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.

Cardiovascular Renal and Metabolism IMED Biotech Unit AstraZeneca Gothenburg Sweden

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

Centre National de la Recherche Scientifique UMR 8104 Paris France

Department for the Study of Obesity and Diabetes 3rd Faculty of Medicine Charles University Prague Czech Republic

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

Department of Experimental Medical Science Lund University Biomedical Centre Lund Sweden

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

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

Department of Nutrition Exercise and Sports Faculty of Science University of Copenhagen Copenhagen Denmark

Department of nutrition Université de Montréal Montreal Canada

Department of Nutritional Sciences University of Surrey Guildford Surrey UK

Franco Czech Laboratory for Clinical Research on Obesity 3rd Faculty of Medicine Prague and Paul Sabatier University Toulouse France

Institut de Recherches Cliniques de Montréal Montreal Canada

Institut National de la Recherche Agronomique UMR1331 Integrative Toxicology and Metabolism Toulouse France

Institut National de la Santé et de la Recherche Médicale U1016 Institut Cochin Paris France

Institut National de la Santé et de la Recherche Médicale UMR1048 Institute of Metabolic and Cardiovascular Diseases Toulouse France

Montreal Diabetes Research Center Montreal Canada

Physiogenex SAS Prologue Biotech Labège France

Pôle Technologique Cancer Research Center of Toulouse Plateau Interactions Moléculaires INSERM UMR1037 Toulouse France

Toulouse University Hospitals Laboratory of Clinical Biochemistry Toulouse France

Université Paris Descartes Sorbonne Paris Cité Paris France

University of Cambridge Metabolic Research Laboratories Wellcome Trust MRC Institute of Metabolic Science Addenbrooke's Hospital Cambridge UK

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

University of Toulouse UMR1331 Institut National Polytechnique Paul Sabatier University Toulouse France

Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Hinxton Cambridgeshire UK

Citace poskytuje Crossref.org

Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics