Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine

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Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine. / Christensen, Louise Wulff; Kuhre, Rune Ehrenreich; Janus, Charlotte; Svendsen, Berit; Holst, Jens Juul.

In: Physiological Reports, Vol. 3, No. 9, e122551, 17.09.2015, p. 1-13.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Christensen, LW, Kuhre, RE, Janus, C, Svendsen, B & Holst, JJ 2015, 'Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine', Physiological Reports, vol. 3, no. 9, e122551, pp. 1-13. https://doi.org/10.14814/phy2.12551

APA

Christensen, L. W., Kuhre, R. E., Janus, C., Svendsen, B., & Holst, J. J. (2015). Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine. Physiological Reports, 3(9), 1-13. [e122551]. https://doi.org/10.14814/phy2.12551

Vancouver

Christensen LW, Kuhre RE, Janus C, Svendsen B, Holst JJ. Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine. Physiological Reports. 2015 Sep 17;3(9):1-13. e122551. https://doi.org/10.14814/phy2.12551

Author

Christensen, Louise Wulff ; Kuhre, Rune Ehrenreich ; Janus, Charlotte ; Svendsen, Berit ; Holst, Jens Juul. / Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine. In: Physiological Reports. 2015 ; Vol. 3, No. 9. pp. 1-13.

Bibtex

@article{199d0269e69848329c1698935751045e,
title = "Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine",
abstract = "Glucagon-like peptide 1 (GLP-1) plays a central role in modern treatment of type 2 diabetes (T2DM) in the form of GLP-1 enhancers and GLP-1 mimetics. An alternative treatment strategy is to stimulate endogenous GLP-1 secretion from enteroendocrine L cells using a targeted approach. The G-protein-cou- pled receptor, FFAR1 (previously GPR40), expressed on L cells and activated by long-chain fatty acids (LCFAs) is a potential target. A link between FFAR1 activation and GLP-1 secretion has been demonstrated in cellular models and small-molecule FFAR1 agonists have been developed. In this study, we exam- ined the effect of FFAR1 activation on GLP-1 secretion using isolated, per- fused small intestines from rats, a physiologically relevant model allowing distinction between direct and indirect effects of FFAR1 activation. The endogenous FFAR1 ligand, linoleic acid (LA), and four synthetic FFAR1 ago- nists (TAK-875, AMG 837, AM-1638, and AM-5262) were administered through intraluminal and intra-arterial routes, respectively, and dynamic changes in GLP-1 secretion were evaluated. Vascular administration of 10 mol/L TAK-875, 10 mol/L AMG 837, 1 mol/L and 0.1 mol/L AM-1638, 1 mol/L AM-6252, and 1 mmol/L LA, all significantly increased GLP-1 secretion compared to basal levels (P<0.05), whereas luminal administration of LA and FFAR1 agonists was ineffective. Thus, both natural and small-mole- cule agonists of the FFAR1 receptor appear to require absorption prior to stimulating GLP-1 secretion, indicating that therapies based on activation of nutrient sensing may be more complex than hitherto expected.",
keywords = "Faculty of Health and Medical Sciences, G-protein-coupled receptor, incretin, long- chain fatty acids",
author = "Christensen, {Louise Wulff} and Kuhre, {Rune Ehrenreich} and Charlotte Janus and Berit Svendsen and Holst, {Jens Juul}",
year = "2015",
month = "9",
day = "17",
doi = "10.14814/phy2.12551",
language = "English",
volume = "3",
pages = "1--13",
journal = "Physiological Reports",
issn = "2051-817X",
publisher = "Wiley Periodicals, Inc.",
number = "9",

}

RIS

TY - JOUR

T1 - Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine

AU - Christensen, Louise Wulff

AU - Kuhre, Rune Ehrenreich

AU - Janus, Charlotte

AU - Svendsen, Berit

AU - Holst, Jens Juul

PY - 2015/9/17

Y1 - 2015/9/17

N2 - Glucagon-like peptide 1 (GLP-1) plays a central role in modern treatment of type 2 diabetes (T2DM) in the form of GLP-1 enhancers and GLP-1 mimetics. An alternative treatment strategy is to stimulate endogenous GLP-1 secretion from enteroendocrine L cells using a targeted approach. The G-protein-cou- pled receptor, FFAR1 (previously GPR40), expressed on L cells and activated by long-chain fatty acids (LCFAs) is a potential target. A link between FFAR1 activation and GLP-1 secretion has been demonstrated in cellular models and small-molecule FFAR1 agonists have been developed. In this study, we exam- ined the effect of FFAR1 activation on GLP-1 secretion using isolated, per- fused small intestines from rats, a physiologically relevant model allowing distinction between direct and indirect effects of FFAR1 activation. The endogenous FFAR1 ligand, linoleic acid (LA), and four synthetic FFAR1 ago- nists (TAK-875, AMG 837, AM-1638, and AM-5262) were administered through intraluminal and intra-arterial routes, respectively, and dynamic changes in GLP-1 secretion were evaluated. Vascular administration of 10 mol/L TAK-875, 10 mol/L AMG 837, 1 mol/L and 0.1 mol/L AM-1638, 1 mol/L AM-6252, and 1 mmol/L LA, all significantly increased GLP-1 secretion compared to basal levels (P<0.05), whereas luminal administration of LA and FFAR1 agonists was ineffective. Thus, both natural and small-mole- cule agonists of the FFAR1 receptor appear to require absorption prior to stimulating GLP-1 secretion, indicating that therapies based on activation of nutrient sensing may be more complex than hitherto expected.

AB - Glucagon-like peptide 1 (GLP-1) plays a central role in modern treatment of type 2 diabetes (T2DM) in the form of GLP-1 enhancers and GLP-1 mimetics. An alternative treatment strategy is to stimulate endogenous GLP-1 secretion from enteroendocrine L cells using a targeted approach. The G-protein-cou- pled receptor, FFAR1 (previously GPR40), expressed on L cells and activated by long-chain fatty acids (LCFAs) is a potential target. A link between FFAR1 activation and GLP-1 secretion has been demonstrated in cellular models and small-molecule FFAR1 agonists have been developed. In this study, we exam- ined the effect of FFAR1 activation on GLP-1 secretion using isolated, per- fused small intestines from rats, a physiologically relevant model allowing distinction between direct and indirect effects of FFAR1 activation. The endogenous FFAR1 ligand, linoleic acid (LA), and four synthetic FFAR1 ago- nists (TAK-875, AMG 837, AM-1638, and AM-5262) were administered through intraluminal and intra-arterial routes, respectively, and dynamic changes in GLP-1 secretion were evaluated. Vascular administration of 10 mol/L TAK-875, 10 mol/L AMG 837, 1 mol/L and 0.1 mol/L AM-1638, 1 mol/L AM-6252, and 1 mmol/L LA, all significantly increased GLP-1 secretion compared to basal levels (P<0.05), whereas luminal administration of LA and FFAR1 agonists was ineffective. Thus, both natural and small-mole- cule agonists of the FFAR1 receptor appear to require absorption prior to stimulating GLP-1 secretion, indicating that therapies based on activation of nutrient sensing may be more complex than hitherto expected.

KW - Faculty of Health and Medical Sciences

KW - G-protein-coupled receptor

KW - incretin

KW - long- chain fatty acids

U2 - 10.14814/phy2.12551

DO - 10.14814/phy2.12551

M3 - Journal article

C2 - 26381015

VL - 3

SP - 1

EP - 13

JO - Physiological Reports

JF - Physiological Reports

SN - 2051-817X

IS - 9

M1 - e122551

ER -

ID: 144403006