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; Geneviève 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; Frédéric Lopez; Hervé Guillou; Charlotte Ling; Cecilia Holm; Remi Rabasa-Lhoret; Wim H M Saris; Vladimir Stich; Peter Arner; Mikael Rydén; Cedric Moro; Nathalie Viguerie; Matthew Harms; Stefan Hallén; 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

Nat Metab. 2019 Jan;1(1):133-146. doi: 10.1038/s42255-018-0007-6. Epub 2018 Dec 3.

Authors

Pauline Morigny^{1

2}, Marianne Houssier^{1

2}, Aline Mairal^{1

2}, Claire Ghilain^{1

2}, Etienne Mouisel^{1

2}, Fadila Benhamed^{3

4

5}, Bernard Masri^{1

2}, Emeline Recazens^{1

2}, Pierre-Damien Denechaud^{1

2}, Geneviève Tavernier^{1

2}, Sylvie Caspar-Bauguil^{1

2

6}, Sam Virtue⁷, Veronika Sramkova^{1

2

8

9}, Laurent Monbrun^{1

2}, Anne Mazars^{1

2}, Madjid Zanoun^{1

2}, Sandra Guilmeau^{3

4

5}, Valentin Barquissau^{1

2}, Diane Beuzelin^{1

2}, Sophie Bonnel^{1

2

9}, Marie Marques^{1

2

9}, Boris Monge-Roffarello^{1

2}, Corinne Lefort^{1

2}, Barbara Fielding¹⁰, Thierry Sulpice¹¹, Arne Astrup¹², Bernard Payrastre^{1

2}, Justine Bertrand-Michel^{1

2}, Emmanuelle Meugnier¹³, Laetitia Ligat¹⁴, Frédéric Lopez¹⁴, Hervé Guillou^{15

16}, Charlotte Ling¹⁷, Cecilia Holm¹⁸, Remi Rabasa-Lhoret^{19

20

21}, Wim H M Saris²², Vladimir Stich^{8

9}, Peter Arner²³, Mikael Rydén²³, Cedric Moro^{1

2

9}, Nathalie Viguerie^{1

2

9}, Matthew Harms²⁴, Stefan Hallén²⁴, Antonio Vidal-Puig^{7

25}, Hubert Vidal¹³, Catherine Postic^{3

4

5}, Dominique Langin^{26

27

28

29}

Affiliations

¹ Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
² University of Toulouse, UMR1048, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, Toulouse, France.
³ Institut National de la Santé et de la Recherche Médicale (Inserm), U1016, Institut Cochin, Paris, France.
⁴ Centre National de la Recherche Scientifique (CNRS), UMR 8104, Paris, France.
⁵ Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
⁶ Toulouse University Hospitals, Laboratory of Clinical Biochemistry, Toulouse, France.
⁷ University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
⁸ Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
⁹ Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague and Paul Sabatier University, Toulouse, France.
¹⁰ Department of Nutritional Sciences, University of Surrey, Guildford, Surrey, UK.
¹¹ Physiogenex SAS, Prologue Biotech, Labège, France.
¹² Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
¹³ CarMeN Laboratory, Inserm U1060, INRA U1397, Université Lyon 1, INSA Lyon, Oullins, France.
¹⁴ Pôle Technologique, Cancer Research Center of Toulouse (CRCT), Plateau Interactions Moléculaires, INSERM-UMR1037, Toulouse, France.
¹⁵ Institut National de la Recherche Agronomique (INRA), UMR1331, Integrative Toxicology and Metabolism, Toulouse, France.
¹⁶ University of Toulouse, UMR1331, Institut National Polytechnique (INP), Paul Sabatier University, Toulouse, France.
¹⁷ Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden.
¹⁸ Department of Experimental Medical Science, Lund University, Biomedical Centre, Lund, Sweden.
¹⁹ Institut de Recherches Cliniques de Montréal, Montreal, Canada.
²⁰ Department of nutrition, Université de Montréal, Montreal, Canada.
²¹ Montreal Diabetes Research Center (MDRC), Montreal, Canada.
²² Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands.
²³ Department of Medicine, H7, Karolinska Institutet and Karolinska University Hospital, Huddinge, Stockholm, Sweden.
²⁴ Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
²⁵ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK.
²⁶ Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France. [email protected].
²⁷ University of Toulouse, UMR1048, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, Toulouse, France. [email protected].
²⁸ Toulouse University Hospitals, Laboratory of Clinical Biochemistry, Toulouse, France. [email protected].
²⁹ Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague and Paul Sabatier University, Toulouse, France. [email protected].

PMID: 32694809
DOI: 10.1038/s42255-018-0007-6

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.

Keywords: ChREBP; ELOVL Fatty Acid Elongase 6; ELOVL6 Expression; Hormone-sensitive Lipase; Insulin Signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes / metabolism*
Adipose Tissue / metabolism
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
Biomarkers
Fatty Acid Elongases / genetics
Fatty Acid Elongases / metabolism
Gene Expression
Glucose / metabolism
Insulin / metabolism*
Insulin Resistance* / genetics
Membrane Fluidity / genetics
Mice
Mice, Transgenic
Protein Interaction Mapping
Protein Interaction Maps
Signal Transduction
Sterol Esterase / metabolism*

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Biomarkers
Elovl6 protein, mouse
Insulin
Mlxipl protein, mouse
Fatty Acid Elongases
Sterol Esterase
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding