Background and PurposeFree fatty acid receptors FFA1 and FFA4 are located on enteroendocrine L cells with the highest gastrointestinal (GI) expression in descending colon. Their activation causes the release of glucagon‐like peptide 1 and peptide YY (PYY) from L cells. Additionally, FFA1 agonism releases insulin from pancreatic β cells. As these receptors are modulators of nutrient‐stimulated glucose regulation, the aim of this study was to compare the pharmacology of commercially available agonists (TUG424, TUG891, GW9508) with proven selective agonists (JTT, TAK‐875, AZ423, Metabolex‐36) in mice.Experimental ApproachMouse mucosa was mounted in Ussing chambers, voltage‐clamped and the resultant short‐circuit current (Isc) was recorded continuously. Pretreatments included antagonists of FFA1, Y1 or Y2 receptors. Glucose sensitivity was investigated by mannitol replacement apically, and colonic and upper GI transit was assessed in vitro and in vivo.Key ResultsFFA1 and FFA4 agonism required glucose and reduced Isc in a PYY‐Y1 receptor‐dependent manner. The novel compounds were more potent than GW9508. The FFA1 antagonists (GW1100 and ANT825) blocked FFA1 activity only and revealed FFA1 tonic activity. The FFA4 agonist, Metabolex‐36, slowed colonic transit in vitro but increased small intestinal transit in vivo.Conclusions and ImplicationsThe selective FFA1 and FFA4 agonists were more potent at reducing Isc than GW9508, a dual FFA1 and FFA4 agonist. A paracrine epithelial mechanism involving PYY‐stimulated Y1 receptors mediated their responses, which were glucose sensitive, potentially limiting hypoglycaemia. ANT825 revealed tonic activity and the possibility of endogenous FFA1 ligands causing PYY release. Finally, FFA4 agonism induced regional differences in transit.
