GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L-cell

Diabetes. 2009 May;58(5):1058-66. doi: 10.2337/db08-1237. Epub 2009 Feb 10.


Objective: Intestinal L-cells secrete the incretin glucagon-like peptide-1 (GLP-1) in response to ingestion of nutrients, especially long-chain fatty acids. The Galphas-coupled receptor GPR119 binds the long-chain fatty acid derivate oleoylethanolamide (OEA), and GPR119 agonists enhance GLP-1 secretion. We therefore hypothesized that OEA stimulates GLP-1 release through a GPR119-dependent mechanism.

Research design and methods: Murine (m) GLUTag, human (h) NCI-H716, and primary fetal rat intestinal L-cell models were used for RT-PCR and for cAMP and GLP-1 radioimmunoassay. Anesthetized rats received intravenous or intraileal OEA, and plasma bioactive GLP-1, insulin, and glucose levels were determined by enzyme-linked immunosorbent assay or glucose analyzer.

Results: GPR119 messenger RNA was detected in all L-cell models. OEA treatment (10 micromol/l) of mGLUTag cells increased cAMP levels (P < 0.05) and GLP-1 secretion (P < 0.001) in all models, with desensitization of the secretory response at higher concentrations. GLP-1 secretion was further enhanced by prevention of OEA degradation using the fatty acid amide hydrolase inhibitor, URB597 (P < 0.05-0.001 vs. OEA alone), and was abolished by H89-induced inhibition of protein kinase A. OEA-induced cAMP levels and GLP-1 secretion were significantly reduced in mGLUTag cells transfected with GPR119-specific small interfering RNA (P < 0.05). Application of OEA (10 micromol/l) directly into the rat ileum, but not intravenously, increased plasma bioactive GLP-1 levels in euglycemic animals by 1.5-fold (P < 0.05) and insulin levels by 3.9-fold (P < 0.01) but only in the presence of hyperglycemia.

Conclusions: The results of these studies demonstrate, for the first time, that OEA increases GLP-1 secretion from intestinal L-cells through activation of the novel GPR119 fatty acid derivate receptor in vitro and in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic AMP / metabolism
  • DNA Primers
  • Endocannabinoids
  • Enteroendocrine Cells / drug effects
  • Enteroendocrine Cells / physiology*
  • Gene Expression Regulation / drug effects
  • Humans
  • Intestines / embryology
  • Intestines / physiology
  • Male
  • Mice
  • Oleic Acids / pharmacology*
  • Polymerase Chain Reaction
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Wistar
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / physiology*
  • Transfection


  • DNA Primers
  • Endocannabinoids
  • GPR119 protein, human
  • GPR119 protein, rat
  • Gpr119 protein, mouse
  • Oleic Acids
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • oleoylethanolamide
  • Cyclic AMP