Ffar4, also known as G protein-coupled receptor 120, is a long-chain fatty acid receptor belonging to the rhodopsin-like G protein-coupled receptor (GPCR) family. It plays a crucial role in maintaining energy homeostasis by regulating adipogenesis, insulin sensitivity, and inflammation. Activation of Ffar4 can trigger signaling pathways such as Gq subunit-mediated CaMKKβ/AMPK signaling [1]. It is widely expressed in adipocytes, endothelial cells, macrophages, and other cell types [2].

Systemic and conditional TEC-specific knockout of Ffar4 in mice aggravated renal function and pathological damage in acute kidney injury (AKI), indicating that Ffar4 is important for kidney function and can regulate cellular senescence in tubular epithelial cells via the AMPK/SirT3 signaling pathway [1]. In metabolic syndrome (MetS) mouse models, conventional and microglial conditional knockout of Ffar4 exacerbated high-fat diet-induced cognitive dysfunction and anxiety, suggesting Ffar4's role in negatively regulating the NF-κB-IFN-β signaling and its potential as a therapeutic target for MetS-associated cognitive decline [3]. In heart failure with preserved ejection fraction secondary to metabolic syndrome (HFpEF-MetS), systemic deletion of Ffar4 in male mice worsened diastolic function and microvascular rarefaction, and altered the balance of inflammatory oxylipins in the heart, highlighting Ffar4's role in controlling the proinflammatory/proresolving oxylipin balance to resolve inflammation and attenuate HFpEF remodeling [4].

In conclusion, Ffar4 is essential for maintaining energy homeostasis, regulating inflammation, and controlling cellular senescence. Gene knockout mouse models, including systemic, conditional, and cell-specific knockouts, have significantly contributed to understanding Ffar4's role in diseases such as AKI, MetS-related cognitive impairment, and HFpEF-MetS. These findings suggest Ffar4 could be a potential therapeutic target for treating these diseases.

References:

1. Yang, Letian, Wang, Bo, Guo, Fan, Fu, Ping, Ma, Liang. 2022. FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury. In Signal transduction and targeted therapy, 7, 384. doi:10.1038/s41392-022-01254-x. https://pubmed.ncbi.nlm.nih.gov/36450712/

2. Stuttgen, Gage M, Sahoo, Daisy. . FFAR4: A New Player in Cardiometabolic Disease? In Endocrinology, 162, . doi:10.1210/endocr/bqab111. https://pubmed.ncbi.nlm.nih.gov/34043793/

3. Wang, Wei, Li, Jinyou, Cui, Siyuan, Chen, Yong Q, Zhu, Shenglong. 2024. Microglial Ffar4 deficiency promotes cognitive impairment in the context of metabolic syndrome. In Science advances, 10, eadj7813. doi:10.1126/sciadv.adj7813. https://pubmed.ncbi.nlm.nih.gov/38306420/

4. Zhang, Naixin, Harsch, Brian, Zhang, Michael J, Murphy, Katherine A, O'Connell, Timothy D. 2023. FFAR4 regulates cardiac oxylipin balance to promote inflammation resolution in HFpEF secondary to metabolic syndrome. In Journal of lipid research, 64, 100374. doi:10.1016/j.jlr.2023.100374. https://pubmed.ncbi.nlm.nih.gov/37075982/