More information on this family may be found on the IUPHAR-DB family and introduction pages.
Free fatty acid receptors (FFA, nomenclature as agreed by NC-IUPHAR Subcommittee on free fatty acid receptors, [20]) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (C16:0 (palmitic acid), C18:0 (stearic acid), C18:1 (oleic acid), C18:2 (linoleic acid), C18:3,n-6 (γ-linolenic acid), C20:4 (arachidonic acid), C20:5,n-3 (EPA), C22:6,n-3 (docosahexaenoic acid), [2,7,10]) activate FFA1 receptors, while short chain fatty acids (C2 (acetic acid), C3 (propanoic acid), C4 (butyric acid) and C5 (pentanoic acid)) activate FFA2 [3,11,14] and FFA3 [3,11] receptors. In addition, thiazolidinedione PPARγ agonists such as rosiglitazone activate FFA1 (pEC50 5.2; [10,17,19]) and small molecule allosteric modulators, such as 4-CMTB, have recently been characterised for FFA2 [12,18].
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Receptors 
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Alquier, T; Poitout, V. (2009) GPR40: good cop, bad cop?. Diabetes, 58 (5): 1035-6. [PMID:19401432]
Hara, T; Hirasawa, A; Ichimura, A; Kimura, I; Tsujimoto, G. (2011) Free fatty acid receptors FFAR1 and GPR120 as novel therapeutic targets for metabolic disorders. J Pharm Sci, 100 (9): 3594-601. [PMID:21618241]
Ichimura, A; Hirasawa, A; Hara, T; Tsujimoto, G. (2009) Free fatty acid receptors act as nutrient sensors to regulate energy homeostasis. Prostaglandins Other Lipid Mediat., 89 (3-4): 82-8. [PMID:19460454]
Maslowski, KM; Mackay, CR. (2011) Diet, gut microbiota and immune responses. Nat. Immunol., 12 (1): 5-9. [PMID:21169997]
Milligan, G; Stoddart, LA; Smith, NJ. (2009) Agonism and allosterism: the pharmacology of the free fatty acid receptors FFA2 and FFA3. Br. J. Pharmacol., 158 (1): 146-53. [PMID:19719777]
Morgan, NG; Dhayal, S. (2009) G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell. Biochem. Pharmacol., 78 (12): 1419-27. [PMID:19660440]
Sleeth, ML; Thompson, EL; Ford, HE; Zac-Varghese, SE; Frost, G. (2010) Free fatty acid receptor 2 and nutrient sensing: a proposed role for fibre, fermentable carbohydrates and short-chain fatty acids in appetite regulation. Nutr Res Rev, 23 (1): 135-45. [PMID:20482937]
Stoddart, LA; Smith, NJ; Milligan, G. (2008) International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions. Pharmacol. Rev., 60 (4): 405-17. [PMID:19047536]
Wellendorph, P; Johansen, LD; Bräuner-Osborne, H. (2009) Molecular pharmacology of promiscuous seven transmembrane receptors sensing organic nutrients. Mol. Pharmacol., 76 (3): 453-65. [PMID:19487246]
1. Briscoe, C. P., Peat, A. J., McKeown, S. C., Corbett, D. F., Goetz, A. S., Littleton, T. R., McCoy, D. C., Kenakin, T. P., Andrews, J. L., Ammala, C., Fornwald, J. A., Ignar, D. M. and Jenkinson, S. (2006) Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules. Br J Pharmacol, 148: 619-628. [PMID:16702987]
2. Briscoe, C. P., Tadayyon, M., Andrews, J. L., Benson, W. G., Chambers, J. K., Eilert, M. M., Ellis, C., Elshourbagy, N. A., Goetz, A. S., Minnick, D. T., Murdock, P. R., Sauls, H. R., Shabon, U., Spinage, L. D., Strum, J. C., Szekeres, P. G., Tan, K. B., Way, J. M., Ignar, D. M., Wilson, S. and Muir, A. I. (2003) The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem, 278: 11303-11311. [PMID:12496284]
3. Brown, A. J., Goldsworthy, S. M., Barnes, A. A., Eilert, M. M., Tcheang, L., Daniels, D., Muir, A. I., Wigglesworth, M. J., Kinghorn, I., Fraser, N. J., Pike, N. B., Strum, J. C., Steplewski, K. M., Murdock, P. R., Holder, J. C., Marshall, F. H., Szekeres, P. G., Wilson, S., Ignar, D. M., Foord, S. M., Wise, A. and Dowell, S. J. (2003) The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem, 278: 11312-11319. [PMID:12496283]
4. Christiansen, E; Urban, C; Merten, N; Liebscher, K; Karlsen, KK; Hamacher, A; Spinrath, A; Bond, AD; Drewke, C; Ullrich, S; et al.. (2008) Discovery of potent and selective agonists for the free fatty acid receptor 1 (FFA(1)/GPR40), a potential target for the treatment of type II diabetes. J. Med. Chem., 51 (22): 7061-4. [PMID:18947221]
5. Gotoh, C; Hong, YH; Iga, T; Hishikawa, D; Suzuki, Y; Song, SH; Choi, KC; Adachi, T; Hirasawa, A; Tsujimoto, G; Sasaki, S; Roh, SG. (2007) The regulation of adipogenesis through GPR120. Biochem. Biophys. Res. Commun., 354 (2): 591-7. [PMID:17250804]
6. Hirasawa, A., Tsumaya, K., Awaji, T., Katsuma, S., Adachi, T., Yamada, M., Sugimoto, Y., Miyazaki, S. and Tsujimoto, G. (2005) Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med, 11: 90-94. [PMID:15619630]
