GPR119 - a major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Co-acting in Synergy with FFA1 (GPR40)
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GPR119 - a major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Co-acting in Synergy with FFA1 (GPR40). / Ekberg, Jeppe H; Pedersen, Maria Hauge; Kristensen, Line V; Madsen, Andreas N; Engelstoft, Maja S; Husted, Anna-Sofie; Sichlau, Rasmus; Egerod, Kristoffer L; Timshel, Pascal; Kowalski, Timothy J; Gribble, Fiona M; Reiman, Frank; Hansen, Harald S; Howard, Andrew D; Holst, Birgitte; Schwartz, Thue W.
In: Endocrinology, Vol. 157, No. 12, en20161334, 25.10.2016, p. 4561-4569.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 169562929