C and D. Western blot showing levels of β-catenin form total cell extracts (C) and nuclear extracts (D) of hippocampal neural stem/progenitor cells treated with DEX (10 μM), leptin (1 nM), or a combination of both for 48 h. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 compared to vehicle/vehicle treatment.

Mentions: To identify the molecular mechanisms by which leptin reversed the effect of DEX on hippocampal neural stem/progenitor cell proliferation, we examined the GSK3β/β-catenin signaling pathway. GSK3β phosphorylationat Ser9 and Tyr216 was detected 20 min after leptin (1 nM) and/or DEX (10 μM) treatment. ANOVA revealed a main effect for both leptin and DEX treatment on GSK3β Ser9 phosphorylation (F(1,15) = 22.62, P < 0.001 for leptin; F(1,15) = 4.88, P < 0.05 for DEX) and only a significant main effect for DEX on Tyr216 phosphorylation (F(1,15) = 0.93, P = 0.35 for leptin; F(1,15) = 5.99, P < 0.05 for DEX). There was no significant interaction between leptin and DEX (F(1,15) = 2.26, P = 0.16 for Ser9 phosphorylation; F(1,15) = 1.04, P = 0.32 for Tyr216 phosphorylation). DEX decreased GSK-3β Ser9 phosphorylationand increased Tyr216 phosphorylation compared to vehicle treatment (P < 0.05), while leptin increased Ser9 phosphorylation (P < 0.001) and had no significant effect on Tyr216 phosphorylation (Figure 5A). When leptin (1 nM) was co-administered with DEX, it reversed DEX-induced reduction of Ser9 phosphorylation (P < 0.001) and attenuated DEX-induced increase in Tyr216 phosphorylation(P = 0.1) (Figure 5A). Similar results were obtained after 48 h treatment with leptin and/or DEX (Figure S2).


Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3β/β-catenin signaling.

Garza JC, Guo M, Zhang W, Lu XY - Mol. Psychiatry (2011)

Effects of leptin and dexamethasone on phosphorylation of GSK3β and nuclear translocation of β-catenin. A. Hippocampal neural stem/progenitor cells were treated with dexamethasone (DEX, 10 μM), leptin (1 nM), or a combination of leptin and DEX for 20 min. Phosphorylation of GSK3β at Ser9 (left panel) and Tyr216 (right panel) was determined using Western blot. B. Representative confocal images demonstrating immunohistochemical staining of β-catenin in cultured hippocampal neural stem/progenitor cells treated with DEX (10 μM), leptin (1 nM), or a combination of both for 48 h. Scale bar = 10 μm. C and D. Western blot showing levels of β-catenin form total cell extracts (C) and nuclear extracts (D) of hippocampal neural stem/progenitor cells treated with DEX (10 μM), leptin (1 nM), or a combination of both for 48 h. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 compared to vehicle/vehicle treatment.
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Figure 5: Effects of leptin and dexamethasone on phosphorylation of GSK3β and nuclear translocation of β-catenin. A. Hippocampal neural stem/progenitor cells were treated with dexamethasone (DEX, 10 μM), leptin (1 nM), or a combination of leptin and DEX for 20 min. Phosphorylation of GSK3β at Ser9 (left panel) and Tyr216 (right panel) was determined using Western blot. B. Representative confocal images demonstrating immunohistochemical staining of β-catenin in cultured hippocampal neural stem/progenitor cells treated with DEX (10 μM), leptin (1 nM), or a combination of both for 48 h. Scale bar = 10 μm. C and D. Western blot showing levels of β-catenin form total cell extracts (C) and nuclear extracts (D) of hippocampal neural stem/progenitor cells treated with DEX (10 μM), leptin (1 nM), or a combination of both for 48 h. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 compared to vehicle/vehicle treatment.
Mentions: To identify the molecular mechanisms by which leptin reversed the effect of DEX on hippocampal neural stem/progenitor cell proliferation, we examined the GSK3β/β-catenin signaling pathway. GSK3β phosphorylationat Ser9 and Tyr216 was detected 20 min after leptin (1 nM) and/or DEX (10 μM) treatment. ANOVA revealed a main effect for both leptin and DEX treatment on GSK3β Ser9 phosphorylation (F(1,15) = 22.62, P < 0.001 for leptin; F(1,15) = 4.88, P < 0.05 for DEX) and only a significant main effect for DEX on Tyr216 phosphorylation (F(1,15) = 0.93, P = 0.35 for leptin; F(1,15) = 5.99, P < 0.05 for DEX). There was no significant interaction between leptin and DEX (F(1,15) = 2.26, P = 0.16 for Ser9 phosphorylation; F(1,15) = 1.04, P = 0.32 for Tyr216 phosphorylation). DEX decreased GSK-3β Ser9 phosphorylationand increased Tyr216 phosphorylation compared to vehicle treatment (P < 0.05), while leptin increased Ser9 phosphorylation (P < 0.001) and had no significant effect on Tyr216 phosphorylation (Figure 5A). When leptin (1 nM) was co-administered with DEX, it reversed DEX-induced reduction of Ser9 phosphorylation (P < 0.001) and attenuated DEX-induced increase in Tyr216 phosphorylation(P = 0.1) (Figure 5A). Similar results were obtained after 48 h treatment with leptin and/or DEX (Figure S2).

Bottom Line: Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis.Leptin treatment elicited a delayed long-lasting antidepressant-like effect in the forced swim behavioral despair test, and this effect was blocked by ablation of neurogenesis with X-irradiation.Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

ABSTRACT
Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis. Our previous studies have shown that leptin, an adipocyte-derived hormone with antidepressant-like properties, promotes baseline neurogenesis in the adult hippocampus. This study aimed to determine whether leptin is able to restore 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 a delayed long-lasting antidepressant-like effect in the forced swim 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 glycogen synthase kinase-3β (GSK-3β) and β-catenin. While DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK-3β, leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK-3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK-3β and a key regulator in controlling hippocampal neural progenitor cell proliferation, and reversed the inhibitory effects of DEX on β-catenin. Taken 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 GSK-3β/β-catenin signaling pathway.

Show MeSH
Related in: MedlinePlus