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

Abstract

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.

Nutrient Sensing Systems in Fish: Impact on Food Intake Regulation and Energy Homeostasis

“…The activity of ${\text{K}}_{\text{ATP}}^{+}$ inhibited by increased capacity of mitochondria to produce ROS in response to increased LCFA levels (Blouet and Schwartz, 2010). Finally, the activity of lipoprotein lipase increases in response to enhanced availability of triglycerides resulting in increased levels of LCFA stimulating G-protein-coupled receptors 40 and 120 (Picard et al, 2013; Ekberg et al, 2016). These systems apparently respond to specific LCFA, such as the monounsaturated fatty acid oleate (C18:1 n-9) (López et al, 2007; Blouet and Schwartz, 2010; Duca and Yue, 2014).…”

Therapeutic application of GPR119 ligands in metabolic disorders

“…The islets in GPR119‐deficient mice were also normal in terms of morphology and response to glucose and GLP‐1, but glucose‐induced GLP‐1 secretion was reduced . Interestingly, GLP‐1 secretion stimulated by triglycerides was significantly attenuated in GPR119‐deficient mice, but not in FFAR1‐ or FFAR4‐deficient mice, suggesting the essential role of GPR119 in the regulation of GLP‐1 release …”

“…18 Interestingly, GLP-1 secretion stimulated by triglycerides was significantly attenuated in GPR119-deficient mice, but not in FFAR1-or FFAR4-deficient mice, suggesting the essential role of GPR119 in the regulation of GLP-1 release. 37 3 | PHARMACOLOGICAL APPLICATIONS OF GPR119 LIGANDS…”

Relationship between diet/exercise and pharmacotherapy to enhance the GLP‐1 levels in type 2 diabetes

“…Several G protein‐coupled receptors (GPRs) including GPR40, GPR43, GPR119, GPR120 act as prime sensors for fats, and free fatty acid receptors (FFAR 1/3) play an important role in inducing GLP‐1 release. GPR40 and GPR119 act synergistically and mediate the triglyceride (TG)‐induced secretion of incretins, whereas GPR120 plays a minor role in the regulation of incretin secretion …”