Ffar3, also known as GPR41, is a G protein-coupled receptor activated by short-chain fatty acids (SCFAs), mainly acetate, butyrate, and propionate [2,3,4,5,7]. It is involved in multiple biological processes, including metabolism and immune regulation. SCFAs, produced by gut microbial fermentation, bind to Ffar3, initiating signaling cascades that intertwine metabolism and immunity [2].

In aging-related studies, reduced butyrate-producing bacteria in aged gut microbiota lead to low butyrate levels and reduced Ffar3 signaling. Young mice with intestine-specific loss of Ffar3/2 exhibited gut and brain abnormalities similar to those in older mice, such as inflammation in the gut and brain, cognitive decline, depression, and anxiety. This indicates that Ffar3 signaling is crucial in maintaining gut-brain health [1]. In pancreatic β cells, islets from global knockout FFAR3 (Ffar3(-/-)) mice secrete more insulin in a glucose-dependent manner compared to wild-type islets, and ligand-induced FFAR3 signaling inhibits glucose-dependent insulin secretion through a Gαi/o pathway [6].

In conclusion, Ffar3 plays a vital role in maintaining gut-brain homeostasis and regulating insulin secretion. The use of Ffar3 knockout mouse models has revealed its significance in age-related gut-brain dysfunction and insulin regulation, providing insights into potential therapeutic strategies for related diseases.

References:

1. Mishra, Sidharth P, Jain, Shalini, Wang, Bo, Rane, Sushil G, Yadav, Hariom. 2024. Abnormalities in microbiota/butyrate/FFAR3 signaling in aging gut impair brain function. In JCI insight, 9, . doi:10.1172/jci.insight.168443. https://pubmed.ncbi.nlm.nih.gov/38329121/

2. 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/

3. Tan, Jian, McKenzie, Craig, Potamitis, Maria, Mackay, Charles R, Macia, Laurence. . The role of short-chain fatty acids in health and disease. In Advances in immunology, 121, 91-119. doi:10.1016/B978-0-12-800100-4.00003-9. https://pubmed.ncbi.nlm.nih.gov/24388214/

4. Parada Venegas, Daniela, De la Fuente, Marjorie K, Landskron, Glauben, Faber, Klaas Nico, Hermoso, Marcela A. 2019. Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases. In Frontiers in immunology, 10, 277. doi:10.3389/fimmu.2019.00277. https://pubmed.ncbi.nlm.nih.gov/30915065/

5. Stilling, Roman M, van de Wouw, Marcel, Clarke, Gerard, Dinan, Timothy G, Cryan, John F. 2016. The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis? In Neurochemistry international, 99, 110-132. doi:10.1016/j.neuint.2016.06.011. https://pubmed.ncbi.nlm.nih.gov/27346602/

6. Priyadarshini, Medha, Layden, Brian T. 2015. FFAR3 modulates insulin secretion and global gene expression in mouse islets. In Islets, 7, e1045182. doi:10.1080/19382014.2015.1045182. https://pubmed.ncbi.nlm.nih.gov/26091414/

7. Sivaprakasam, Sathish, Prasad, Puttur D, Singh, Nagendra. 2016. Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis. In Pharmacology & therapeutics, 164, 144-51. doi:10.1016/j.pharmthera.2016.04.007. https://pubmed.ncbi.nlm.nih.gov/27113407/