Ffar4, also known as G protein-coupled receptor 120, is a long-chain fatty acid receptor belonging to the G protein-coupled receptor (GPCR) family. It plays a crucial role in maintaining energy homeostasis by regulating processes like adipogenesis, insulin sensitivity, and inflammation [2]. FFAR4 is involved in pathways such as Gq subunit-mediated CaMKKβ/AMPK signaling [1]. Genetic models, especially knockout mouse models, have been instrumental in studying its functions.

In AKI mouse models, the expression of Ffar4 was decreased in tubular epithelial cells. Systemic and conditional TEC-specific knockout of Ffar4 aggravated renal function and pathological damage, while its activation alleviated disease severity. Ffar4 was found to regulate cellular senescence via the AMPK/SirT3 signaling pathway [1]. In metabolic syndrome mouse models, conventional and microglial conditional knockout of Ffar4 exacerbated high-fat diet-induced cognitive dysfunction and anxiety, while microglial Ffar4 overexpression improved these conditions. Ffar4 regulated microglial activation through type I interferon signaling [3]. In HFpEF-MetS mouse models, systemic deletion of Ffar4 in male mice worsened diastolic function and microvascular rarefaction, along with altering the balance of inflammatory oxylipins [4]. The double knockout of Ffar4 and FGF21 in mice led to severe metabolic disorders, likely due to decreased energy expenditure [5].

In conclusion, Ffar4 is essential for maintaining metabolic and immune-related homeostasis. Studies using gene knockout and conditional knockout mouse models have revealed its roles in acute kidney injury, metabolic syndrome-related cognitive impairment, heart failure with preserved ejection fraction secondary to metabolic syndrome, and metabolic disorders. These findings suggest Ffar4 as a potential therapeutic target for 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/

5. Wei, Lengyun, Ye, Xianlong, Cui, Siyuan, Li, Dashuai, Zhu, Shenglong. 2023. Double knockout of FFAR4 and FGF21 aggravates metabolic disorders in mice. In International journal of biological macromolecules, 253, 126553. doi:10.1016/j.ijbiomac.2023.126553. https://pubmed.ncbi.nlm.nih.gov/37657572/