Short-chain fatty acids are generated in large amounts by the intestinal microbiota. They activate both the closely related G protein-coupled receptors free fatty acid receptor 2 (FFA2) and free fatty acid receptor 3 (FFA3) that are considered therapeutic targets in diseases of immuno-metabolism. Limited and species-selective small-molecule pharmacology has restricted our understanding of the distinct roles of these receptors. Replacement of mouse FFA2 with a designer receptor exclusively activated by designer drug form of human FFA2 (hFFA2-DREADD) has allowed definition of specific roles of FFA2 in pharmacological and physiological studies conducted both ex vivo and in vivo, whilst overlay of murine disease models offers opportunities for therapeutic validation prior to human studies. Similar approaches can potentially be used to define roles of other poorly characterised receptors.
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