title: Pharmacological inhibition of stearoyl-CoA desaturase 1 improves insulin sensitivity in insulin-resistant rat models.
abstract: Stearoyl-CoA Desaturase 1 (SCD1) is a central enzyme that catalyzes the biosynthesis of monounsaturated fatty acids from saturated fatty acids. SCD1 is an emerging target in obesity and insulin resistance due to the improved metabolic profile obtained when the enzyme is genetically inactivated. Here, we have investigated if the pharmacological inhibition of SCD1 could elicit the same profile. We have identified a small molecule, GSK993 and characterized it as a potent and orally available SCD1 inhibitor. In Zucker(fa/fa) rats, GSK993 exerted a marked reduction in hepatic lipids as well as a significant improvement of glucose tolerance. Furthermore, in a diet-induced insulin resistant rat model, GSK993 induced a very strong reduction in Triton-induced hepatic Very Low Density Lipoprotein-Triglyceride production. In addition, following a hyperinsulinemic-euglycemic clamp in GSK993-treated animals, we observed an improvement in the whole body insulin sensitivity as reflected by an increase in the glucose infusion rate. Taken together, these findings demonstrate that the pharmacological inhibition of SCD1 translates into improved lipid and glucose metabolic profiles and raises the interest of SCD1 inhibitors as potential new drugs for the treatment of insulin resistance.
authors.affiliation: GlaxoSmithKline, Les Ulis Cedex, France. marc.issandou@GSK.com
authors.forename: Marc
authors.initials: M
authors.lastname: Issandou
authors.forename: Anne
authors.initials: A
authors.lastname: Bouillot
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Brusq
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Forest
authors.forename: Didier
authors.initials: D
authors.lastname: Grillot
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Guillard
authors.forename: Sandrine
authors.initials: S
authors.lastname: Martin
authors.forename: Christelle
authors.initials: C
authors.lastname: Michiels
authors.forename: Thierry
authors.initials: T
authors.lastname: Sulpice
authors.forename: Alain
authors.initials: A
authors.lastname: Daugan
mesh_terms: D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D007546:Isoquinolines / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C546024:GSK 993; D007328:Insulin; D007546:Isoquinolines; D011720:Pyrazoles; D013230:Stearoyl-CoA Desaturase; D005947:Glucose