Utilizing the human genome database, the recently developed G-protein-coupled receptor (GPCR) deorphanizing strategy successfully identified multiple receptors of free fatty acids (FFAs) and is proposed to play a critical role in a variety of physiologic homeostasis mechanisms. GPR40 and GPR120 are activated by medium- and long-chain FFAs, whereas GPR41 and GPR43 are activated by short-chain FFAs. GPR40, which is preferentially expressed in pancreatic β-cells, mediates insulin secretion. On the other hand, GPR120, which is abundantly expressed in the intestine, functions as a receptor for unsaturated long-chain FFAs and promotes the secretion of glucagon-like peptide-1 (GLP-1). In this review, we summarize the identification, structure, and pharmacology of the receptors and speculate on the respective physiologic roles that FFA receptor family members may play.
2008 The Pharmaceutical Society of Japan