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Interaction between Hormone-Sensitive Lipase and ChREBP in Fat Cells Controls Insulin Sensitivity

Pauline Morigny 1 Marianne Houssier 1 Aline Mairal 1 Claire Ghilain 1 Etienne Mouisel 1 Fadila Benhamed 2 Bernard Masri 1 Emeline Recazens 1 Pierre-Damien Denechaud 1 Geneviève Tavernier 1 Sylvie Caspar-Bauguil 1, 3 Sam Virtue 4 Veronika Sramkova 1, 5, 6 Laurent Monbrun 1 Anne Mazars 1 Madjid Zanoun 1 Sandra Guilmeau 2 Valentin Barquissau 1 Diane Beuzelin 1 Sophie Bonnel 1, 6 Marie Marques 1, 6 Boris Monge-Roffarello 1 Corinne Lefort 1 Barbara Fielding 7 Thierry Sulpice 8 Arne Astrup 9 Bernard Payrastre 1 Justine Bertrand-Michel 1 Emmanuelle Meugnier 10 Laetitia Ligat 11 Frédéric Lopez 11 Hervé Guillou 12 Charlotte Ling 13 Cecilia Holm 14 Remi Rabasa-Lhoret 15 Rémi Rabasa-Lhoret 15, 16, 17 Wim H. M. Saris 18 Vladimir Stich 5, 6 Peter Arner 19 Mikael Rydén 19 Cédric Moro 1, 6 Nathalie Viguerie 1, 6 Matthew Harms 20 Stefan Hallén 20 Antonio Vidal-Puig 4, 21 Hubert Vidal 10 Catherine Postic 2 Dominique Langin 1, 3, 6, * 
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
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Submitted on : Friday, June 7, 2019 - 10:40:37 AM
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Pauline Morigny, Marianne Houssier, Aline Mairal, Claire Ghilain, Etienne Mouisel, et al.. Interaction between Hormone-Sensitive Lipase and ChREBP in Fat Cells Controls Insulin Sensitivity. Nature Metabolism, Nature Publishing Group, 2019, 1 (1), pp.133-146. ⟨10.1038/s42255-018-0007-6⟩. ⟨inserm-02150261⟩



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