Short-chain fatty acid G protein-coupled receptor (SCFA GPCR)

Short-chain fatty acid G protein-coupled receptors (SCFA GPCRs) are a family of metabolite-sensing receptors, primarily including Free fatty acid receptor 2 (FFAR2/GPR43) and Free fatty acid receptor 3 (FFAR3/GPR41), that detect short-chain fatty acids like acetate, propionate, and butyrate produced by gut microbiota fermentation [1, 2]. These receptors are expressed in diverse tissues, including the intestinal epithelium, immune cells, adipose tissue, and the pancreas, where they integrate microbial signals with host physiological processes [4, 9]. Their biological functions include the regulation of energy homeostasis, the secretion of gut hormones such as glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), and the modulation of inflammatory responses [11, 13]. In disease contexts, SCFA GPCRs are implicated in the pathogenesis of type 2 diabetes, obesity, and inflammatory bowel disease, making them attractive therapeutic targets [3, 10]. Pharmacological modulation of these receptors, through both agonists and antagonists, aims to restore metabolic balance and suppress chronic inflammation [1, 12]. For instance, FFAR2 antagonists like GLPG0974 have been investigated for inflammatory bowel disease, while multi-target agonists like PBI-4050 are explored for metabolic and fibrotic conditions [10, 12]. However, therapeutic development is complicated by the receptors' complex signaling through multiple G protein pathways and significant differences in pharmacology between human and rodent models [7, 12].

Other names

Free fatty acid receptor 2Free fatty acid receptor 3FFAR2FFAR3GPR43GPR41FFA2FFA3G-protein coupled receptor 43G-protein coupled receptor 41GPR109AHydroxycarboxylic acid receptor 2Olfactory receptor 78Olfr78

Activation or inhibition of G protein-coupled receptors (Gi/o and Gq/11) to modulate intracellular cAMP levels, calcium mobilization, and MAPK signaling pathways, thereby regulating hormone release and immune cell activity.