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 journalArticleAcademicpeer-review

28 Citations (Web of Science)

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 languageEnglish
Pages (from-to)133-146
Number of pages14
JournalNature Metabolism
Volume1
Issue number1
DOIs
Publication statusPublished - Jan 2019

Keywords

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

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