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; Genevieve 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; Frederic Lopez; Herve Guillou; Charlotte Ling; Cecilia Holm; Remi Rabasa-Lhoret; Wim H. M. Saris; Vladimir Stich; Peter Arner; Mikael Ryden; Cedric Moro; Nathalie Viguerie; Matthew Harms; Stefan Hallen; Antonio Vidal-Puig; Hubert Vidal; Catherine Postic; Dominique Langin

doi:10.1038/s42255-018-0007-6

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, Genevieve 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, Frederic Lopez, Herve Guillou, Charlotte Ling, Cecilia Holm, Remi Rabasa-Lhoret, Wim H. M. Saris, Vladimir Stich, Peter Arner, Mikael Ryden, Cedric Moro, Nathalie Viguerie, Matthew Harms, Stefan Hallen, Antonio Vidal-Puig, Hubert Vidal, Catherine Postic, Dominique Langin^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 ChREBP alpha impairs ChREBP alpha translocation into the nucleus and induction of ChREBP beta, 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.

Original language	English
Pages (from-to)	133-146
Number of pages	14
Journal	Nature Metabolism
Volume	1
Issue number	1
DOIs	https://doi.org/10.1038/s42255-018-0007-6
Publication status	Published - Jan 2019

Keywords

ACID ELONGASE
DE-NOVO LIPOGENESIS
DNA METHYLATION
ELEMENT-BINDING PROTEIN
HUMAN ADIPOCYTE
HUMAN PREADIPOCYTES
MEDITERRANEAN DIET
OLEIC-ACID
STEAROYL-COA DESATURASE
SUBCUTANEOUS ADIPOSE-TISSUE

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10.1038/s42255-018-0007-6

Cite this

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://doi.org/10.1038/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 ChREBP alpha impairs ChREBP alpha translocation into the nucleus and induction of ChREBP beta, 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 = "ACID ELONGASE, DE-NOVO LIPOGENESIS, DNA METHYLATION, ELEMENT-BINDING PROTEIN, HUMAN ADIPOCYTE, HUMAN PREADIPOCYTES, MEDITERRANEAN DIET, OLEIC-ACID, STEAROYL-COA DESATURASE, SUBCUTANEOUS ADIPOSE-TISSUE",

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 Genevieve 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 Frederic Lopez and Herve Guillou and Charlotte Ling and Cecilia Holm and Remi Rabasa-Lhoret and Saris, {Wim H. M.} and Vladimir Stich and Peter Arner and Mikael Ryden and Cedric Moro and Nathalie Viguerie and Matthew Harms and Stefan Hallen and Antonio Vidal-Puig and Hubert Vidal and Catherine Postic and Dominique Langin",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

month = jan,

doi = "10.1038/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, 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, Ryden, M, Moro, C, Viguerie, N, Harms, M, Hallen, 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, vol. 1, no. 1, pp. 133-146. https://doi.org/10.1038/s42255-018-0007-6

TY - JOUR

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, Genevieve

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, Frederic

AU - Guillou, Herve

AU - Ling, Charlotte

AU - Holm, Cecilia

AU - Rabasa-Lhoret, Remi

AU - Saris, Wim H. M.

AU - Stich, Vladimir

AU - Arner, Peter

AU - Ryden, Mikael

AU - Moro, Cedric

AU - Viguerie, Nathalie

AU - Harms, Matthew

AU - Hallen, Stefan

AU - Vidal-Puig, Antonio

AU - Vidal, Hubert

AU - Postic, Catherine

AU - Langin, Dominique

PY - 2019/1

Y1 - 2019/1

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 ChREBP alpha impairs ChREBP alpha translocation into the nucleus and induction of ChREBP beta, 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 ChREBP alpha impairs ChREBP alpha translocation into the nucleus and induction of ChREBP beta, 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 - ACID ELONGASE

KW - DE-NOVO LIPOGENESIS

KW - DNA METHYLATION

KW - ELEMENT-BINDING PROTEIN

KW - HUMAN ADIPOCYTE

KW - HUMAN PREADIPOCYTES

KW - MEDITERRANEAN DIET

KW - OLEIC-ACID

KW - STEAROYL-COA DESATURASE

KW - SUBCUTANEOUS ADIPOSE-TISSUE

U2 - 10.1038/s42255-018-0007-6

DO - 10.1038/s42255-018-0007-6

M3 - Article

C2 - 32694809

VL - 1

SP - 133

EP - 146

JO - Nature Metabolism

JF - Nature Metabolism

IS - 1

ER -