The primary means of production of short chain fatty acids in the body is by fermentation of non-digestible carbohydrates by the microbiota in the lower intestine. Such short chain fatty acids have wide ranging functions in the body both locally in the gut and after entry into the systemic circulation. It is increasing clear, as for many other metabolic products of ingested foodstuffs, that short chain fatty acids produce a number of effects via activation of G protein-coupled receptors. Two such receptors, now designated FFA2 and FFA3, were de-orphanised more than 10 years aso. Still, however, in lage part due to a limited pharmacological tool box of ligands that activate or block these receptors selectivity and with high affinity, there remains considerable confusion as to their specific functions and whether they offer interesting, novel therapeutic targets. Moreover, at least three other poorly characterised G protein-coupled receptors have been shown to be regulated by short chain fatty acids. To unravel specifically the roles of FFA2 we have adopted a number of chemogenetic approachs. As the only classes of FFA2 antagonist ligands act only at human and other primate orthologues of this recpetor and not at rodent orthologues we intially generated a transgenic mouse line in which a humanised sequence of FFA2 was ‘knocked-in’ to the mouse FFA2 receptor gene locus to replace the mouse orthologue. In an extension to this approach we developed a ‘Designer Receptor Exclusively Activated by Designer Drugs’ (DREADD) variant of this human receptor which is no longer responsive to short chain fatty acids but instead is activated by either sorbic acid or a benzoic acid derivative we designate ‘compound 36’ and then used this to generate a transgenic mouse line in which this variant replaces the mouse orthologue of FFA2. In both of these situations, because anti-G protein-coupled receptors antisera are notoriously poorly selective we also added a haemagluttin (HA) epitope tag to allow effective immunodetection of receptor expression patterns. I will discuss studies performed using these mice and demonstrate the specific roles of FFA2 in the release of the incretin glucagon-lipe peptide 1 from dissociated colonic crypts and intact colonic preparations, in neutrophil chemotaxis and in the regulation of lipolysis.