7. Itoh, Y., Kawamata, Y., Harada, M., Kobayashi, M., Fujii, R., Fukusumi, S., Ogi, K., Hosoya, M., Tanaka, Y., Uejima, H., Tanaka, H., Maruyama, M., Satoh, R., Okubo, S., Kizawa, H., Komatsu, H., Matsumura, F., Noguchi, Y., Shinohara, T., Hinuma, S., Fujisawa, Y. and Fujino, M. (2003) Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature, 422: 173-176. [PMID:12629551]
8. Katsuma, S; Hatae, N; Yano, T; Ruike, Y; Kimura, M; Hirasawa, A; Tsujimoto, G. (2005) Free fatty acids inhibit serum deprivation-induced apoptosis through GPR120 in a murine enteroendocrine cell line STC-1. J. Biol. Chem., 280 (20): 19507-15. [PMID:15774482]
9. Kotarsky, K., Nilsson, N. E., Flodgren, E., Owman, C. and Olde, B. (2003) A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun, 301: 406-410. [PMID:12565875]
10. Kotarsky, K; Nilsson, NE; Olde, B; Owman, C. (2003) Progress in methodology. Improved reporter gene assays used to identify ligands acting on orphan seven-transmembrane receptors. Pharmacol. Toxicol., 93 (6): 249-58. [PMID:14675457]
11. Le Poul, E., Loison, C., Struyf, S., Springael, J. Y., Lannoy, V., Decobecq, M. E., Brezillon, S., Dupriez, V., Vassart, G., Van Damme, J., Parmentier, M. and Detheux, M. (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem, 278: 25481-25489. [PMID:12711604]
12. Lee, T; Schwandner, R; Swaminath, G; Weiszmann, J; Cardozo, M; Greenberg, J; Jaeckel, P; Ge, H; Wang, Y; Jiao, X; et al.. (2008) Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Mol. Pharmacol., 74 (6): 1599-609. [PMID:18818303]
13. Liaw, CW; Connolly, DT. (2009) Sequence polymorphisms provide a common consensus sequence for GPR41 and GPR42. DNA Cell Biol., 28 (11): 555-60. [PMID:19630535]
14. Nilsson, N. E., Kotarsky, K., Owman, C. and Olde, B. (2003) Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem Biophys Res Commun, 303: 1047-1052. [PMID:12684041]
15. Sawzdargo, M., George, S. R., Nguyen, T., Xu, S., Kolakowski, L. F. and O'Dowd, B. F. (1997) A cluster of four novel human G protein-coupled receptor genes occurring in close proximity to CD22 gene on chromosome 19q13.1. Biochem Biophys Res Commun, 239: 543-547. [PMID:9344866]
16. Senga, T., Iwamoto, S., Yoshida, T., Yokota, T., Adachi, K., Azuma, E., Hamaguchi, M. and Iwamoto, T. (2003) LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3. Blood, 101: 1185-1187. [PMID:12393494]
17. Smith, NJ; Stoddart, LA; Devine, NM; Jenkins, L; Milligan, G. (2009) The action and mode of binding of thiazolidinedione ligands at free fatty acid receptor 1. J. Biol. Chem., 284 (26): 17527-39. [PMID:19398560]
18. Smith, NJ; Ward, RJ; Stoddart, LA; Hudson, BD; Kostenis, E; Ulven, T; Morris, JC; Tränkle, C; Tikhonova, IG; Adams, DR; et al.. (2011) Extracellular loop 2 of the free fatty acid receptor 2 mediates allosterism of a phenylacetamide ago-allosteric modulator. Mol. Pharmacol., 80 (1): 163-73. [PMID:21498659]
19. Stoddart, L. A., Brown, A. J. and Milligan, G. (2007) Uncovering the pharmacology of the G protein-coupled receptor GPR40: high apparent constitutive activity in guanosine 5'-O-(3-[35S]thio)triphosphate binding studies reflects binding of an endogenous agonist. Mol Pharmacol, 71: 994-1005. [PMID:17200419]
20. Stoddart, LA; Smith, NJ; Milligan, G. (2008) International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions. Pharmacol. Rev., 60 (4): 405-17. [PMID:19047536]
21. Sum, C. S., Tikhonova, I. G., Neumann, S., Engel, S., Raaka, B. M., Costanzi, S. and Gershengorn, M. C. (2007) Identification of Residues Important for Agonist Recognition and Activation in GPR40. J Biol Chem, 282: 29248-29255. [PMID:17699519]
22. Tan, CP; Feng, Y; Zhou, YP; Eiermann, GJ; Petrov, A; Zhou, C; Lin, S; Salituro, G; Meinke, P; Mosley, R; et al.. (2008) Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice. Diabetes, 57 (8): 2211-9. [PMID:18477808]
23. Wang, J., Wu, X., Simonavicius, N., Tian, H. and Ling, L. (2006) Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J Biol Chem, 281: 34457-34464. [PMID:16966319]
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GW1100 is also an oxytocin receptor antagonist [1].
GPR42 (ENSG00000126251) was originally described as a pseudogene within the family (ENSFM00250000002583), but the recent discovery of several polymorphisms suggests that some versions of GPR42 may be functional [13]. GPR120 (ENSG00000186188) and GPR84 (ENSG00000139572) are structurally-unrelated G protein-coupled receptors. GPR120 is activated by unsaturated long chain free fatty acids [5-6,8] and GW9508 (pEC50 5.7; [1]), while GPR84 was found to respond to medium chain fatty acids [23].