TY - JOUR
T1 - Enteroendocrine cell-derived peptide YY signalling is stimulated by pinolenic acid or Intralipid and involves coactivation of fatty acid receptors FFA1, FFA4 and GPR119
AU - Cox, Helen
AU - Tough, Iain R.
AU - Moodaley, Runisha
N1 - Publisher Copyright:
© 2024
PY - 2024/10/18
Y1 - 2024/10/18
N2 - 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.
AB - 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.
KW - enteroendocrine L cell, peptide YY-Y1 receptor, free fatty acid receptors (FFA)1 and FFA4; FFA and GPR119 co-agonism, pinolenic acid, Intralipid, epithelia ion transport
UR - http://www.scopus.com/inward/record.url?scp=85206523604&partnerID=8YFLogxK
U2 - 10.1016/j.npep.2024.102477
DO - 10.1016/j.npep.2024.102477
M3 - Article
SN - 0143-4179
VL - 108
JO - Neuropeptides
JF - Neuropeptides
M1 - 102477
ER -