Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity

Pauline Morigny; Marianne Houssier; Aline Mairal; Claire Ghilain; Etienne Mouisel; Fadila Benhamed; Bernard Masri; Emeline Recazens; Pierre-Damien Denechaud; Geneviève Tavernier; Sylvie Caspar-Bauguil; Sam Virtue; Veronika Sramkova; Laurent Monbrun; Anne Mazars; Madjid Zanoun; Sandra Guilmeau; Valentin Barquissau; Diane Beuzelin; Sophie Bonnel; Marie Marques; Boris Monge-Roffarello; Corinne Lefort; Barbara Fielding; Thierry Sulpice; Arne Astrup; Bernard Payrastre; Justine Bertrand-Michel; Emmanuelle Meugnier; Laetitia Ligat; Frédéric Lopez; Hervé Guillou; Charlotte Ling; Cecilia Holm; Remi Rabasa-Lhoret; Wim H M Saris; Vladimir Stich; Peter Arner; Mikael Rydén; Cedric Moro; Nathalie Viguerie; Matthew Harms; Stefan Hallén; Antonio Vidal-Puig; Hubert Vidal; Catherine Postic; Dominique Langin

Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity

Pauline Morigny, Marianne Houssier, Aline Mairal, Claire Ghilain, Etienne Mouisel, Fadila Benhamed, Bernard Masri, Emeline Recazens, Pierre-Damien Denechaud, Geneviève Tavernier, Sylvie Caspar-Bauguil, Sam Virtue, Veronika Sramkova, Laurent Monbrun, Anne Mazars, Madjid Zanoun, Sandra Guilmeau, Valentin Barquissau, Diane Beuzelin, Sophie BonnelMarie Marques, Boris Monge-Roffarello, Corinne Lefort, Barbara Fielding, Thierry Sulpice, Arne Astrup, Bernard Payrastre, Justine Bertrand-Michel, Emmanuelle Meugnier, Laetitia Ligat, Frédéric Lopez, Hervé Guillou, Charlotte Ling, Cecilia Holm, Remi Rabasa-Lhoret, Wim H M Saris, Vladimir Stich, Peter Arner, Mikael Rydén, Cedric Moro, Nathalie Viguerie, Matthew Harms, Stefan Hallén, Antonio Vidal-Puig, Hubert Vidal, Catherine Postic, Dominique Langin

Institut for Idræt og Ernæring - Fedmeforskning

16 Citationer (Scopus)

Abstract

Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency–mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL–ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.

Originalsprog	Engelsk
Tidsskrift	Nature Metabolism
Vol/bind	1
Udgave nummer	1
Sider (fra-til)	133-146
Antal sider	14
ISSN	2522-5812
Status	Udgivet - 1 jan. 2019

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https://www.nature.com/articles/s42255-018-0007-6

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Morigny, P., Houssier, M., Mairal, A., Ghilain, C., Mouisel, E., Benhamed, F., Masri, B., Recazens, E., Denechaud, P-D., Tavernier, G., Caspar-Bauguil, S., Virtue, S., Sramkova, V., Monbrun, L., Mazars, A., Zanoun, M., Guilmeau, S., Barquissau, V., Beuzelin, D., ... Langin, D. (2019). Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity. Nature Metabolism, 1(1), 133-146. https://www.nature.com/articles/s42255-018-0007-6

Morigny, P, Houssier, M, Mairal, A, Ghilain, C, Mouisel, E, Benhamed, F, Masri, B, Recazens, E, Denechaud, P-D, Tavernier, G, Caspar-Bauguil, S, Virtue, S, Sramkova, V, Monbrun, L, Mazars, A, Zanoun, M, Guilmeau, S, Barquissau, V, Beuzelin, D, Bonnel, S, Marques, M, Monge-Roffarello, B, Lefort, C, Fielding, B, Sulpice, T, Astrup, A, Payrastre, B, Bertrand-Michel, J, Meugnier, E, Ligat, L, Lopez, F, Guillou, H, Ling, C, Holm, C, Rabasa-Lhoret, R, Saris, WHM, Stich, V, Arner, P, Rydén, M, Moro, C, Viguerie, N, Harms, M, Hallén, S, Vidal-Puig, A, Vidal, H, Postic, C & Langin, D 2019, 'Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity', Nature Metabolism, bind 1, nr. 1, s. 133-146. <https://www.nature.com/articles/s42255-018-0007-6>

