Microglial Ffar4 deficiency promotes cognitive impairment in the context of metabolic syndrome.
Sci Adv
; 10(5): eadj7813, 2024 Feb 02.
Article
em En
| MEDLINE
| ID: mdl-38306420
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-ß signaling and provide an attractive therapeutic target for delaying MetS-associated cognitive decline.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Síndrome Metabólica
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Receptores Acoplados a Proteínas G
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Disfunção Cognitiva
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article