Pharmacological inhibition of stearoyl-CoA desaturase 1 improves insulin sensitivity in insulin-resistant rat models.
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.
Issandou
Marc
M
GlaxoSmithKline, Les Ulis Cedex, France. marc.issandou@GSK.com
Bouillot
Anne
A
Brusq
Jean-Marie
JM
Forest
Marie-Claire
MC
Grillot
Didier
D
Guillard
Raphaelle
R
Martin
Sandrine
S
Michiels
Christelle
C
Sulpice
Thierry
T
Daugan
Alain
A
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*
D004791:Enzyme Inhibitors; C546024:GSK 993; D007328:Insulin; D007546:Isoquinolines; D011720:Pyrazoles; D013230:Stearoyl-CoA Desaturase; D005947:Glucose