Enteroendocrine cell-derived peptide YY signalling is stimulated by pinolenic acid or Intralipid and involves coactivation of fatty acid receptors FFA1, FFA4 and GPR119

Abstract

Long chain fatty acids are sensed by enteroendocrine L cells that express free-fatty acid receptors, including FFA1, FFA4 and the acylethanolamine receptor GPR119. Here we investigated the acute effects of single or multiple agonism at these G protein-coupled receptors in intestinal mucosae where L cell-derived peptide YY (PYY) is anti-secretory and acts via epithelial Y1 receptors. Mouse ileal or colonic mucosae were mounted in Ussing chambers, voltage-clamped and the resultant short-circuit current (Isc) recorded continuously. The agonists used were; FFA1, TAK-875 or AM-1638; for FFA4, Merck A; or for GPR119, AR231453, PSN632408 or AR440006. Their responses were compared with those of pinolenic acid (PA, a presumed dual FFA1/FFA4 agonist) and the lipid emulsion, Intralipid. The FFA1 agonist AM-1638 (EC50 = 38.2 nM) was more potent than TAK-875 (EC50 = 203.1 nM) but exhibited similar efficacy. GPR119 agonism (AR231453) pretreatment enhanced subsequent FFA1 (AM-1638 or TAK-875) and FFA4 (Merck A) signalling. PA (EC50 = 298.2 nM) co-activated epithelial FFA1 and FFA4 and involved endogenous PYY Y1/Y2-receptor mechanisms but desensitisation was observed between PA and high GPR119 agonist concentrations. Apical Intralipid co-activated FFA1, FFA4 and GPR119 with a residual component not being attributable to PYY, or this trio of fatty acid receptors.