{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T23:35:06Z","timestamp":1772580906220,"version":"3.50.1"},"reference-count":63,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2017,11,8]],"date-time":"2017-11-08T00:00:00Z","timestamp":1510099200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>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\u2010like peptide 1 and peptide YY (PYY) from L cells. Additionally, FFA1 agonism releases insulin from pancreatic \u03b2 cells. As these receptors are modulators of nutrient\u2010stimulated 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\u2010875, AZ423, Metabolex\u201036) in mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Mouse mucosa was mounted in Ussing chambers, voltage\u2010clamped and the resultant short\u2010circuit current (I<jats:sub>sc<\/jats:sub>) was recorded continuously. Pretreatments included antagonists of FFA1, Y<jats:sub>1<\/jats:sub>\u00a0or\u00a0Y<jats:sub>2<\/jats:sub> receptors. Glucose sensitivity was investigated by mannitol replacement apically, and colonic and upper GI transit was assessed <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>FFA1 and FFA4 agonism required glucose and reduced I<jats:sub>sc<\/jats:sub> in a PYY\u2010Y<jats:sub>1<\/jats:sub> receptor\u2010dependent 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\u201036, slowed colonic transit <jats:italic>in vitro<\/jats:italic> but increased small intestinal transit <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>The selective FFA1 and FFA4 agonists were more potent at reducing I<jats:sub>sc<\/jats:sub> than GW9508, a dual FFA1 and FFA4 agonist. A paracrine epithelial mechanism involving PYY\u2010stimulated Y<jats:sub>1<\/jats:sub> 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14054","type":"journal-article","created":{"date-parts":[[2017,10,3]],"date-time":"2017-10-03T07:26:39Z","timestamp":1507015599000},"page":"4508-4522","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Agonism of free fatty acid receptors 1 and 4 generates peptide YY\u2010mediated inhibitory responses in mouse colon"],"prefix":"10.1111","volume":"174","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3013-6374","authenticated-orcid":false,"given":"Runisha","family":"Moodaley","sequence":"first","affiliation":[{"name":"Wolfson Centre for Age\u2010Related Diseases King's College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M","family":"Smith","sequence":"additional","affiliation":[{"name":"Discovery Sciences, Innovative Medicines &amp; Early Development Biotech Unit AstraZeneca  Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iain R","family":"Tough","sequence":"additional","affiliation":[{"name":"Wolfson Centre for Age\u2010Related Diseases King's College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus","family":"Schindler","sequence":"additional","affiliation":[{"name":"AstraZeneca M\u00f6lndal, Innovative Medicines &amp; 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