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Microglial Feimin Alleviates Cognitive Impairment in High-Fat Diet-Fed Mice
Ran Gao1,2, Zhonghua Xiong3, Wenting Su1,2
1Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, China.
Abstract:
Lipid droplet accumulation in microglia, microglia-mediated neuroinflammation, and subsequent neuronal damage are hallmark features of high-fat diet (HFD)-induced cognitive impairment. In this analysis, this is proposed that a new molecule feimin (B230219D22Rik in mice) is a key negative regulator of LD accumulation and the inflammatory response in HFD-induced cognitive impairment. To test this hypothesis, BV2 microglia is exposed to palmitic acid (PA) in vitro, mimicking the effects of an HFD. This is found that feimin expression is significantly increased following high-lipid stimulation. Feimin-specific knockdown in BV2 cells led to enhanced LD accumulation, exacerbated inflammatory responses and neuronal apoptosis, whereas feimin overexpression has the opposite effect. Mechanistically, immunoprecipitation (IP) assays revealed that an interaction between feimin and AKT suppressed the AKT-mTOR signaling pathway. To further investigate the role of feimin in vivo, microglial feimin-conditional knockout mice (feiminMic-/-) is developed. In the HFD model, feiminMic-/- mice exhibited increased LD accumulation in hippocampal microglia, enhanced inflammation, and neuronal apoptosis, resulting in significant cognitive decline. In conclusion, this findings identified feimin as a key negative regulator of HFD-induced LD accumulation and the microglia-mediated inflammation response, suggesting that it is an attractive therapeutic target for cognitive decline associated with HFDs.
Insights
Feimin is identified as a key regulator that reduces lipid droplet accumulation and inflammation in the brain, offering a potential therapeutic target for high-fat diet-induced cognitive decline.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- High-fat diets (HFDs) induce cognitive impairment through lipid droplet accumulation in microglia, neuroinflammation, and neuronal damage.
- Microglia play a critical role in mediating HFD-induced neuroinflammation and cognitive deficits.
Purpose of the Study:
- To investigate the role of the molecule feimin as a negative regulator of lipid droplet accumulation and neuroinflammation in HFD-induced cognitive impairment.
- To elucidate the molecular mechanisms underlying feimin's function in microglia.
Main Methods:
- In vitro studies using BV2 microglia exposed to palmitic acid to mimic HFD effects.
- Feimin knockdown and overexpression experiments in BV2 cells.
- Immunoprecipitation (IP) assays to identify protein interactions.
- In vivo studies using microglial feimin-conditional knockout mice (feiminMic-/-) in an HFD model.
Main Results:
- Feimin expression increased upon high-lipid stimulation.
- Feimin knockdown exacerbated lipid droplet accumulation, inflammation, and neuronal apoptosis in vitro.
- Feimin overexpression had protective effects.
- Feimin interacts with AKT, suppressing the AKT-mTOR signaling pathway.
- Feimin-deficient mice showed increased lipid accumulation, inflammation, neuronal apoptosis, and cognitive decline under HFD conditions.
Conclusions:
- Feimin acts as a crucial negative regulator of HFD-induced lipid droplet accumulation and microglia-mediated inflammation.
- Feimin is a promising therapeutic target for mitigating cognitive decline associated with high-fat diets.
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