Mechanisms of activation of mouse and human enteroendocrine cells by nutrients.

Erin Symonds, Madusha Peiris, Amanda Page, Bridgette Chia, Harween Dogra, Abigail Masding, Vasileios Galanakis, Michael Atiba, David Bulmer, Richard Young, L Blackshaw

    Research output: Contribution to journalArticle

    51 Citations (Scopus)

    Abstract

    Objective 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 Speci fic nutrient receptors associate with distinct activation pathways within EEC. These may provide discrete, complementary pharmacological targets for intervention in obesity and type II diabetes.

    Original languageEnglish
    Pages (from-to)618-621
    Number of pages4
    JournalGut
    Volume64
    Issue number4
    DOIs
    Publication statusPublished - 2014

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  • Cite this

    Symonds, E., Peiris, M., Page, A., Chia, B., Dogra, H., Masding, A., Galanakis, V., Atiba, M., Bulmer, D., Young, R., & Blackshaw, L. (2014). Mechanisms of activation of mouse and human enteroendocrine cells by nutrients. Gut, 64(4), 618-621. https://doi.org/10.1136/gutjnl-2014-306834