Fu Jing-Ting, Huang Hui-Ting, Chen Pei-Chun, Kuo Yu-Min, Chen Po-See, Tzeng Shun-Fen
Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
Institute of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
J Neurochem. 2025 Jan;169(1):e16236. doi: 10.1111/jnc.16236. Epub 2024 Oct 7.
High-fat diet (HFD)-induced obesity induces peripheral inflammation and hypothalamic pathogenesis linking the activation of astrocytes and microglia. Clinical evidence indicates a positive correlation between obesity and psychiatric disorders, such as depression. The connectivity of the frontal-striatal (FS) circuit, involving the caudate putamen (CPu) and anterior cingulate cortex (ACC) within the prefrontal cortex (PFC), is known for its role in stress-induced depression. Thus, there is a need for a thorough investigation into whether chronic obesity-induced gliosis, characterized by the activation of astrocytes and microglia, in these brain regions of individuals with chronic obesity. The results revealed increased S100β astrocytes and Iba1 microglia in the CPu and ACC of male obese mice, along with immune cell accumulation in meningeal lymphatic drainage. Activated GFAP astrocytes and Iba1 microglia were observed in the corpus callosum of obese mice. Gliosis in the CPu and ACC was linked to elevated cleaved caspase-3 levels, indicating potential neural cell death by chronic HFD feeding. There was a loss of myelin and adenomatous polyposis coli (APC) oligodendrocytes (OLs) in the corpus callosum, an area known to be linked with injury to the CPu. Additionally, reduced levels of aquaporin-4 (AQP4), a protein associated within the glymphatic systems, were noted in the CPu and ACC, while ciliary neurotrophic factor (CNTF) gene expression was upregulated in these brain regions of obese mice. The in vitro study revealed that high-dose CNTF causing a trend of reduced astrocytic AQP4 expression, but it significantly impaired OL maturation. This pathological evidence highlights that prolonged HFD consumption induces persistent FS gliosis and demyelination in the corpus callosum. An elevated level of CNTF appears to act as a potential regulator, leading to AQP4 downregulation in the FS areas and demyelination in the corpus callosum. This cascade of events might contribute to neural cell damage within these regions and disrupt the glymphatic flow.
高脂饮食（HFD）诱导的肥胖会引发外周炎症和下丘脑病变，这与星形胶质细胞和小胶质细胞的激活有关。临床证据表明肥胖与精神疾病（如抑郁症）之间存在正相关。额叶-纹状体（FS）回路的连接性，涉及前额叶皮质（PFC）内的尾状壳核（CPu）和前扣带回皮质（ACC），因其在应激诱导的抑郁症中的作用而闻名。因此，有必要深入研究慢性肥胖个体的这些脑区中，以星形胶质细胞和小胶质细胞激活为特征的慢性肥胖诱导的胶质增生情况。结果显示，雄性肥胖小鼠的CPu和ACC中S100β星形胶质细胞和Iba1小胶质细胞增加，同时脑膜淋巴引流中有免疫细胞积聚。在肥胖小鼠的胼胝体中观察到活化的GFAP星形胶质细胞和Iba1小胶质细胞。CPu和ACC中的胶质增生与裂解的半胱天冬酶-3水平升高有关，表明长期高脂饮食喂养可能导致神经细胞死亡。胼胝体中存在髓鞘丢失和腺瘤性息肉病大肠杆菌（APC）少突胶质细胞（OLs），该区域已知与CPu损伤有关。此外，在CPu和ACC中发现水通道蛋白-4（AQP4）水平降低，AQP4是一种与类淋巴系统相关的蛋白质，而肥胖小鼠这些脑区中的睫状神经营养因子（CNTF）基因表达上调。体外研究表明，高剂量CNTF导致星形胶质细胞AQP4表达有降低趋势，但显著损害OL成熟。这一病理证据突出表明，长期食用高脂饮食会诱导FS持续胶质增生和胼胝体脱髓鞘。CNTF水平升高似乎起到潜在调节作用，导致FS区域AQP4下调和胼胝体脱髓鞘。这一系列事件可能导致这些区域的神经细胞损伤并扰乱类淋巴流动。
