title: Lipid derivatives activate GPR119 and trigger GLP-1 secretion in primary murine L-cells.
abstract: Glucagon-like peptide-1 (GLP-1) is an incretin hormone derived from proglucagon, which is released from intestinal L-cells and increases insulin secretion in a glucose dependent manner. GPR119 is a lipid derivative receptor present in L-cells, believed to play a role in the detection of dietary fat. This study aimed to characterize the responses of primary murine L-cells to GPR119 agonism and assess the importance of GPR119 for the detection of ingested lipid.
  
  
  
  GLP-1 secretion was measured from murine primary cell cultures stimulated with a panel of GPR119 ligands. Plasma GLP-1 levels were measured in mice lacking GPR119 in proglucagon-expressing cells and controls after lipid gavage. Intracellular cAMP responses to GPR119 agonists were measured in single primary L-cells using transgenic mice expressing a cAMP FRET sensor driven by the proglucagon promoter.
  
  
  
  L-cell specific knockout of GPR119 dramatically decreased plasma GLP-1 levels after a lipid gavage. GPR119 ligands triggered GLP-1 secretion in a GPR119 dependent manner in primary epithelial cultures from the colon, but were less effective in the upper small intestine. GPR119 agonists elevated cAMP in ∼70% of colonic L-cells and 50% of small intestinal L-cells.
  
  
  
  GPR119 ligands strongly enhanced GLP-1 release from colonic cultures, reflecting the high proportion of colonic L-cells that exhibited cAMP responses to GPR119 agonists. Less GPR119-dependence could be demonstrated in the upper small intestine. In vivo, GPR119 in L-cells plays a key role in oral lipid-triggered GLP-1 secretion.
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Daryl
authors.initials: D
authors.lastname: Hodge
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Glass
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Diakogiannaki
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Ramona
authors.initials: R
authors.lastname: Pais
authors.affiliation: AstraZeneca, Cardiovascular & Metabolic Diseases iMed, Alderley Park, Cheshire, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Lenaghan
authors.affiliation: AstraZeneca, Cardiovascular & Metabolic Diseases iMed, Mölndal, Sweden.
authors.forename: David M
authors.initials: DM
authors.lastname: Smith
authors.affiliation: AstraZeneca, Transgenics Group, Reagents & Assay Development, Discovery Sciences, Mölndal, Sweden.
authors.forename: Marianne
authors.initials: M
authors.lastname: Wedin
authors.affiliation: AstraZeneca, Transgenics Group, Reagents & Assay Development, Discovery Sciences, Mölndal, Sweden.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Bohlooly-Y
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address: fmg23@cam.ac.uk.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.affiliation: Metabolic Research Laboratories and MRC Metabolic Diseases Unit, WT-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address: fr222@cam.ac.uk.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003314:Corn Oil / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D000069463:Olive Oil / Q000008:administration & dosage / Q000494:pharmacology*; D061251:Primary Cell Culture; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015290:Second Messenger Systems
chemical_list: C516207:Gpr119 protein, mouse; D000069463:Olive Oil; D043562:Receptors, G-Protein-Coupled; D003314:Corn Oil; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP
keywords: GLP-1; GPR119; Incretin