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Free fatty acid receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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Free fatty acid receptors (FFA, nomenclature as agreed by the NC-IUPHAR Subcommittee on free fatty acid receptors [10,38]) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (including C14.0 (myristic acid), C16:0 (palmitic acid), C18:1 (oleic acid), C18:2 (linoleic acid), C18:3, (α-linolenic acid), C20:4 (arachidonic acid), C20:5,n-3 (EPA) and C22:6,n-3 (docosahexaenoic acid)) activate FFA1 [3,16,19] and FFA4 receptors [12,15,29], while short chain fatty acids (C2 (acetic acid), C3 (propanoic acid), C4 (butyric acid) and C5 (pentanoic acid)) activate FFA2 [4,20,27] and FFA3 [4,20] receptors. The crystal structure for agonist bound FFA1 has been described [36].
Receptors
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FFA1 receptor
C
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FFA2 receptor
C
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FFA3 receptor
C
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FFA4 receptor
C
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GPR42
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Further reading
* Key recommended reading is highlighted with an asterisk
* Bolognini D, Tobin AB, Milligan G, Moss CE. (2016) The Pharmacology and Function of Receptors for Short-Chain Fatty Acids. Mol Pharmacol, 89 (3): 388-98. [PMID:26719580]
* Mancini AD, Poitout V. (2013) The fatty acid receptor FFA1/GPR40 a decade later: how much do we know?. Trends Endocrinol Metab, 24 (8): 398-407. [PMID:23631851]
Maslowski KM, Mackay CR. (2011) Diet, gut microbiota and immune responses. Nat Immunol, 12 (1): 5-9. [PMID:21169997]
* Milligan G, Shimpukade B, Ulven T, Hudson BD. (2017) Complex Pharmacology of Free Fatty Acid Receptors. Chem Rev, 117 (1): 67-110. [PMID:27299848]
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]
* Moniri NH. (2016) Free-fatty acid receptor-4 (GPR120): Cellular and molecular function and its role in metabolic disorders. Biochem Pharmacol, 110-111: 1-15. [PMID:26827942]
Reimann F, Tolhurst G, Gribble FM. (2012) G-protein-coupled receptors in intestinal chemosensation. Cell Metab, 15 (4): 421-31. [PMID:22482725]
* 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]
Talukdar S, Olefsky JM, Osborn O. (2011) Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. Trends Pharmacol Sci, 32 (9): 543-50. [PMID:21663979]
* Watterson KR, Hudson BD, Ulven T, Milligan G. (2014) Treatment of type 2 diabetes by free Fatty Acid receptor agonists. Front Endocrinol (Lausanne), 5: 137. [PMID:25221541]
References
1. Bolognini D, Moss CE, Nilsson K, Petersson AU, Donnelly I, Sergeev E, König GM, Kostenis E, Kurowska-Stolarska M, Miller A et al.. (2016) A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias. J Biol Chem, 291 (36): 18915-31. [PMID:27385588]
2. Briscoe CP, Peat AJ, McKeown SC, Corbett DF, Goetz AS, Littleton TR, McCoy DC, Kenakin TP, Andrews JL, Ammala C et al.. (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 (5): 619-28. [PMID:16702987]
3. Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS, Minnick DT et al.. (2003) The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem, 278 (13): 11303-11. [PMID:12496284]
4. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ et al.. (2003) The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem, 278 (13): 11312-9. [PMID:12496283]
5. Chen Y, Ren Q, Zhou Z, Deng L, Hu L, Zhang L, Li Z. (2020) HWL-088, a new potent free fatty acid receptor 1 (FFAR1) agonist, improves glucolipid metabolism and acts additively with metformin in ob/ob diabetic mice. Br J Pharmacol, 177 (10): 2286-2302. [PMID:31971610]
6. Christiansen E, Due-Hansen ME, Urban C, Grundmann M, Schröder R, Hudson BD, Milligan G, Cawthorne MA, Kostenis E, Kassack MU et al.. (2012) Free fatty acid receptor 1 (FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophilicity and improves ADME properties. J Med Chem, 55 (14): 6624-8. [PMID:22724451]
7. Christiansen E, Hansen SV, Urban C, Hudson BD, Wargent ET, Grundmann M, Jenkins L, Zaibi M, Stocker CJ, Ullrich S et al.. (2013) Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes. ACS Med Chem Lett, 4 (5): 441-445. [PMID:23687558]
8. Christiansen E, Hudson BD, Hansen AH, Milligan G, Ulven T. (2016) Development and Characterization of a Potent Free Fatty Acid Receptor 1 (FFA1) Fluorescent Tracer. J Med Chem, 59 (10): 4849-58. [PMID:27074625]
