title: Hippocampal GSK3β as a Molecular Link Between Obesity and Depression.
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.
authors.affiliation: Neuroendocrinologie Moléculaire de la Prise Alimentaire, University of Paris-Sud 11, UMR 8195, F-91405, Orsay, France.
authors.forename: Ioannis K
authors.initials: IK
authors.lastname: Papazoglou
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jean
authors.forename: Arieh
authors.initials: A
authors.lastname: Gertler
authors.forename: Mohammed
authors.initials: M
authors.lastname: Taouis
authors.forename: Claire-Marie
authors.initials: CM
authors.lastname: Vacher
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018891:Dentate Gyrus / Q000201:enzymology / Q000473:pathology; D003863:Depression / Q000150:complications* / Q000201:enzymology* / Q000503:physiopathology; D059305:Diet, High-Fat; D002149:Energy Intake / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology; D007150:Immunohistochemistry; D007328:Insulin / Q000494:pharmacology; D020738:Leptin / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000201:enzymology* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism
chemical_list: D007328:Insulin; D020738:Leptin; D012701:Serotonin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3