Reduction of Dietary Fat Rescues High-Fat Diet-Induced Depressive Phenotypes and the Associated Hippocampal Astrocytic Deficits in Mice

• Published in: Metabolites Vol. 15; no. 7; p. 485
• Main Authors: Cheng, Kai-Pi, Chao, Hsin-Hao, Hsu, Chin-Ju, Tsai, Sheng-Feng, Chiu, Yen-Ju, Kuo, Yu-Min, Chen, Yun-Wen
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.07.2025; MDPI
• Subjects: Animal models; astrocyte; Behavior; Body fat; Brain; depression; Depression, Mental; Diet; Dietary fat; Dyslipidemia; Genetic aspects; GLAST; GLT-1; Glucose; Glutamate; Glutamatergic transmission; Glutamic acid transporter; High fat diet; Hippocampus; Hypothalamus; IKK protein; Inflammation; Insulin; Insulin resistance; Laboratory animals; Mental depression; Mental disorders; Mental health; Metabolic disorders; Metabolism; NF-κB protein; Nucleus accumbens; Obesity; Phenotype; Phenotypes; Plasma; Public health; Signal transduction; Sucrose; Trifluoperazine; Tumor necrosis factor-α; Weight control; United States; Taiwan; St Louis Missouri; United States > US; GLAST; depression; astrocyte; obesity; GLT-1
• ISSN: 2218-1989; 2218-1989
• DOI: 10.3390/metabo15070485

Background/Objectives: Depression is frequently comorbid with obesity. We previously showed that astrocyte-mediated hyperactive ventral hippocampal glutamatergic afferents to the nucleus accumbens determined the exhibition of depression-like behaviors in obese murine models. However, it remains unclear if the metabolic disorder-induced depressive phenotypes and astrocytic maladaptation in the ventral hippocampus (vHPC) could be reversed following the amelioration of key metabolic impairments such as insulin resistance and dyslipidemia. Method: Male mice were fed a high-fat diet (HFD) for 12 weeks, followed by either continued HFD feeding (HFD/HFD group) or a switch to a standard diet for 4 weeks (HFD/SD group). Results: Results showed that HFD/HFD mice displayed not only glucose/lipid metabolic dysfunction, but also depression-like behaviors. In contrast, HFD/SD mice showed improvements in metabolic disorders and depressive phenotypes. Mechanistically, dietary fat reduction restored astrocyte morphology and glutamate transporter expression (GLT-1, GLAST) in the vHPC and suppressed neuroinflammatory signaling, as evidenced by reduced levels of phospho-IKK, TNF-α, IL-1β, and IL-6 in the vHPC. Conclusions: These findings suggest that dietary fat reduction reverses obesity-induced depressive phenotypes, astrocytic deficits, at least in part via suppression of neuroinflammation through the NF-κB signaling pathway.