Microglial Ffar4 deficiency promotes cognitive impairment in the context of metabolic syndrome
Wei Wang, Jinyou Li, Jinyou Li, Siyuan Cui, Jiayu Li, Jiayu Li, Xianlong Ye, Zhe Wang, Tingting Zhang, Xuan Jiang, Yulin Kong, Xin Chen, Yong Q. Chen, Shenglong Zhu
Abstract
Metabolic syndrome (MetS) is closely associated with an increased risk of dementia and cognitive impairment, and a complex interaction of genetic and environmental dietary factors may be implicated. Free fatty acid receptor 4 (Ffar4) may bridge the genetic and dietary aspects of MetS development. However, the role of Ffar4 in MetS-related cognitive dysfunction is unclear. In this study, we found that Ffar4 expression is down-regulated in MetS mice and MetS patients with cognitive impairment. Conventional and microglial conditional knockout of Ffar4 exacerbated high-fat diet (HFD)–induced cognitive dysfunction and anxiety, whereas microglial Ffar4 overexpression improved HFD-induced cognitive dysfunction and anxiety. Mechanistically, we found that microglial Ffar4 regulated microglial activation through type I interferon signaling. Microglial depletion and NF-κB inhibition partially reversed cognitive dysfunction and anxiety in microglia-specific Ffar4 knockout MetS mice. Together, these findings uncover a previously unappreciated role of Ffar4 in negatively regulating the NF-κB–IFN-β signaling and provide an attractive therapeutic target for delaying MetS-associated cognitive decline.