Cell Research, 9 January, 2024, DOI：https://doi.org/10.1038/s41422-023-00914-z

Molecular recognition and activation mechanism of short-chain fatty acid receptors FFAR2/3

Fahui Li, Linhua Tai, Xiaoyu Sun, Zhenyu Lv, Wenqin Tang, Tianxin Wang, Ziyi Zhao, Daohong Gong, Shaohua Ma, Shichen Tang, Quanchang Gu, Xiaolei Zhu, Minling Yu, Xiaohong Liu & Jiangyun Wang

Abstract

Saturated short-chain fatty acids (SCFAs) (with carbon chains containing 1–6 carbon atoms) a aliphatic organic acids derived from gut bacterial fermentation products. Different bacterial taxa are associated with the production of distinct SCFAs, which mediate diverse biological effects (Supplementary information, Table S1). SCFAs act as agonists for free fatty acid receptors 2 and 3 (FFAR2/3), which belong to G protein-coupled receptor (GPCR) superfamily. FFAR2/3 serve as messengers connecting gut microbiota and host, playing vital roles in regulating metabolism, inflammation and hormone homeostasis (Supplementary information, Fig. S1). They are also valuable targets for treating diabetes, obesity, asthma, allergies and inflammatory bowel disease (Supplementary information, Table S2). FFAR2 is activated by acetate (AA), propionate (PA) and butyrate (BA), while FFAR3 is primarily activated by C3–C6 saturated fatty acids, including PA, BA, valerate (VA) and caproate (CA). FFAR2 couples to Gα_i and Gα_q pathways, while FFAR3 primarily couples to Gα_i pathway. Considering the vital physiological functions of SCFAs, a paucity of knowledge about the recognition patterns of C2–C4 and C3–C6 SCFAs by FFAR2 and FFAR3 results in the urgent need to elucidate the molecular mechanisms behind FFAR2/3 signaling.

Article link：https://www.nature.com/articles/s41422-023-00914-z