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title = "Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity",

abstract = "Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency–mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL–ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.",

keywords = "Faculty of Science, Insulin resistance, Hormone-sensitive lipase, HSL, Glucose-responsive transcription factor, ChREBP, Fatty acid elongase, ELOVL6, HSL-ChREBP interaction, Therapeutic strategies, Insulin sensitivity",

author = "Pauline Morigny and Marianne Houssier and Aline Mairal and Claire Ghilain and Etienne Mouisel and Fadila Benhamed and Bernard Masri and Emeline Recazens and Pierre-Damien Denechaud and Genevi{\`e}ve Tavernier and Sylvie Caspar-Bauguil and Sam Virtue and Veronika Sramkova and Laurent Monbrun and Anne Mazars and Madjid Zanoun and Sandra Guilmeau and Valentin Barquissau and Diane Beuzelin and Sophie Bonnel and Marie Marques and Boris Monge-Roffarello and Corinne Lefort and Barbara Fielding and Thierry Sulpice and Arne Astrup and Bernard Payrastre and Justine Bertrand-Michel and Emmanuelle Meugnier and Laetitia Ligat and Fr{\'e}d{\'e}ric Lopez and Herv{\'e} Guillou and Charlotte Ling and Cecilia Holm and Remi Rabasa-Lhoret and Saris, {Wim H M} and Vladimir Stich and Peter Arner and Mikael Ryd{\'e}n and Cedric Moro and Nathalie Viguerie and Matthew Harms and Stefan Hall{\'e}n and Antonio Vidal-Puig and Hubert Vidal and Catherine Postic and Dominique Langin",

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T1 - Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity

AU - Morigny, Pauline

AU - Houssier, Marianne

AU - Mairal, Aline

AU - Ghilain, Claire

AU - Mouisel, Etienne

AU - Benhamed, Fadila

AU - Masri, Bernard

AU - Recazens, Emeline

AU - Denechaud, Pierre-Damien

AU - Tavernier, Geneviève

AU - Caspar-Bauguil, Sylvie

AU - Virtue, Sam

AU - Sramkova, Veronika

AU - Monbrun, Laurent

AU - Mazars, Anne

AU - Zanoun, Madjid

AU - Guilmeau, Sandra

AU - Barquissau, Valentin

AU - Beuzelin, Diane

AU - Bonnel, Sophie

AU - Marques, Marie

AU - Monge-Roffarello, Boris

AU - Lefort, Corinne

AU - Fielding, Barbara

AU - Sulpice, Thierry

AU - Astrup, Arne

AU - Payrastre, Bernard

AU - Bertrand-Michel, Justine

AU - Meugnier, Emmanuelle

AU - Ligat, Laetitia

AU - Lopez, Frédéric

AU - Guillou, Hervé

AU - Ling, Charlotte

AU - Holm, Cecilia

AU - Rabasa-Lhoret, Remi

AU - Saris, Wim H M

AU - Stich, Vladimir

AU - Arner, Peter

AU - Rydén, Mikael

AU - Moro, Cedric

AU - Viguerie, Nathalie

AU - Harms, Matthew

AU - Hallén, Stefan

AU - Vidal-Puig, Antonio

AU - Vidal, Hubert

AU - Postic, Catherine

AU - Langin, Dominique

N1 - CURIS 2019 NEXS 013

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency–mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL–ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.

AB - Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency–mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL–ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.

KW - Faculty of Science

KW - Insulin resistance

KW - Hormone-sensitive lipase

KW - HSL

KW - Glucose-responsive transcription factor

KW - ChREBP

KW - Fatty acid elongase

KW - ELOVL6

KW - HSL-ChREBP interaction

KW - Therapeutic strategies

KW - Insulin sensitivity

M3 - Journal article

SN - 2522-5812

VL - 1

SP - 133

EP - 146

JO - Nature Metabolism

JF - Nature Metabolism

IS - 1

ER -

Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity

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