College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin 300071, China.
Institute of Robotics & Automatic Information System, College of Artificial Intelligence, Nankai University, Tianjin 300071, China.
ACS Chem Neurosci. 2024 Nov 20;15(22):4229-4240. doi: 10.1021/acschemneuro.4c00540. Epub 2024 Oct 30.
High-fat diet (HFD) induced obesity is associated with depression-related behavioral and neurogenic changes and may lead to cognitive impairment. Fluoxetine (FXT), the most commonly used antidepressant, may alleviate depressive symptoms by increasing neurogenesis, but the potential efficacy of FXT for HFD-induced cognitive deficits is unclear. In this study, we established an obese HFD mouse model by feeding three-week-old male C57BL/6N mice with a chronic HFD for 18 weeks, then assessed adipose tissue morphology by magnetic resonance imaging and histopathology, assessed cognitive function by Morris water maze and novel object recognition tests, and detected DCX and BrdU expression in the hippocampal dentate gyrus (DG) region by immunofluorescence bioassay. Western blot detected brain-derived neurotrophic factor (BDNF) levels and pathway-related genes were assayed by Quantitative RT-PCR. The results of the study showed that HFD contributes to obesity and cognitive deficits, and more importantly, it also reduces BDNF expression and neurogenesis levels in the hippocampus. Subsequently, we found that treatment with FXT (10 mg/kg/day) ameliorated chronic HFD-induced cognitive deficits and increased the expression of Nestin, BrdU, and DCX in the DG, restored BDNF expression in the hippocampus and increased the expression of genes related to , , , and . In conclusion, our data elucidated that FXT ameliorates cognitive deficits and reduces chronic HFD-induced neurogenesis by restoring BDNF expression and signaling, this provides a good basis and scientific significance for future research on the clinical treatment of obesity.
高脂饮食（HFD）诱导的肥胖与抑郁相关的行为和神经发生变化有关，并可能导致认知障碍。氟西汀（FXT）是最常用的抗抑郁药，通过增加神经发生可能缓解抑郁症状，但 FXT 对 HFD 诱导的认知缺陷的潜在疗效尚不清楚。在这项研究中，我们通过用慢性 HFD 喂养三周龄雄性 C57BL/6N 小鼠 18 周来建立肥胖 HFD 小鼠模型，然后通过磁共振成像和组织病理学评估脂肪组织形态，通过 Morris 水迷宫和新物体识别测试评估认知功能，并通过免疫荧光生物测定检测海马齿状回（DG）区的 DCX 和 BrdU 表达。Western blot 检测脑源性神经营养因子（BDNF）水平，定量 RT-PCR 检测 通路相关基因。研究结果表明，HFD 导致肥胖和认知缺陷，更重要的是，它还降低了海马体中的 BDNF 表达和神经发生水平。随后，我们发现 FXT（10mg/kg/天）治疗可改善慢性 HFD 诱导的认知缺陷，并增加 DG 中 Nestin、BrdU 和 DCX 的表达，恢复海马体中的 BDNF 表达并增加与 、 、 、 和 相关的基因的表达。总之，我们的数据表明 FXT 通过恢复 BDNF 表达和 信号通路改善认知缺陷并减少慢性 HFD 诱导的神经发生，这为未来肥胖症的临床治疗研究提供了良好的基础和科学意义。
