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Lipid derivatives activate GPR119 and trigger GLP-1 secretion in primary murine L-cells.

Published version
Peer-reviewed

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Type

Article

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Authors

Hodge, Daryl 
Glass, Leslie L 
Diakogiannaki, Eleftheria 
Pais, Ramona 
Lenaghan, Carol 

Abstract

AIMS/HYPOTHESIS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS/INTERPRETATION: 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.

Description

Keywords

GLP-1, GPR119, Incretin, Animals, Cells, Cultured, Corn Oil, Cyclic AMP, Enteroendocrine Cells, Female, Glucagon-Like Peptide 1, Male, Mice, Transgenic, Olive Oil, Primary Cell Culture, Receptors, G-Protein-Coupled, Second Messenger Systems

Journal Title

Peptides

Conference Name

Journal ISSN

0196-9781
1873-5169

Volume Title

77

Publisher

Elsevier BV
Sponsorship
Medical Research Council (MC_UU_12012/3)
Medical Research Council (MC_PC_12012)
This work was funded by grants from the Wellcome Trust (WT088357/Z/09/Z and WT084210/Z/07/Z), the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/3), Full4Health (FP7/2011-2015, grant agreement n° 266408) and a BBSRC/AstraZeneca CASE studentship to CEM.