Gq and Gs signaling acting in synergy to control GLP-1 secretion

Maria Hauge Pedersen; Jeppe Hvidtfeldt Ekberg; Maja Storm Engelstoft; Pascal Timshel; Andreas N Madsen; Thue W Schwartz

doi:10.1016/j.mce.2016.11.024

Gq and Gs signaling acting in synergy to control GLP-1 secretion

Maria Hauge Pedersen, Jeppe Hvidtfeldt Ekberg, Maja Storm Engelstoft, Pascal Timshel, Andreas N Madsen, Thue W Schwartz

24 Citations (Scopus)

Abstract

GPR40 is generally known to signal through Gq. However, in transfected cells, certain synthetic agonists can make the receptor signal also through Gs and cAMP (Hauge et al., 2015). Here we find that, in colonic crypt cultures, the GLP-1 secretion induced by such Gq + Gs GPR40 agonists is indeed inhibited by blockers of both Gq and Gs and is eliminated by combining these. This in contrast to Gq-only GPR40 agonists which only are affected by the Gq inhibitor. Importantly, Gq-only GPR40 agonists in combination with low doses of selective synthetic agonists for Gs coupled receptors, e.g. GPR119 and TGR5 provide more than additive GLP-1 secretion both ex vivo and in vivo in mice. It is concluded that under physiological circumstances triglyceride metabolites, i.e. long chain fatty acids and 2-monoacyl glycerol plus bile acids, act synergistically through their respective receptors, GPR40, GPR119 and TGR5 to stimulate GLP-1 secretion robustly by combining Gq and Gs signaling pathways.

Original language	English
Journal	Molecular and Cellular Endocrinology
Volume	449
Pages (from-to)	64-73
ISSN	0303-7207
DOIs	https://doi.org/10.1016/j.mce.2016.11.024
Publication status	Published - 5 Jul 2017

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10.1016/j.mce.2016.11.024

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title = "Gq and Gs signaling acting in synergy to control GLP-1 secretion",

abstract = "GPR40 is generally known to signal through Gq. However, in transfected cells, certain synthetic agonists can make the receptor signal also through Gs and cAMP (Hauge et al., 2015). Here we find that, in colonic crypt cultures, the GLP-1 secretion induced by such Gq + Gs GPR40 agonists is indeed inhibited by blockers of both Gq and Gs and is eliminated by combining these. This in contrast to Gq-only GPR40 agonists which only are affected by the Gq inhibitor. Importantly, Gq-only GPR40 agonists in combination with low doses of selective synthetic agonists for Gs coupled receptors, e.g. GPR119 and TGR5 provide more than additive GLP-1 secretion both ex vivo and in vivo in mice. It is concluded that under physiological circumstances triglyceride metabolites, i.e. long chain fatty acids and 2-monoacyl glycerol plus bile acids, act synergistically through their respective receptors, GPR40, GPR119 and TGR5 to stimulate GLP-1 secretion robustly by combining Gq and Gs signaling pathways.",

author = "Pedersen, {Maria Hauge} and Ekberg, {Jeppe Hvidtfeldt} and Engelstoft, {Maja Storm} and Pascal Timshel and Madsen, {Andreas N} and Schwartz, {Thue W}",

year = "2017",

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day = "5",

doi = "10.1016/j.mce.2016.11.024",

language = "English",

volume = "449",

pages = "64--73",

journal = "Molecular and Cellular Endocrinology",

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T1 - Gq and Gs signaling acting in synergy to control GLP-1 secretion

AU - Pedersen, Maria Hauge

AU - Ekberg, Jeppe Hvidtfeldt

AU - Engelstoft, Maja Storm

AU - Timshel, Pascal

AU - Madsen, Andreas N

AU - Schwartz, Thue W

PY - 2017/7/5

Y1 - 2017/7/5

N2 - GPR40 is generally known to signal through Gq. However, in transfected cells, certain synthetic agonists can make the receptor signal also through Gs and cAMP (Hauge et al., 2015). Here we find that, in colonic crypt cultures, the GLP-1 secretion induced by such Gq + Gs GPR40 agonists is indeed inhibited by blockers of both Gq and Gs and is eliminated by combining these. This in contrast to Gq-only GPR40 agonists which only are affected by the Gq inhibitor. Importantly, Gq-only GPR40 agonists in combination with low doses of selective synthetic agonists for Gs coupled receptors, e.g. GPR119 and TGR5 provide more than additive GLP-1 secretion both ex vivo and in vivo in mice. It is concluded that under physiological circumstances triglyceride metabolites, i.e. long chain fatty acids and 2-monoacyl glycerol plus bile acids, act synergistically through their respective receptors, GPR40, GPR119 and TGR5 to stimulate GLP-1 secretion robustly by combining Gq and Gs signaling pathways.

AB - GPR40 is generally known to signal through Gq. However, in transfected cells, certain synthetic agonists can make the receptor signal also through Gs and cAMP (Hauge et al., 2015). Here we find that, in colonic crypt cultures, the GLP-1 secretion induced by such Gq + Gs GPR40 agonists is indeed inhibited by blockers of both Gq and Gs and is eliminated by combining these. This in contrast to Gq-only GPR40 agonists which only are affected by the Gq inhibitor. Importantly, Gq-only GPR40 agonists in combination with low doses of selective synthetic agonists for Gs coupled receptors, e.g. GPR119 and TGR5 provide more than additive GLP-1 secretion both ex vivo and in vivo in mice. It is concluded that under physiological circumstances triglyceride metabolites, i.e. long chain fatty acids and 2-monoacyl glycerol plus bile acids, act synergistically through their respective receptors, GPR40, GPR119 and TGR5 to stimulate GLP-1 secretion robustly by combining Gq and Gs signaling pathways.

U2 - 10.1016/j.mce.2016.11.024

DO - 10.1016/j.mce.2016.11.024

M3 - Journal article

C2 - 27908836

SN - 0303-7207

VL - 449

SP - 64

EP - 73

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

ER -

Gq and Gs signaling acting in synergy to control GLP-1 secretion

Abstract

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