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Free fatty acid receptor (FFA) and lipid receptor (GPR119) signalling mediates nutrient-sensing in mouse intestine

Student thesis: Doctoral ThesisDoctor of Philosophy

Medium and long chain fatty acids exhibit affinity for free-fatty acid receptor 1 (FFA1) and 4 (FFA4). FFA1 and FFA4 are expressed in the pancreas with a third lipid G-protein coupled receptor, GPR119, and all three GPCRs are also highly expressed by gastrointestinal (GI) enteroendocrine L cells, which release glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). GLP-1 is a stimulant of insulin secretion postprandially, whereas PYY slows GI motility and reduces food intake. The receptor expression patterns raise these receptors’ potential as targets for anti-diabetic and anti-obesity therapeutics. This thesis compares the pharmacology and cellular signalling of novel FFA1, FFA4 and GPR119 agonists from AstraZeneca, with that of commercially available agonists in mouse colonic mucosa.
Mucosa was mounted in Ussing chambers, voltage-clamped and the resultant short-circuit current (Isc) was recorded continuously, as a measurement of vectorial epithelial ion transport in vitro. Colonic bead propulsion and charcoal-meal gavage assessments were used to measure lower and upper GI transit in vivo, respectively.
FFA1, FFA4 or GPR119 selective agonism potently inhibited mucosal anion secretion via a PYY-Y1 paracrine mechanism. These anti-secretory responses showed area-specificity and the descending colon was selected for further interrogation. Here, FFA1 and FFA4 agonists displayed low maximal responses, whereas GPR119 agonists exhibited partial efficacy in comparison to PSN632408. All agonists required glucose for activity, minimising the potential for hypoglycaemia, a limitation of current anti-diabetic drugs. Furthermore, dual agonism of FFA1, FFA4 or GPR119 was additive. The FFA1 antagonist, ANT825 revealed endogenous intestinal FFA1 tone, and this was inhibited in the presence of the competitive Y1 and Y2 antagonists. FFA4 agonism slowed transit in the colon and increased transit in the small intestine, whereas FFA1 agonism had no effect on transit in vivo. As the FFA4 receptor is more broadly expressed in the GI tract compared to FFA1 and GPR119, luminal-restricted GPR119 agonists in combination with FFA1 agonists should be considered as future T2DM therapeutics.
Original languageEnglish
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Award date2018

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