Microglial Feimin Alleviates Cognitive Impairment in High‐Fat Diet‐Fed Mice

Microglial feimin deletion exacerbates lipotoxicity‐induced neuroinflammation and cognitive decline. In both in vitro and in vivo models, loss of feimin aggravated lipid droplet accumulation, IL‐1β/IL‐6 release, and neuronal injury through the PI3K–AKT–mTOR pathway, ultimately leading to severe neuronal apoptosis and cognitive impairment under high‐fat diet conditions. 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. Microglial feimin deletion exacerbates lipotoxicity-induced neuroinflammation and cognitive decline. In both in vitro and in vivo models, loss of feimin aggravated lipid droplet accumulation, IL-1β/IL-6 release, and neuronal injury through the PI3K–AKT–mTOR pathway, ultimately leading to severe neuronal apoptosis and cognitive impairment under high-fat diet conditions. 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 (feimin Mic-/− ) is developed. In the HFD model, feimin Mic-/− 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. Advanced Science, Volume 12, Issue 48, December 29, 2025.