Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

Johannes Schmidt; Kathrin Liebscher; Nicole Merten; Manuel Grundmann; Manfred Mielenz; Helga Sauerwein; Elisabeth Christiansen; Maria E Due-Hansen; Trond Ulven; Susanne Ullrich; Jesús Gomeza; Christel Drewke; Evi Kostenis

doi:10.1074/jbc.c110.200477

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

Johannes Schmidt, Kathrin Liebscher, Nicole Merten, Manuel Grundmann, Manfred Mielenz, Helga Sauerwein, Elisabeth Christiansen, Maria E Due-Hansen, Trond Ulven, Susanne Ullrich, Jesús Gomeza, Christel Drewke, Evi Kostenis

47 Citationer (Scopus)

Abstract

Among dietary components, conjugated linoleic acids (CLAs) have attracted considerable attention as weight loss supplements in the Western world because they reduce fat stores and increase muscle mass. However, a number of adverse effects are also ascribed to the intake of CLAs such as aggravation of insulin resistance and the risk of developing diabetes. However, the mechanisms accounting for the effects of CLAs on glucose homeostasis are incompletely understood. Herein we provide evidence that CLAs specifically activate the cell surface receptor FFA1, an emerging therapeutic target to treat type 2 diabetes. Using different recombinant cellular systems engineered to stably express FFA1 and a set of diverse functional assays including the novel, label-free non-invasive dynamic mass redistribution technology (Corning® Epic® biosensor), both CLA isomers cis-9, trans-11-CLA and trans-10, cis-12-CLA were found to activate FFA1 in vitro at concentrations sufficient to also account for FFA1 activation in vivo. Each CLA isomer markedly increased glucose-stimulated insulin secretion in insulin-producing INS-1E cells that endogenously express FFA1 and in primary pancreatic β-cells of wild type but not FFA1(-/-) knock-out mice. Our findings establish a clear mechanistic link between CLAs and insulin production and identify the cell surface receptor FFA1 as a molecular target for CLAs, explaining their acute stimulatory effects on insulin secretion in vivo. CLAs are also revealed as insulinotropic components in widely used nutraceuticals, a finding with significant implication for development of FFA1 modulators to treat type 2 diabetes.

Originalsprog	Engelsk
Tidsskrift	Journal of Biological Chemistry
Vol/bind	286
Udgave nummer	14
Sider (fra-til)	11890-11894
Antal sider	5
ISSN	0021-9258
DOI	https://doi.org/10.1074/jbc.c110.200477
Status	Udgivet - 8 apr. 2011
Udgivet eksternt	Ja

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10.1074/jbc.c110.200477

http://www.jbc.org/content/286/14/11890.full.pdfLicens: CC BY

Citationsformater

Schmidt, J., Liebscher, K., Merten, N., Grundmann, M., Mielenz, M., Sauerwein, H., Christiansen, E., Due-Hansen, M. E., Ulven, T., Ullrich, S., Gomeza, J., Drewke, C., & Kostenis, E. (2011). Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40. Journal of Biological Chemistry, 286(14), 11890-11894. https://doi.org/10.1074/jbc.c110.200477

Schmidt, J, Liebscher, K, Merten, N, Grundmann, M, Mielenz, M, Sauerwein, H, Christiansen, E, Due-Hansen, ME, Ulven, T, Ullrich, S, Gomeza, J, Drewke, C & Kostenis, E 2011, 'Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40', Journal of Biological Chemistry, bind 286, nr. 14, s. 11890-11894. https://doi.org/10.1074/jbc.c110.200477

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abstract = "Among dietary components, conjugated linoleic acids (CLAs) have attracted considerable attention as weight loss supplements in the Western world because they reduce fat stores and increase muscle mass. However, a number of adverse effects are also ascribed to the intake of CLAs such as aggravation of insulin resistance and the risk of developing diabetes. However, the mechanisms accounting for the effects of CLAs on glucose homeostasis are incompletely understood. Herein we provide evidence that CLAs specifically activate the cell surface receptor FFA1, an emerging therapeutic target to treat type 2 diabetes. Using different recombinant cellular systems engineered to stably express FFA1 and a set of diverse functional assays including the novel, label-free non-invasive dynamic mass redistribution technology (Corning{\textregistered} Epic{\textregistered} biosensor), both CLA isomers cis-9, trans-11-CLA and trans-10, cis-12-CLA were found to activate FFA1 in vitro at concentrations sufficient to also account for FFA1 activation in vivo. Each CLA isomer markedly increased glucose-stimulated insulin secretion in insulin-producing INS-1E cells that endogenously express FFA1 and in primary pancreatic β-cells of wild type but not FFA1(-/-) knock-out mice. Our findings establish a clear mechanistic link between CLAs and insulin production and identify the cell surface receptor FFA1 as a molecular target for CLAs, explaining their acute stimulatory effects on insulin secretion in vivo. CLAs are also revealed as insulinotropic components in widely used nutraceuticals, a finding with significant implication for development of FFA1 modulators to treat type 2 diabetes.",

