Fatty acids have long been recognized for the variety of their effects in the body. Yet, until recently, these actions were thought to be mediated exclusively via actions on cellular metabolism. There are currently three known receptors for free fatty acids: FFA1, FFA2, and FFA3.

Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor containing seven hydrophobic regions, consistent with transmembrane (TM) spanning helices. FFA2 contains cysteine residues in the first and second extracellular loops that are likely to contribute to structure via the formation of intramolecular disulfide bonds. FFA2 mRNA is detected in a number of tissues, but the highest expression is found in immune cells such as neutrophils, monocytes, peripheral blood mononuclear cells, B-lymphocytes, and polymorphonuclear cells.

Short chain fatty acids (SCFAs) are fatty acids of less than six carbons and were found to be endogenous agonists of FFA2. The most potent agonist of the receptor is acetate (C2) and propionate (C3) being equipotent followed by butyrate (C4) and then valerate (C5) and formate (C1)¹.

FFA2 is implicated in the pathogenesis of several diseases. Stimulation of FFA2 by acetate allows resolution of a colitis-related inflammatory response. FFA2 knockout mice show exacerbated or unresolved inflammation in cases of acute and chronic colitis, arthritis, and asthma. In contrast, other studies show that knockout mice exhibit an increased mortality compared to control mice, despite reduced immune cell recruitment, decreased colonic inflammation, and attenuated colonic tissue damage².