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

Nature Metabolism volume 1, pages 133–146 (2019)Cite this article

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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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Fig. 1: Reduced HSL expression promotes glucose metabolism and insulin signalling in human adipocytes.
Fig. 2: HSL inhibition is associated with increased insulin sensitivity and adipose tissue ELOVL6 expression in vivo.
Fig. 3: ELOVL6 has a positive effect on insulin signalling in adipocytes.
Fig. 4: Oleic acid content in phospholipids and plasma membrane fluidity mediates the ELOVL6 positive effect on insulin signalling.
Fig. 5: The glucose-sensitive transcription factor ChREBP mediates the beneficial effect of diminished HSL expression on glucose metabolism and insulin signalling in adipocytes.
Fig. 6: HSL inhibits ChREBP activity through protein-protein interaction.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors acknowledge N. Venteclef (Centre de Recherche des Cordeliers, Paris) and J. Boucher (AstraZeneca, Göteborg, Sweden) for critical reading and comments on the manuscript. E. Courty and J. Personnaz participated in mouse studies during internship at I2MC. The GenoToul Animal Care, Anexplo, Imaging-TRI (especially F. Gaits-Iacovoni for helpful discussion) and Quantitative Transcriptomics facilities contributed to the work. This work was supported by Inserm, Paul Sabatier University, Fondation pour la Recherche Médicale (DEQ20170336720 to D.L.), Agence Nationale de la Recherche (ANR-12-BSV1-0025Obelip and ANR-17-CE14-0015Hepadialogue to D.L.), Région Midi-Pyrénées (OBELIP and ILIP projects to D.L.), FORCE/F-CRIN for clinical research on obesity, EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant 115372 to P.A., A.V.P. and D.L.) and AstraZeneca France (TALIP project to D.L.). D.L. is a member of Institut Universitaire de France.

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Author notes

  1. These authors contributed equally: P. Morigny, M. Houssier.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France

    Pauline Morigny, Marianne Houssier, Aline Mairal, Claire Ghilain, Etienne Mouisel, Bernard Masri, Emeline Recazens, Pierre-Damien Denechaud, Geneviève Tavernier, Sylvie Caspar-Bauguil, Veronika Sramkova, Laurent Monbrun, Anne Mazars, Madjid Zanoun, Valentin Barquissau, Diane Beuzelin, Sophie Bonnel, Marie Marques, Boris Monge-Roffarello, Corinne Lefort, Bernard Payrastre, Justine Bertrand-Michel, Cedric Moro, Nathalie Viguerie & Dominique Langin

  2. University of Toulouse, UMR1048, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, Toulouse, France

    Pauline Morigny, Marianne Houssier, Aline Mairal, Claire Ghilain, Etienne Mouisel, Bernard Masri, Emeline Recazens, Pierre-Damien Denechaud, Geneviève Tavernier, Sylvie Caspar-Bauguil, Veronika Sramkova, Laurent Monbrun, Anne Mazars, Madjid Zanoun, Valentin Barquissau, Diane Beuzelin, Sophie Bonnel, Marie Marques, Boris Monge-Roffarello, Corinne Lefort, Bernard Payrastre, Justine Bertrand-Michel, Cedric Moro, Nathalie Viguerie & Dominique Langin

  3. Institut National de la Santé et de la Recherche Médicale (Inserm), U1016, Institut Cochin, Paris, France

    Fadila Benhamed, Sandra Guilmeau & Catherine Postic

  4. Centre National de la Recherche Scientifique (CNRS), UMR 8104, Paris, France

    Fadila Benhamed, Sandra Guilmeau & Catherine Postic

  5. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Fadila Benhamed, Sandra Guilmeau & Catherine Postic

  6. Toulouse University Hospitals, Laboratory of Clinical Biochemistry, Toulouse, France

    Sylvie Caspar-Bauguil & Dominique Langin

  7. University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke′s Hospital, Cambridge, UK

    Sam Virtue & Antonio Vidal-Puig

  8. Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czech Republic

    Veronika Sramkova & Vladimir Stich

  9. Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague and Paul Sabatier University, Toulouse, France

