Free fatty acid receptor 2 and 3 (FFAR2/3)

Free fatty acid receptor 2 (FFAR2, GPR43) and Free fatty acid receptor 3 (FFAR3, GPR41) are G protein-coupled receptors that serve as the primary sensors for short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate, which are produced by the gut microbiota through the fermentation of dietary fiber (1.1.1, 1.2.2). These receptors act as a critical molecular link between the microbiome, diet, and host physiology, regulating diverse processes including energy metabolism, gut hormone secretion, and immune cell function (1.2.1, 1.3.2). FFAR2 is predominantly expressed in immune cells and adipose tissue, where it modulates inflammatory responses and lipid storage, while FFAR3 is found in enteroendocrine cells and the peripheral nervous system, influencing gut motility and energy expenditure (1.1.2, 1.4.3). Due to their roles in glucose homeostasis and inflammation, FFAR2 and FFAR3 are investigated as therapeutic targets for metabolic disorders like type 2 diabetes and obesity, as well as inflammatory conditions such as inflammatory bowel disease and asthma (1.2.3, 1.2.4). Pharmacological modulation includes both agonists to enhance metabolic benefits and antagonists to mitigate excessive inflammatory signaling (1.3.2). Clinical development has faced challenges regarding efficacy and selectivity, partly due to the high structural similarity between the two receptors and their complex signaling through multiple G protein families (1.4.2).

Other names

GPR43GPR41FFA2FFA3Free fatty acid receptor 2Free fatty acid receptor 3FFA2RFFA3R

FFAR2 and FFAR3 are G protein-coupled receptors activated by short-chain fatty acids. FFAR2 couples to both Gi/o and Gq/11 families, while FFAR3 primarily couples to Gi/o. Activation leads to the inhibition of adenylyl cyclase (reducing cAMP) and, for FFAR2, the activation of phospholipase C (increasing intracellular calcium), thereby modulating metabolic and inflammatory signaling pathways.