GPR119, a Major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Coacting in Synergy With FFA1 (GPR40)

Endocrinology. 2016 Dec;157(12):4561-4569. doi: 10.1210/en.2016-1334. Epub 2016 Oct 25.


Triglycerides (TGs) are among the most efficacious stimulators of incretin secretion; however, the relative importance of FFA1 (G Protein-coupled Receptor [GPR] 40), FFA4 (GPR120), and GPR119, which all recognize TG metabolites, ie, long-chain fatty acid and 2-monoacylglycerol, respectively, is still unclear. Here, we find all 3 receptors to be highly expressed and highly enriched in fluorescence-activated cell sorting-purified GLP-1 and GIP cells isolated from transgenic reporter mice. In vivo, the TG-induced increase in plasma GIP was significantly reduced in FFA1-deficient mice (to 34%, mean of 4 experiments each with 8-10 animals), in GPR119-deficient mice (to 24%) and in FFA1/FFA4 double deficient mice (to 15%) but not in FFA4-deficient mice. The TG-induced increase in plasma GLP-1 was only significantly reduced in the GPR119-deficient and the FFA1/FFA4 double deficient mice, but not in the FFA1, and FFA4-deficient mice. In mouse colonic crypt cultures the synthetic FFA1 agonists, TAK-875 stimulated GLP-1 secretion to a similar extent as the prototype GLP-1 secretagogue neuromedin C; this, however, only corresponded to approximately half the maximal efficiency of the GPR119 agonist AR231453, whereas the GPR120 agonist Metabolex-209 had no effect. Importantly, when the FFA1 agonist was administered on top of appropriately low doses of the GPR119 agonist, a clear synergistic, ie, more than additive, effect was observed. It is concluded that the 2-monoacylglycerol receptor GPR119 is at least as important as the long-chain fatty acid receptor FFA1 in mediating the TG-induced secretion of incretins and that the 2 receptors act in synergy, whereas FFA4 plays a minor if any role.

MeSH terms

  • Animals
  • Benzofurans / pharmacology
  • Bombesin / pharmacology
  • Colon / drug effects
  • Colon / metabolism*
  • Dietary Fats
  • Glucagon-Like Peptide 1 / metabolism
  • Mice
  • Mice, Knockout
  • Peptide Fragments / pharmacology
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Sulfones / pharmacology
  • Triglycerides / metabolism*


  • Benzofurans
  • Dietary Fats
  • FFAR4 protein, mouse
  • Ffar1 protein, mouse
  • Gpr119 protein, mouse
  • Peptide Fragments
  • Receptors, G-Protein-Coupled
  • Sulfones
  • TAK-875
  • Triglycerides
  • neuromedin C
  • Glucagon-Like Peptide 1
  • Bombesin