Short-chain fatty acid receptor (SCFA receptor)

Short-chain fatty acid (SCFA) receptors are a group of G protein-coupled receptors, primarily FFAR2 (GPR43), FFAR3 (GPR41), and HCAR2 (GPR109A), that sense metabolic byproducts of gut microbiota fermentation such as acetate, propionate, and butyrate [1, 2]. These receptors are expressed in diverse tissues including the intestinal epithelium, adipocytes, and immune cells, where they serve as critical mediators of the gut-immune-metabolic axis [3]. FFAR2 and FFAR3 are involved in regulating energy homeostasis, gut hormone secretion (e.g., GLP-1), and leukocyte function, while HCAR2 mediates the anti-inflammatory effects of butyrate and niacin [4, 5]. Dysregulation of these receptors is linked to metabolic disorders like obesity and type 2 diabetes, as well as chronic inflammatory diseases such as asthma and inflammatory bowel disease [5]. Consequently, they are significant therapeutic targets for modulating metabolic health and immune responses, with several small-molecule agonists and antagonists in various stages of development [6].

Other names

Free fatty acid receptor 2Free fatty acid receptor 3Hydroxycarboxylic acid receptor 2GPR43GPR41GPR109AFFA2FFA3HCAR2

Agonism or antagonism of G protein-coupled receptors (specifically FFAR2, FFAR3, and HCAR2) to modulate intracellular signaling pathways such as Gi/o-mediated inhibition of adenylate cyclase or Gq-mediated calcium mobilization, thereby regulating inflammatory cytokine production, gut hormone secretion, and lipid metabolism.