International immunopharmacology · 2025
Aerobic exercise improves the high-fat diet/streptozotocin-induced depression-like behaviors by reducing hippocampal neuroinflammation through suppressing the BTK/NF-κB signaling pathway.
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Zhang Xiao-Yong, Xu Dan-Hong, Huang Jing-Qian, Zhan Jun-Hui, Han Feng, Du Jian-Kui, Liu Jun, Li Zong-Bin, Zhu Xiao-Yan, Liu Yu-Jian
Аннотация
BACKGROUND: Aerobic exercise can help reduce depression symptoms by alleviating hippocampal neuron injury and neuroinflammation. However, the specific mechanisms by which aerobic exercise inhibits neuroinflammation in individuals with diabetes-related depression are not fully understood.
METHODS: This study subjected high-fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic mice to five weeks of moderate-intensity aerobic treadmill training. Two publicly available GEO datasets were then analyzed to identify differentially expressed genes (DEGs) in the hippocampus of type 2 diabetic rodent models. Subsequently, we conducted a comprehensive batch query using the connectivity map (CMap), which led to the identification of Bruton tyrosine kinase (BTK) inhibitors as the most promising candidates for therapeutic intervention.
RESULTS: In high glucose/palmitate (HG/PA)-treated BV2 microglial cells, the BTK inhibitor acalabrutinib inactivated nuclear factor kappa B (NF-κB) and attenuated microglial activation. Systemic administration of acalabrutinib two weeks after the onset of diabetes inactivated the BTK/NF-κB signaling pathway, reduced microglial activation and neuroinflammation in the hippocampus, and led to an improvement in depression-like behaviors in type 2 diabetic mice. Additionally, aerobic exercise was found to inactivate the BTK/NF-κB pathway in the hippocampus of type 2 diabetic mice. The results showed that exercise training decreased depression-like behaviors and reduced microglial activation and neuroinflammation in the hippocampus, effects that were largely blocked by systemic administration of an NF-κB activator.
CONCLUSIONS: Overall, the findings indicate that aerobic exercise could alleviate type 2 diabetes-associated depression by reducing microglial activation and neuroinflammation in the hippocampus, primarily through suppression of the BTK/NF-κB pathway. BTK is identified as a druggable target for the treatment of type 2 diabetes-associated depression.
METHODS: This study subjected high-fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic mice to five weeks of moderate-intensity aerobic treadmill training. Two publicly available GEO datasets were then analyzed to identify differentially expressed genes (DEGs) in the hippocampus of type 2 diabetic rodent models. Subsequently, we conducted a comprehensive batch query using the connectivity map (CMap), which led to the identification of Bruton tyrosine kinase (BTK) inhibitors as the most promising candidates for therapeutic intervention.
RESULTS: In high glucose/palmitate (HG/PA)-treated BV2 microglial cells, the BTK inhibitor acalabrutinib inactivated nuclear factor kappa B (NF-κB) and attenuated microglial activation. Systemic administration of acalabrutinib two weeks after the onset of diabetes inactivated the BTK/NF-κB signaling pathway, reduced microglial activation and neuroinflammation in the hippocampus, and led to an improvement in depression-like behaviors in type 2 diabetic mice. Additionally, aerobic exercise was found to inactivate the BTK/NF-κB pathway in the hippocampus of type 2 diabetic mice. The results showed that exercise training decreased depression-like behaviors and reduced microglial activation and neuroinflammation in the hippocampus, effects that were largely blocked by systemic administration of an NF-κB activator.
CONCLUSIONS: Overall, the findings indicate that aerobic exercise could alleviate type 2 diabetes-associated depression by reducing microglial activation and neuroinflammation in the hippocampus, primarily through suppression of the BTK/NF-κB pathway. BTK is identified as a druggable target for the treatment of type 2 diabetes-associated depression.