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Hippocampal GSK3β as a Molecular Link Between Obesity and Depression

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Abstract

Obesity is considered as a risk factor for mood disorders including depression. Nevertheless, the mechanisms underlying this association are not clearly understood. To address this issue, we investigated the impact of high-fat (HF)-diet-induced obesity on depressive-like behavior and on serotonin (5-HT)-dependent Akt/glycogen synthase kinase 3β (GSK3β) signaling in the dentate gyrus (DG) of the hippocampus, which has been associated with mood regulation. We first showed that a HF diet induced significant overweight and hyperglycemia as well as a depressive-like behavior in adult Wistar rats. By using an ex vivo approach on brain slices, we demonstrated that 5-HT activates the Akt/GSK3β cascade in the DG of control chow (C) diet-fed animals and that a 16-week HF diet feeding abolishes this activation, concurrently with a desensitization of leptin and insulin signaling in the same region. Furthermore, depressive-like behavior inversely correlated with 5-HT-induced phosphorylation of GSK3β in the subgranular neurons of the DG. Interestingly, a substitution of HF with C diet for 6 weeks induced a total loss of depressive symptoms, whereas body weight and glycemia remained significantly higher compared to control rats. In addition, food restoration led to a recovery of the Akt/GSK3β signaling pathway activation in the DG. In parallel, we observed a negative correlation between body weight and cell proliferation in the subgranular zone of the DG. To conclude, we provide evidence for a desensitization of 5-HT-induced Akt/GSK3β signaling and an impaired cell proliferation in the DG by HF diet, suggesting novel molecular mechanisms linking obesity to depression.

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Acknowledgments

We thank Alain Aubourg for technical assistance. We also thank Dr. Valérie Grange-Messent for her advice in designing the ex vivo brain slice experiments and Dr. Daniel Toledano for his help in performing the circular corridor test. We also thank Dr. Cristina Dalla for providing Observador ethological software and for her useful advice in analysis FST data and Joël Lefebvre for animal caring. This work was supported by the University Paris-Sud 11 and CNRS.

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Authors and Affiliations

  1. Neuroendocrinologie Moléculaire de la Prise Alimentaire, University of Paris-Sud 11, UMR 8195, F-91405, Orsay, France

    Ioannis K. Papazoglou, Arnaud Jean, Mohammed Taouis & Claire-Marie Vacher

  2. Neuroendocrinologie Moléculaire de la Prise Alimentaire, CNRS, Centre de Neurosciences, Paris-Sud UMR 8195, F-91405, Orsay, France

    Ioannis K. Papazoglou, Arnaud Jean, Mohammed Taouis & Claire-Marie Vacher

  3. Faculty of Agricultural, Food and Environmental Quality Sciences Institute of Biochemistry Food Science and Nutrition, The Hebrew University of Jerusalem, 76100, Rehovot, Israel

    Arieh Gertler

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  1. Ioannis K. Papazoglou
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  2. Arnaud Jean
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Correspondence to Claire-Marie Vacher.

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Papazoglou, I.K., Jean, A., Gertler, A. et al. Hippocampal GSK3β as a Molecular Link Between Obesity and Depression. Mol Neurobiol 52, 363–374 (2015). https://doi.org/10.1007/s12035-014-8863-x

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  • DOI: https://doi.org/10.1007/s12035-014-8863-x

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