Fluoxetine\nAmeliorates Cognitive Deficits in High-Fat\nDiet Mice by Regulating BDNF Expression

High-fat diet (HFD) induced obesity is associated with\ndepression-related\nbehavioral and neurogenic changes and may lead to cognitive impairment.\nFluoxetine (FXT), the most commonly used antidepressant, may alleviate\ndepressive symptoms by increasing neurogenesis, but the potential\nefficacy of FXT for HFD-induced cognitive deficits is unclear. In\nthis study, we established an obese HFD mouse model by feeding three-week-old\nmale C57BL/6N mice with a chronic HFD for 18 weeks, then assessed\nadipose tissue morphology by magnetic resonance imaging and histopathology,\nassessed cognitive function by Morris water maze and novel object\nrecognition tests, and detected DCX<sup>+</sup> and BrdU<sup>+</sup> expression in the hippocampal dentate gyrus (DG) region by immunofluorescence\nbioassay. Western blot detected brain-derived neurotrophic factor\n(BDNF) levels and <i>CREB-BDNF</i> pathway-related genes\nwere assayed by Quantitative RT-PCR. The results of the study showed\nthat HFD contributes to obesity and cognitive deficits, and more importantly,\nit also reduces BDNF expression and neurogenesis levels in the hippocampus.\nSubsequently, we found that treatment with FXT (10 mg/kg/day) ameliorated\nchronic HFD-induced cognitive deficits and increased the expression\nof Nestin, BrdU<sup>+</sup>, and DCX<sup>+</sup> in the DG, restored\nBDNF expression in the hippocampus and increased the expression of\ngenes related to <i>CREB</i>, <i>BDNF</i>, <i>NGF</i>, and <i>MAPK1</i>. In conclusion, our data\nelucidated that FXT ameliorates cognitive deficits and reduces chronic\nHFD-induced neurogenesis by restoring BDNF expression and <i>CREB-BDNF</i> signaling, this provides a good basis and scientific\nsignificance for future research on the clinical treatment of obesity.