TY - JOUR

T1 - GPR119 - a major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Co-acting in Synergy with FFA1 (GPR40)

AU - Ekberg, Jeppe H

AU - Pedersen, Maria Hauge

AU - Kristensen, Line V

AU - Madsen, Andreas N

AU - Engelstoft, Maja S

AU - Husted, Anna-Sofie

AU - Sichlau, Rasmus

AU - Egerod, Kristoffer L

AU - Timshel, Pascal

AU - Kowalski, Timothy J

AU - Gribble, Fiona M

AU - Reiman, Frank

AU - Hansen, Harald S

AU - Howard, Andrew D

AU - Holst, Birgitte

AU - Schwartz, Thue W

PY - 2016/10/25

Y1 - 2016/10/25

N2 - Triglycerides are among the most efficacious stimulators of incretin secretion; however the relative importance of FFA1 (GPR40), FFA4 (GPR120) and GPR119 which all recognize triglyceride metabolites, i.e. LCFA and 2-MAG respectively, is still unclear. Here, we find all three receptors to be highly expressed and highly enriched in FACS-purified GLP-1 and GIP cells isolated from transgenic reporter mice. In vivo, the triglyceride-induced increase in plasma GIP was significantly reduced in FFA1 deficient mice (to 34% - mean of four 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 triglyceride-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 approx. half the maximal efficiency of the GPR119 agonist AR231453 whereas the GPR120 agonist Metabolix-209 had no effect. Importantly, when the FFA1 agonist was administered on top of appropriately low doses of the GPR119 agonist a clear synergistic, i.e. more than additive effect was observed. It is concluded that the 2-MAG receptor GPR119 is at least as important as the LCFA receptor FFA1 in mediating the triglyceride-induced secretion of incretins and that the two receptors act in synergy whereas FFA4 plays a minor if any role.

AB - Triglycerides are among the most efficacious stimulators of incretin secretion; however the relative importance of FFA1 (GPR40), FFA4 (GPR120) and GPR119 which all recognize triglyceride metabolites, i.e. LCFA and 2-MAG respectively, is still unclear. Here, we find all three receptors to be highly expressed and highly enriched in FACS-purified GLP-1 and GIP cells isolated from transgenic reporter mice. In vivo, the triglyceride-induced increase in plasma GIP was significantly reduced in FFA1 deficient mice (to 34% - mean of four 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 triglyceride-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 approx. half the maximal efficiency of the GPR119 agonist AR231453 whereas the GPR120 agonist Metabolix-209 had no effect. Importantly, when the FFA1 agonist was administered on top of appropriately low doses of the GPR119 agonist a clear synergistic, i.e. more than additive effect was observed. It is concluded that the 2-MAG receptor GPR119 is at least as important as the LCFA receptor FFA1 in mediating the triglyceride-induced secretion of incretins and that the two receptors act in synergy whereas FFA4 plays a minor if any role.

U2 - 10.1210/en.2016-1334

DO - 10.1210/en.2016-1334

M3 - Journal article

C2 - 27779915

VL - 157

SP - 4561

EP - 4569

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0013-7227

IS - 12

M1 - en20161334

ER -