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

Peptides. 2016 Mar;77:16-20. doi: 10.1016/j.peptides.2015.06.012. Epub 2015 Jul 2.

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.

Keywords: GLP-1; GPR119; Incretin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Corn Oil / pharmacology*
  • Cyclic AMP / metabolism
  • Enteroendocrine Cells / drug effects
  • Enteroendocrine Cells / metabolism*
  • Female
  • Glucagon-Like Peptide 1 / metabolism*
  • Male
  • Mice, Transgenic
  • Olive Oil / administration & dosage
  • Olive Oil / pharmacology*
  • Primary Cell Culture
  • Receptors, G-Protein-Coupled / metabolism*
  • Second Messenger Systems

Substances

  • Gpr119 protein, mouse
  • Olive Oil
  • Receptors, G-Protein-Coupled
  • Corn Oil
  • Glucagon-Like Peptide 1
  • Cyclic AMP