Mechanisms of activation of mouse and human enteroendocrine cells by nutrients

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dc.contributor.authorSymonds, E.
dc.contributor.authorPeiris, M.
dc.contributor.authorPage, A.
dc.contributor.authorChia, B.
dc.contributor.authorDogra, H.
dc.contributor.authorMasding, A.
dc.contributor.authorGalanakis, V.
dc.contributor.authorAtiba, M.
dc.contributor.authorBulmer, D.
dc.contributor.authorYoung, R.
dc.contributor.authorBlackshaw, L.
dc.date.issued2015
dc.description.abstractOBJECTIVE: Inhibition of food intake and glucose homeostasis are both promoted when nutrients stimulate enteroendocrine cells (EEC) to release gut hormones. Several specific nutrient receptors may be located on EEC that respond to dietary sugars, amino acids and fatty acids. Bypass surgery for obesity and type II diabetes works by shunting nutrients to the distal gut, where it increases activation of nutrient receptors and mediator release, but cellular mechanisms of activation are largely unknown. We determined which nutrient receptors are expressed in which gut regions and in which cells in mouse and human, how they are associated with different types of EEC, how they are activated leading to hormone and 5-HT release. DESIGN AND RESULTS: mRNA expression of 17 nutrient receptors and EEC mediators was assessed by quantitative PCR and found throughout mouse and human gut epithelium. Many species similarities emerged, in particular the dense expression of several receptors in the distal gut. Immunolabelling showed specific colocalisation of receptors with EEC mediators PYY and GLP-1 (L-cells) or 5-HT (enterochromaffin cells). We exposed isolated proximal colonic mucosa to specific nutrients, which recruited signalling pathways within specific EEC extracellular receptor-regulated kinase (p-ERK) and calmodulin kinase II (pCAMKII), as shown by subsequent immunolabelling, and activated release of these mediators. Aromatic amino acids activated both pathways in mouse, but in humans they induced only pCAMKII, which was colocalised mainly with 5-HT expression. Activation was pertussis toxin-sensitive. Fatty acid (C12) potently activated p-ERK in human in all EEC types and evoked potent release of all three mediators. CONCLUSIONS: Specific nutrient receptors associate with distinct activation pathways within EEC. These may provide discrete, complementary pharmacological targets for intervention in obesity and type II diabetes.
dc.description.statementofresponsibilityErin L Symonds, Madusha Peiris, Amanda J Page, Bridgette Chia, Harween Dogra, Abigail Masding, Vasileios Galanakis, Michael Atiba, David Bulmer, Richard L Young, L Ashley Blackshaw
dc.identifier.citationGut, 2015; 64(4):618-626
dc.identifier.doi10.1136/gutjnl-2014-306834
dc.identifier.issn0017-5749
dc.identifier.issn1468-3288
dc.identifier.orcidPage, A. [0000-0002-7086-5865]
dc.identifier.orcidYoung, R. [0000-0001-5116-4951] [0009-0004-8274-9863]
dc.identifier.urihttp://hdl.handle.net/2440/95264
dc.language.isoen
dc.publisherBMJ Publishing Group
dc.rightsThis is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/
dc.source.urihttps://doi.org/10.1136/gutjnl-2014-306834
dc.subjectGut Hormones
dc.subjectObesity
dc.titleMechanisms of activation of mouse and human enteroendocrine cells by nutrients
dc.typeJournal article
pubs.publication-statusPublished

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