Ffar2, also known as GPR43, is a G-protein-coupled receptor. It functions as a microbial metabolite-sensing receptor, being activated by short-chain fatty acids (SCFAs) like acetate, butyrate, and propionate. This activation is involved in multiple biological pathways related to metabolism and immunity, playing a crucial role in maintaining physiological homeostasis [5]. Genetic models, such as gene knockout (KO) mouse models, have been instrumental in studying its functions.

In KO mouse models, Ffar2 deficiency in colonic group 3 innate lymphoid cells (ILC3s) decreased their in-situ proliferation and interleukin-22 (IL-22) production, leading to impaired gut epithelial function and increased susceptibility to colonic injury and bacterial infection [1]. In lung adenocarcinoma models, whole or myeloid Ffar2 gene deletion inhibited tumor growth, reduced myeloid-derived suppressor cells (MDSCs), and increased CD8+ T-cell infiltration [2]. Also, in colitis-associated colorectal tumorigenesis models, sodium butyrate-mediated ferroptosis and tumor growth inhibition was related to FFAR2-mTOR signaling, and this effect could be eliminated by mTORC1 activator and ferroptosis inhibitor [3]. Mice lacking ffar2 exhibited reduced short-chain fatty acid-triggered glucagon-like peptide-1 secretion and impaired glucose tolerance [4]. Ffar2-deficient mice also showed microglia defects similar to germ-free conditions, indicating its role in microglia homeostasis [6].

In conclusion, Ffar2 is essential for regulating various biological processes. Its functions span across gut immunity, cancer immunoevasion, ferroptosis, glucose metabolism, and microglia homeostasis. The use of Ffar2 KO mouse models has been key in uncovering its role in these processes, offering potential therapeutic targets for diseases such as gut-related disorders, cancer, diabetes, and central nervous system diseases [1,2,3,4,6].

References:

1. Chun, Eunyoung, Lavoie, Sydney, Fonseca-Pereira, Diogo, Layden, Brian T, Garrett, Wendy S. 2019. Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity. In Immunity, 51, 871-884.e6. doi:10.1016/j.immuni.2019.09.014. https://pubmed.ncbi.nlm.nih.gov/31628054/

2. Zhao, Zeda, Qin, Juliang, Qian, Ying, Liu, Mingyao, Du, Bing. 2024. FFAR2 expressing myeloid-derived suppressor cells drive cancer immunoevasion. In Journal of hematology & oncology, 17, 9. doi:10.1186/s13045-024-01529-6. https://pubmed.ncbi.nlm.nih.gov/38402237/

3. Wang, GuoYan, Qin, SenLin, Chen, Lei, Yao, JunHu, Deng, Lu. 2023. Butyrate dictates ferroptosis sensitivity through FFAR2-mTOR signaling. In Cell death & disease, 14, 292. doi:10.1038/s41419-023-05778-0. https://pubmed.ncbi.nlm.nih.gov/37185889/

4. Tolhurst, Gwen, Heffron, Helen, Lam, Yu Shan, Reimann, Frank, Gribble, Fiona M. 2011. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. In Diabetes, 61, 364-71. doi:10.2337/db11-1019. https://pubmed.ncbi.nlm.nih.gov/22190648/

5. Kimura, Ikuo, Ichimura, Atsuhiko, Ohue-Kitano, Ryuji, Igarashi, Miki. 2019. Free Fatty Acid Receptors in Health and Disease. In Physiological reviews, 100, 171-210. doi:10.1152/physrev.00041.2018. https://pubmed.ncbi.nlm.nih.gov/31487233/

6. Erny, Daniel, Hrabě de Angelis, Anna Lena, Jaitin, Diego, Amit, Ido, Prinz, Marco. 2015. Host microbiota constantly control maturation and function of microglia in the CNS. In Nature neuroscience, 18, 965-77. doi:10.1038/nn.4030. https://pubmed.ncbi.nlm.nih.gov/26030851/