Microglial Ffar4 deficiency promotes cognitive impairment in the context of metabolic syndrome.

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 <i>Ffar4</i> expression is down-regulated in MetS mice and MetS patients with cognitive impairment. Conventional and microglial conditional knockout of <i>Ffar4</i> exacerbated high-fat diet (HFD)-induced cognitive dysfunction and anxiety, whereas microglial <i>Ffar4</i> overexpression improved HFD-induced cognitive dysfunction and anxiety. Mechanistically, we found that microglial <i>Ffar4</i> regulated microglial activation through type I interferon signaling. Microglial depletion and NF-κB inhibition partially reversed cognitive dysfunction and anxiety in microglia-specific <i>Ffar4</i> 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.