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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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Proposed mechanisms of leptin and glucocorticoid stress hormones in the GSK3β/β-catenin signaling pathway. Leptin binds to the functional form of the leptin receptor, LepRb, and results in phosphorylation and activation of PI3K/AKT signaling pathway. This in turn phosphorylates GSK3β on Ser9 resulting in decreased GSK3β activity. In parallel, activated LepRb recruits JAK2 and initiates phosphorylation of STAT3. Phosphorylated STAT3 acts on GSK3β to reduce its activity. Glucocorticoids binding to GR induce phosphorylation of GSK3β on Tyr216 and decreases phosphorylation on Ser9, consequently increasing GSK3β activity. Increased GSK3β activity reduces the stability of β-catenin and leads to β-catenin degradation through ubiquitination. Decreased GSK3β activity increases the stability of β-catenin and results in accumulation of β-catenin and its translocation into the nucleus, allowing interaction with members of the lymphoid enhancer factor/T-cell factor (LEF/TCF) family of transcription factors and, as a consequence, promoting the expression of cell proliferation genes.
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Figure 6: Proposed mechanisms of leptin and glucocorticoid stress hormones in the GSK3β/β-catenin signaling pathway. Leptin binds to the functional form of the leptin receptor, LepRb, and results in phosphorylation and activation of PI3K/AKT signaling pathway. This in turn phosphorylates GSK3β on Ser9 resulting in decreased GSK3β activity. In parallel, activated LepRb recruits JAK2 and initiates phosphorylation of STAT3. Phosphorylated STAT3 acts on GSK3β to reduce its activity. Glucocorticoids binding to GR induce phosphorylation of GSK3β on Tyr216 and decreases phosphorylation on Ser9, consequently increasing GSK3β activity. Increased GSK3β activity reduces the stability of β-catenin and leads to β-catenin degradation through ubiquitination. Decreased GSK3β activity increases the stability of β-catenin and results in accumulation of β-catenin and its translocation into the nucleus, allowing interaction with members of the lymphoid enhancer factor/T-cell factor (LEF/TCF) family of transcription factors and, as a consequence, promoting the expression of cell proliferation genes.

Mentions: Possible signal transduction mechanisms underlying leptin regulation of GSK3β/β-catenin activity may involve activation of the phosphatidylinositol-3-kinase (PI3K)/AKT and the signal transducer and activator of transcription pathway 3 (STAT3) signaling pathways 2 (Figure 6). Both AKT and STAT3 signaling pathways are stimulated once leptin binds to LepRb 133–137. It is well known that Akt phosphorylates GSK3β on Ser9 and thereby inhibits GSK3β activity 92, 138. STAT3 has also been implicated in negative regulation of GSK3β. Loss of STAT3 in peripheral tissue results in a net increase in active form of GSK-3β 139. Inhibition of GSK3β by leptin-stimulated Akt and STAT3 signaling pathways would lead to increased β-catenin signaling and thus contribute to increased neurogenesis. Interestingly, β-catenin has been reported to induce de novo synthesis of brain-derived neurotrophic factor (BDNF) 140, which is an important regulator of adult hippocampal neurogenesis and behavioral effects of antidepressants 23, 141–148. Specifically, knockdown or knockout of BDNF in the dentate gyrus reduces neurogenesis, induces depression-like behavioral deficits and blocks behavioral response to antidepressants 149, 150. Direct ablation of the BDNF receptor, TrkB, in neural progenitor cells, leads to decreased basal proliferation and insensitivity to antidepressants 143, further supporting the critical role of BDNF in neurogenesis and behavioral effects of antidepressants. Very recently, leptin was shown to increase BDNF levels in the hippocampus 151. Whether leptin interacts with BDNF in mediating neurogenesis under basal and stress conditions awaits future investigation.


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)

Proposed mechanisms of leptin and glucocorticoid stress hormones in the GSK3β/β-catenin signaling pathway. Leptin binds to the functional form of the leptin receptor, LepRb, and results in phosphorylation and activation of PI3K/AKT signaling pathway. This in turn phosphorylates GSK3β on Ser9 resulting in decreased GSK3β activity. In parallel, activated LepRb recruits JAK2 and initiates phosphorylation of STAT3. Phosphorylated STAT3 acts on GSK3β to reduce its activity. Glucocorticoids binding to GR induce phosphorylation of GSK3β on Tyr216 and decreases phosphorylation on Ser9, consequently increasing GSK3β activity. Increased GSK3β activity reduces the stability of β-catenin and leads to β-catenin degradation through ubiquitination. Decreased GSK3β activity increases the stability of β-catenin and results in accumulation of β-catenin and its translocation into the nucleus, allowing interaction with members of the lymphoid enhancer factor/T-cell factor (LEF/TCF) family of transcription factors and, as a consequence, promoting the expression of cell proliferation genes.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368076&req=5

Figure 6: Proposed mechanisms of leptin and glucocorticoid stress hormones in the GSK3β/β-catenin signaling pathway. Leptin binds to the functional form of the leptin receptor, LepRb, and results in phosphorylation and activation of PI3K/AKT signaling pathway. This in turn phosphorylates GSK3β on Ser9 resulting in decreased GSK3β activity. In parallel, activated LepRb recruits JAK2 and initiates phosphorylation of STAT3. Phosphorylated STAT3 acts on GSK3β to reduce its activity. Glucocorticoids binding to GR induce phosphorylation of GSK3β on Tyr216 and decreases phosphorylation on Ser9, consequently increasing GSK3β activity. Increased GSK3β activity reduces the stability of β-catenin and leads to β-catenin degradation through ubiquitination. Decreased GSK3β activity increases the stability of β-catenin and results in accumulation of β-catenin and its translocation into the nucleus, allowing interaction with members of the lymphoid enhancer factor/T-cell factor (LEF/TCF) family of transcription factors and, as a consequence, promoting the expression of cell proliferation genes.
Mentions: Possible signal transduction mechanisms underlying leptin regulation of GSK3β/β-catenin activity may involve activation of the phosphatidylinositol-3-kinase (PI3K)/AKT and the signal transducer and activator of transcription pathway 3 (STAT3) signaling pathways 2 (Figure 6). Both AKT and STAT3 signaling pathways are stimulated once leptin binds to LepRb 133–137. It is well known that Akt phosphorylates GSK3β on Ser9 and thereby inhibits GSK3β activity 92, 138. STAT3 has also been implicated in negative regulation of GSK3β. Loss of STAT3 in peripheral tissue results in a net increase in active form of GSK-3β 139. Inhibition of GSK3β by leptin-stimulated Akt and STAT3 signaling pathways would lead to increased β-catenin signaling and thus contribute to increased neurogenesis. Interestingly, β-catenin has been reported to induce de novo synthesis of brain-derived neurotrophic factor (BDNF) 140, which is an important regulator of adult hippocampal neurogenesis and behavioral effects of antidepressants 23, 141–148. Specifically, knockdown or knockout of BDNF in the dentate gyrus reduces neurogenesis, induces depression-like behavioral deficits and blocks behavioral response to antidepressants 149, 150. Direct ablation of the BDNF receptor, TrkB, in neural progenitor cells, leads to decreased basal proliferation and insensitivity to antidepressants 143, further supporting the critical role of BDNF in neurogenesis and behavioral effects of antidepressants. Very recently, leptin was shown to increase BDNF levels in the hippocampus 151. Whether leptin interacts with BDNF in mediating neurogenesis under basal and stress conditions awaits future investigation.

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