author = "Johannes Schmidt and Kathrin Liebscher and Nicole Merten and Manuel Grundmann and Manfred Mielenz and Helga Sauerwein and Elisabeth Christiansen and Due-Hansen, {Maria E} and Trond Ulven and Susanne Ullrich and Jes{\'u}s Gomeza and Christel Drewke and Evi Kostenis",

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doi = "10.1074/jbc.c110.200477",

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T1 - Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

AU - Schmidt, Johannes

AU - Liebscher, Kathrin

AU - Merten, Nicole

AU - Grundmann, Manuel

AU - Mielenz, Manfred

AU - Sauerwein, Helga

AU - Christiansen, Elisabeth

AU - Due-Hansen, Maria E

AU - Ulven, Trond

AU - Ullrich, Susanne

AU - Gomeza, Jesús

AU - Drewke, Christel

AU - Kostenis, Evi

PY - 2011/4/8

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N2 - Among dietary components, conjugated linoleic acids (CLAs) have attracted considerable attention as weight loss supplements in the Western world because they reduce fat stores and increase muscle mass. However, a number of adverse effects are also ascribed to the intake of CLAs such as aggravation of insulin resistance and the risk of developing diabetes. However, the mechanisms accounting for the effects of CLAs on glucose homeostasis are incompletely understood. Herein we provide evidence that CLAs specifically activate the cell surface receptor FFA1, an emerging therapeutic target to treat type 2 diabetes. Using different recombinant cellular systems engineered to stably express FFA1 and a set of diverse functional assays including the novel, label-free non-invasive dynamic mass redistribution technology (Corning® Epic® biosensor), both CLA isomers cis-9, trans-11-CLA and trans-10, cis-12-CLA were found to activate FFA1 in vitro at concentrations sufficient to also account for FFA1 activation in vivo. Each CLA isomer markedly increased glucose-stimulated insulin secretion in insulin-producing INS-1E cells that endogenously express FFA1 and in primary pancreatic β-cells of wild type but not FFA1(-/-) knock-out mice. Our findings establish a clear mechanistic link between CLAs and insulin production and identify the cell surface receptor FFA1 as a molecular target for CLAs, explaining their acute stimulatory effects on insulin secretion in vivo. CLAs are also revealed as insulinotropic components in widely used nutraceuticals, a finding with significant implication for development of FFA1 modulators to treat type 2 diabetes.

AB - Among dietary components, conjugated linoleic acids (CLAs) have attracted considerable attention as weight loss supplements in the Western world because they reduce fat stores and increase muscle mass. However, a number of adverse effects are also ascribed to the intake of CLAs such as aggravation of insulin resistance and the risk of developing diabetes. However, the mechanisms accounting for the effects of CLAs on glucose homeostasis are incompletely understood. Herein we provide evidence that CLAs specifically activate the cell surface receptor FFA1, an emerging therapeutic target to treat type 2 diabetes. Using different recombinant cellular systems engineered to stably express FFA1 and a set of diverse functional assays including the novel, label-free non-invasive dynamic mass redistribution technology (Corning® Epic® biosensor), both CLA isomers cis-9, trans-11-CLA and trans-10, cis-12-CLA were found to activate FFA1 in vitro at concentrations sufficient to also account for FFA1 activation in vivo. Each CLA isomer markedly increased glucose-stimulated insulin secretion in insulin-producing INS-1E cells that endogenously express FFA1 and in primary pancreatic β-cells of wild type but not FFA1(-/-) knock-out mice. Our findings establish a clear mechanistic link between CLAs and insulin production and identify the cell surface receptor FFA1 as a molecular target for CLAs, explaining their acute stimulatory effects on insulin secretion in vivo. CLAs are also revealed as insulinotropic components in widely used nutraceuticals, a finding with significant implication for development of FFA1 modulators to treat type 2 diabetes.

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DO - 10.1074/jbc.c110.200477

M3 - Journal article

SN - 0021-9258

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JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 14

ER -

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

Abstract

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