Physical contact between HSL and ChREBP in human adipose cells. Each red dot represents an interaction between the two proteins. The cell nucleus is stained in blue. (Credit: I2MC).
Restoring the action of insulin is one of the keys to fighting type 2 diabetes. Researchers from Inserm led by Dominique Langin at the Institute of Cardiovascular and Metabolic Diseases (Inserm/Université de Toulouse) are developing a therapeutic strategy that uses the properties of an enzyme (hormone-sensitive lipase) which, when stimulating fatty-acid synthesis in the fat cells, has a beneficial effect on insulin action. This research has been published in Nature Metabolism.
Diabetes is a disease in which blood sugar levels are high over a prolonged period (hyperglycemia). In the case of type 2 diabetes, this phenomenon which is caused by a disruption of the glucose metabolism develops progressively and insidiously. In France, the prevalence of diabetes is estimated at over 5 % of the 2015 population, with type 2 accounting for 90 % of cases. These figures do not include those who are unaware of their condition, particularly among the overweight or obese.
Hormone-sensitive lipase (HSL) is an enzyme which converts fats into fatty acids and releases them into the bloodstream. In obese patients, these fatty acids trigger the gradual insulin resistance at the origin of type 2 diabetes. Previous research by the Inserm team of Dominique Langin had shown that a decrease in HSL expression in the adipocytes led to a better response to insulin, a sign of good health for these cells.
Surprisingly, the researchers observed that the beneficial effect of a reduction in HSL was not actually due to the reduced release of fatty acid. It was explained by the increased synthesis of oleic acid, the principal fatty acid component of olive oil.
This initial observation gave a glimpse of an interesting avenue for treating obese patients who are at greater risk of developing type 2 diabetes.To envisage a therapeutic strategy, it therefore had to be elucidated how reducing HSL exerted this beneficial effect on the action of insulin. The group of Prof. Langin discovered the existence of a physical interaction between HSL and a transcription factor responsible for the synthesis of fatty acids, ChREBP. HSL, when binding to ChREBP, blocks its activity. As such, a decrease in HSL leads to the release of this factor in the nucleus, promoting its activity, oleic acid synthesis and sensitivity to insulin.
Preliminary results indicate that a known inhibitor of HSL blocks the interaction with ChREBP. These data therefore pave the way for the development of molecules which target this interaction. In collaboration with global biopharmaceutical company AstraZeneca, the researchers in Toulouse are currently testing different approaches to block the interaction between HSL and ChREBP. Ultimately this project could lead to the development of new drugs to treat the increasing global epidemic of type 2 diabetes.
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Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity Pauline Morigny1,2,26, Marianne Houssier1,2,26, Aline Mairal1,2, Claire Ghilain1,2, Etienne Mouisel1,2, Fadila Benhamed3,4,5, Bernard Masri 1,2, Emeline Recazens1,2, Pierre-Damien Denechaud 1,2, Geneviève Tavernier1,2, Sylvie Caspar-Bauguil 1,2,6, Sam Virtue7, Veronika Sramkova 1,2,8,9, Laurent Monbrun1,2, Anne Mazars1,2, Madjid Zanoun1,2, Sandra Guilmeau3,4,5, Valentin Barquissau1,2, Diane Beuzelin 1,2, Sophie Bonnel1,2,9, Marie Marques1,2,9, Boris Monge-Roffarello1,2, Corinne Lefort1,2, Barbara Fielding10, Thierry Sulpice11, Arne Astrup12, Bernard Payrastre 1,2, Justine Bertrand-Michel1,2, Emmanuelle Meugnier13, Laetitia Ligat14, Frédéric Lopez14, Hervé Guillou15,16, Charlotte Ling17, Cecilia Holm18, Remi Rabasa-Lhoret19,20,21, Wim H. M. Saris22, Vladimir Stich8,9, Peter Arner23, Mikael Rydén 23, Cedric Moro1,2,9, Nathalie Viguerie 1,2,9, Matthew Harms24, Stefan Hallén24, Antonio Vidal-Puig7,25, Hubert Vidal13, Catherine Postic3,4,5 and Dominique Langin 1,2,6,9* 1Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France. 2University of Toulouse, UMR1048, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, Toulouse, France. 3Institut National de la Santé et de la Recherche Médicale (Inserm), U1016, Institut Cochin, Paris, France. 4Centre National de la Recherche Scientifique (CNRS), UMR 8104, Paris, France. 5Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 6Toulouse University Hospitals, Laboratory of Clinical Biochemistry, Toulouse,France. 7University 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-CzechLaboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague and Paul Sabatier University, Toulouse, France. 10 Department of NutritionalSciences, University of Surrey, Guildford, Surrey, UK. 11Physiogenex SAS, Prologue Biotech, Labège, France. 12Department of Nutrition, Exercise and Sports,Faculty of Science, University of Copenhagen, Copenhagen, Denmark. 13CarMeN Laboratory, Inserm U1060, INRA U1397, Université Lyon 1, INSA Lyon,Oullins, France. 14Pôle Technologique, Cancer Research Center of Toulouse (CRCT), Plateau Interactions Moléculaires, INSERM-UMR1037, Toulouse,France. 15Institut National de la Recherche Agronomique (INRA), UMR1331, Integrative Toxicology and Metabolism, Toulouse, France. 16University of Toulouse, UMR1331, Institut National Polytechnique (INP), Paul Sabatier University, Toulouse, France. 17Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden. 18Department of Experimental Medical Science, Lund University, Biomedical Centre, Lund, Sweden. 19Institut de Recherches Cliniques de Montréal, Montreal, Canada. 20Department of nutrition, Université de Montréal, Montreal, Canada. 21Montreal Diabetes Research Center (MDRC), Montreal, Canada. 22Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, Netherlands. 23Department of Medicine, H7 Karolinska Institutet and Karolinska University Hospital, Huddinge, Stockholm, Sweden. 24Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden. 25Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK. 26These authors contributed equally: P.Morigny, M. Houssier. Nature Metabolism https://doi.org/10.1038/s42255-018-0007-6