9. Christiansen E, Watterson KR, Stocker CJ, Sokol E, Jenkins L, Simon K, Grundmann M, Petersen RK, Wargent ET, Hudson BD et al.. (2015) Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases. Br J Nutr, 113 (11): 1677-88. [PMID:25916176]
10. Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR et al.. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol Rev, 65 (3): 967-86. [PMID:23686350]
11. Hansen AH, Sergeev E, Bolognini D, Sprenger RR, Ekberg JH, Ejsing CS, McKenzie CJ, Rexen Ulven E, Milligan G, Ulven T. (2018) Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties. J Med Chem, 61 (21): 9534-9550. [PMID:30247908]
12. Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G. (2005) Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med, 11: 90-94. [PMID:15619630]
13. Hudson BD, Christiansen E, Murdoch H, Jenkins L, Hansen AH, Madsen O, Ulven T, Milligan G. (2014) Complex pharmacology of novel allosteric free fatty acid 3 receptor ligands. Mol Pharmacol, 86 (2): 200-10. [PMID:24870406]
14. Hudson BD, Tikhonova IG, Pandey SK, Ulven T, Milligan G. (2012) Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3. J Biol Chem, 287 (49): 41195-209. [PMID:23066016]
15. Ichimura A, Hirasawa A, Poulain-Godefroy O, Bonnefond A, Hara T, Yengo L, Kimura I, Leloire A, Liu N, Iida K et al.. (2012) Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature, 483 (7389): 350-4. [PMID:22343897]
16. Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H et al.. (2003) Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature, 422 (6928): 173-6. [PMID:12629551]
17. Kaku K, Enya K, Nakaya R, Ohira T, Matsuno R. (2015) Efficacy and safety of fasiglifam (TAK-875), a G protein-coupled receptor 40 agonist, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise: a randomized, double-blind, placebo-controlled, phase III trial. Diabetes Obes Metab, 17 (7): 675-81. [PMID:25787200]
18. Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, Kobayashi M, Hirasawa A, Tsujimoto G. (2011) Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci USA, 108 (19): 8030-5. [PMID:21518883]
19. Kotarsky K, Nilsson NE, Flodgren E, Owman C, Olde B. (2003) A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun, 301 (2): 406-10. [PMID:12565875]
20. Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, Decobecq ME, Brezillon S, Dupriez V, Vassart G, Van Damme J et al.. (2003) Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem, 278 (28): 25481-9. [PMID:12711604]
21. 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]
22. Lin DC, Guo Q, Luo J, Zhang J, Nguyen K, Chen M, Tran T, Dransfield PJ, Brown SP, Houze J et al.. (2012) Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor. Mol Pharmacol, 82 (5): 843-59. [PMID:22859723]
23. Ma L, Wang T, Shi M, Fu P, Pei H, Ye H. (2016) Synthesis, Activity, and Docking Study of Novel Phenylthiazole-Carboxamido Acid Derivatives as FFA2 Agonists. Chem Biol Drug Des, 88 (1): 26-37. [PMID:26808470]
24. Moore K, Zhang Q, Murgolo N, Hosted T, Duffy R. (2009) Cloning, expression, and pharmacological characterization of the GPR120 free fatty acid receptor from cynomolgus monkey: comparison with human GPR120 splice variants. Comp Biochem Physiol B, Biochem Mol Biol, 154 (4): 419-26. [PMID:19723586]
25. Namour F, Galien R, Van Kaem T, Van der Aa A, Vanhoutte F, Beetens J, Van't Klooster G. (2016) Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects. Br J Clin Pharmacol, 82 (1): 139-48. [PMID:26852904]
26. Negoro N, Sasaki S, Mikami S, Ito M, Suzuki M, Tsujihata Y, Ito R, Harada A, Takeuchi K, Suzuki N et al.. (2010) Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist. ACS Med Chem Lett, 1 (6): 290-4. [PMID:24900210]
27. Nilsson NE, Kotarsky K, Owman C, 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 (4): 1047-52. [PMID:12684041]
28. Oh da Y, Walenta E, Akiyama TE, Lagakos WS, Lackey D, Pessentheiner AR, Sasik R, Hah N, Chi TJ, Cox JM et al.. (2014) A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nat Med, 20 (8): 942-7. [PMID:24997608]
29. Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, Olefsky JM. (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell, 142 (5): 687-98. [PMID:20813258]
30. Pizzonero M, Dupont S, Babel M, Beaumont S, Bienvenu N, Blanqué R, Cherel L, Christophe T, Crescenzi B, De Lemos E et al.. (2014) Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: from hit to clinic. J Med Chem, 57 (23): 10044-57. [PMID:25380412]
