Free fatty acid

Overview: Free fatty acid receptors (FFA, nomenclature as agreed by NC-IUPHAR Subcommittee on free fatty acid receptors, Stoddart et al., 2008) are activated by free fatty acids, such that long-chain saturated and unsaturated fatty acids (C16:0, C18:0, C18:1, C18:2, C18:3,n-6, C20:4, C20:5,n-3, C22:6,n-3, Briscoe et al., 2003; Itoh et al., 2003; Kotarsky et al., 2003) activate FFA₁ receptors, while short-chain fatty acids (C2, C3, C4 and C5) activate FFA₂ (Brown et al., 2003; Le Poul et al., 2003; Nilsson et al., 2003) and FFA₃ (Brown et al., 2003; Le Poul et al., 2003) receptors. In addition, thiazolidinedione PPARγ agonists such as rosiglitazone activate FFA₁ (pEC₅₀ 5.2; Kotarsky et al., 2003; Stoddart et al., 2007; Smith et al., 2009).

Nomenclature	FFA1	FFA2	FFA3
Other names	GPR40 (Sawzdargo et al., 1997)	GPR43 (Sawzdargo et al., 1997)	GPR41 (Sawzdargo et al., 1997) LSSIG (Senga et al., 2003)
Ensembl ID	ENSG00000126266	ENSG00000126262	ENSG00000185897
Principal transduction	Gq/11 (Briscoe et al., 2003; Itoh et al., 2003; Stoddart et al., 2007)	Gq/11, Gi/o (Brown et al., 2003; Le Poul et al., 2003; Nilsson et al., 2003)	Gi/o (Brown et al., 2003; Le Poul et al., 2003; Stoddart et al., 2007)
Selective agonists	Linoleic acid (Briscoe et al., 2003); Itoh et al., 2003), GW9508 (pEC50 7.3; Briscoe et al., 2006; Sum et al., 2007), Cpd B (pEC50 6.1; Tan et al., 2008)	(S)-2-(4-chlorophenyl)-N-(5-fluorothiazol-2-yl)-3-methylbutanamide (pEC50 6.4; Lee et al., 2008)	–
Selective antagonists	GW1100 (Briscoe et al., 2006; Stoddart et al., 2007)	–	–

GW1100 is also an oxytocin receptor antagonist (Briscoe et al., 2006).

GPR42 (ENSG00000126251) was originally described as a pseudogene within the family, but the recent discovery of several polymorphisms suggests that some versions of GPR42 may be functional (Liaw and Connolly, 2009) (ENSFM00250000002583). GPR120 (ENSG00000186188) and GPR84 (ENSG00000139572) are structurally unrelated 7TM receptors. GPR120 is activated by unsaturated long-chain free fatty acids (Hirasawa et al., 2005; Katsuma et al., 2005; Gotoh et al., 2007) and GW9508 (pEC₅₀ 5.7; Briscoe et al., 2006), while GPR84 was found to respond to medium chain fatty acids (Wang et al., 2006).

Glossary

Abbreviations:

C16:0

palmitic acid

C18:0

stearic acid

C18:1

oleic acid

C18:2

linoleic acid

C18:3,n-6

γ-linolenic acid

C2

acetic acid

C20:4

arachidonic acid

C20:5,n-3

5z,8z,11z,14z,17z-eicosapentaenoic acid, EPA

C22:6,n-3

4z,7z,10z,13z,16z,19z-docosahexaenoic acid, DHA

C3

propionic acid

C4

butyric acid

C5

valeric acid

Cpd B

3-chloro-5-trifluoromethyl-pyridin-2-yl-methoxy(4-(3-methylphenyl)methyl-1, 3-thiazolidinedione-2, 4-dione

GW1100

ethyl 4-(5-[{2-(ethyloxy)-5-pyrimidinyl}methyl]-2-[{(4-fluorophenyl)methyl]thio}-4-oxo-1[4H]-pyrimidinyl)benzoate

GW9508

3-(4-[{(3-[phenyloxy]phenyl)methyl}amino]phenyl)propanoic acid

Further Reading

Alquier T, Poitout V (2009). GPR40: good cop, bad cop? Diabetes58: 1035–1036.

Rayasam GV, Tulasi VK, Davis JA, Bansal VS (2007). Fatty acid receptors as new therapeutic targets for diabetes. Expert Opin Ther Targets11: 661–671.

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 Rev60: 405–417.