Agonism of free fatty acid receptors 1 and 4 generates peptide YY-mediated inhibitory responses in mouse colon.

Free 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. Mouse mucosa was mounted in Ussing chambers, voltage-clamped and the resultant short-circuit current (I FFA1 and FFA4 agonism required glucose and reduced I The selective FFA1 and FFA4 agonists were more potent at reducing I