31. Sawzdargo M, George SR, Nguyen T, Xu S, Kolakowski LF, O'Dowd BF. (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 (2): 543-7. [PMID:9344866]
32. Schmidt J, Smith NJ, Christiansen E, Tikhonova IG, Grundmann M, Hudson BD, Ward RJ, Drewke C, Milligan G, Kostenis E et al.. (2011) Selective orthosteric free fatty acid receptor 2 (FFA2) agonists: identification of the structural and chemical requirements for selective activation of FFA2 versus FFA3. J Biol Chem, 286 (12): 10628-40. [PMID:21220428]
33. Schröder R, Janssen N, Schmidt J, Kebig A, Merten N, Hennen S, Müller A, Blättermann S, Mohr-Andrä M, Zahn S et al.. (2010) Deconvolution of complex G protein-coupled receptor signaling in live cells using dynamic mass redistribution measurements. Nat Biotechnol, 28 (9): 943-9. [PMID:20711173]
34. Senga T, Iwamoto S, Yoshida T, Yokota T, Adachi K, Azuma E, Hamaguchi M, Iwamoto T. (2003) LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3. Blood, 101 (3): 1185-7. [PMID:12393494]
35. Shimpukade B, Hudson BD, Hovgaard CK, Milligan G, Ulven T. (2012) Discovery of a potent and selective GPR120 agonist. J Med Chem, 55 (9): 4511-5. [PMID:22519963]
36. Srivastava A, Yano J, Hirozane Y, Kefala G, Gruswitz F, Snell G, Lane W, Ivetac A, Aertgeerts K, Nguyen J et al.. (2014) High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature, 513 (7516): 124-7. [PMID:25043059]
37. Stoddart LA, Brown AJ, 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 (4): 994-1005. [PMID:17200419]
38. 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]
39. Sun Q, Hirasawa A, Hara T, Kimura I, Adachi T, Awaji T, Ishiguro M, Suzuki T, Miyata N, Tsujimoto G. (2010) Structure-Activity Relationships of GPR120 Agonists Based on a Docking Simulation. Mol Pharmacol, 78 (5): 804-10. [PMID:20685848]
40. Suzuki T, Igari S, Hirasawa A, Hata M, Ishiguro M, Fujieda H, Itoh Y, Hirano T, Nakagawa H, Ogura M et al.. (2008) Identification of G protein-coupled receptor 120-selective agonists derived from PPARgamma agonists. J Med Chem, 51 (23): 7640-4. [PMID:19007110]
41. Tanaka T, Yano T, Adachi T, Koshimizu TA, Hirasawa A, Tsujimoto G. (2008) Cloning and characterization of the rat free fatty acid receptor GPR120: in vivo effect of the natural ligand on GLP-1 secretion and proliferation of pancreatic beta cells. Naunyn Schmiedebergs Arch Pharmacol, 377 (4-6): 515-22. [PMID:18320172]
42. Tsujihata Y, Ito R, Suzuki M, Harada A, Negoro N, Yasuma T, Momose Y, Takeuchi K. (2011) TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats. J Pharmacol Exp Ther, 339 (1): 228-37. [PMID:21752941]
43. Wang J, Wu X, Simonavicius N, Tian H, Ling L. (2006) Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J Biol Chem, 281 (45): 34457-64. [PMID:16966319]
44. Watson SJ, Brown AJ, Holliday ND. (2012) Differential signaling by splice variants of the human free fatty acid receptor GPR120. Mol Pharmacol, 81 (5): 631-42. [PMID:22282525]
45. Xiong Y, Miyamoto N, Shibata K, Valasek MA, Motoike T, Kedzierski RM, Yanagisawa M. (2004) Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc Natl Acad Sci USA, 101 (4): 1045-50. [PMID:14722361]
46. Xiong Y, Swaminath G, Cao Q, Yang L, Guo Q, Salomonis H, Lu J, Houze JB, Dransfield PJ, Wang Y et al.. (2013) Activation of FFA1 mediates GLP-1 secretion in mice. Evidence for allosterism at FFA1. Mol Cell Endocrinol, 369 (1-2): 119-29. [PMID:23403053]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Leigh Stoddart (Chairperson)
Nick Holliday (Co-chairperson) |
Other contributors:
Celia Briscoe
Andrew Brown
Stephen Jenkinson
Graeme Milligan (Past chairperson)
Amy E. Monaghan |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
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Short (361 amino acids) and long (377 amino acids) splice variants of human FFA4 have been reported [24], which differ by a 16 amino acid insertion in intracellular loop 3, and exhibit differences in intracellular signalling properties in recombinant systems [44]. The long FFA4 splice variant has not been identified in other primates or rodents to date [12,24].
GPR42 was originally described as a pseudogene within the family (ENSFM00250000002583), but the discovery of several polymorphisms suggests that some versions of GPR42 may be functional [21]. GPR84 is a structurally-unrelated G protein-coupled receptor which has been found to respond to medium chain fatty acids [43].