title: Mechanisms of activation of mouse and human enteroendocrine cells by nutrients.
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.
  
  
  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.
authors.affiliation: Nerve-Gut Research Laboratory, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Symonds
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary, University of London, London, UK.
authors.forename: Madusha
authors.initials: M
authors.lastname: Peiris
authors.affiliation: Nerve-Gut Research Laboratory, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia, Australia Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Page
authors.affiliation: Nerve-Gut Research Laboratory, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: Bridgette
authors.initials: B
authors.lastname: Chia
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary, University of London, London, UK.
authors.forename: Harween
authors.initials: H
authors.lastname: Dogra
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary, University of London, London, UK.
authors.forename: Abigail
authors.initials: A
authors.lastname: Masding
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary, University of London, London, UK.
authors.forename: Vasileios
authors.initials: V
authors.lastname: Galanakis
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary, University of London, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Atiba
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary, University of London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bulmer
authors.affiliation: Nerve-Gut Research Laboratory, Hanson Institute, Royal Adelaide Hospital, Adelaide, South Australia, Australia Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Young
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary, University of London, London, UK Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: L Ashley
authors.initials: LA
authors.lastname: Blackshaw
mesh_terms: D000818:Animals; D019858:Enteroendocrine Cells / Q000502:physiology*; D005260:Female; D005502:Food; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: D011956:Receptors, Cell Surface
keywords: Gut Hormones; Obesity