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.

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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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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.

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Correspondence to Dominique Langin.

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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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Keywords

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

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