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

Abstract

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 Gαs-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 RIA. Anesthetized rats received intravenous or intraileal OEA, and plasma bioactive GLP-1, insulin and glucose levels were determined by Elisa or glucose analyzer.

Results: GPR119 mRNA was detected in all L-cell models. OEA treatment (10μM) 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 PKA. OEA-induced cAMP levels and GLP-1 secretion were significantly reduced in mGLUTag cells transfected with GPR119-specific siRNA (p<0.05). Application of OEA (10μM) 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 were increased by 3.9-fold (p<0.01) but only in the presence of hyperglycemia.

Conclusion: 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.