    Veronika Sramkova, Sophie Bonnel, Marie Marques, Vladimir Stich, Cedric Moro, Nathalie Viguerie & Dominique Langin

  10. Department of Nutritional Sciences, University of Surrey, Guildford, Surrey, UK

    Barbara Fielding

  11. Physiogenex SAS, Prologue Biotech, Labège, France

    Thierry Sulpice

  12. Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark

    Arne Astrup

  13. CarMeN Laboratory, Inserm U1060, INRA U1397, Université Lyon 1, INSA Lyon, Oullins, France

    Emmanuelle Meugnier & Hubert Vidal

  14. Pôle Technologique, Cancer Research Center of Toulouse (CRCT), Plateau Interactions Moléculaires, INSERM-UMR1037, Toulouse, France

    Laetitia Ligat & Frédéric Lopez

  15. Institut National de la Recherche Agronomique (INRA), UMR1331, Integrative Toxicology and Metabolism, Toulouse, France

    Hervé Guillou

  16. University of Toulouse, UMR1331, Institut National Polytechnique (INP), Paul Sabatier University, Toulouse, France

    Hervé Guillou

  17. Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden

    Charlotte Ling

  18. Department of Experimental Medical Science, Lund University, Biomedical Centre, Lund, Sweden

    Cecilia Holm

  19. Institut de Recherches Cliniques de Montréal, Montreal, Canada

    Remi Rabasa-Lhoret

  20. Department of nutrition, Université de Montréal, Montreal, Canada

    Remi Rabasa-Lhoret

  21. Montreal Diabetes Research Center (MDRC), Montreal, Canada

    Remi Rabasa-Lhoret

  22. Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands

    Wim H. M. Saris

  23. Department of Medicine, H7, Karolinska Institutet and Karolinska University Hospital, Huddinge, Stockholm, Sweden

    Peter Arner & Mikael Rydén

  24. Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden

    Matthew Harms & Stefan Hallén

  25. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK

    Antonio Vidal-Puig

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  1. Pauline Morigny
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  47. Dominique Langin
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Contributions

P.M. and M. Houssier performed the majority of in vitro experiments and analyzed data with the contribution of A. Mairal, C.G., F.B., B.M., E.R., P.D.D., V. Sramkova, V.B., D.B., M.M., C.L., L.L., F.L. and M. Harms. P.M., M. Houssier, E. Mouisel, G.T., S.V., L.M., S.G., B.M.-R., T.S., H.G., C.H., A.V.P. and C.P. performed and analyzed in vivo data from mouse models. P.M., S.B., M.M., B.F., A.A., E. Meugnier, C.L., R.R.L., W.S., V. Stich, P.A., M.R., N.V. and H.V. performed and analyzed in vivo data in human clinical studies. S.C.-B., S.V. and J.B.-M. analyzed lipidomics data. A. Mazars and M.Z. performed and analyzed FRAP experiments. B.P., C.M., N.V., S.H. and H.V. interpreted the data. P.M., M. Houssier and D.L. conceived the study, interpreted the data and wrote the manuscript. D.L. supervised the study.

Corresponding author

Correspondence to Dominique Langin.

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Competing interests

T.S. is an employee of Physiogenex. M. Harms and S.H. are employees of AstraZeneca. The other authors declare no competing financial and non-financial interests.

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Morigny, P., Houssier, M., Mairal, A. et al. Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity. Nat Metab 1, 133–146 (2019). https://doi.org/10.1038/s42255-018-0007-6

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  • DOI: https://doi.org/10.1038/s42255-018-0007-6

Keywords

  • ChREBP
  • Hormone-sensitive Lipase
  • ELOVL Fatty Acid Elongase 6
  • Insulin Signaling
  • ELOVL6 Expression

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