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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.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Issandou M,Bouillot A,Brusq JM,Forest MC,Grillot D,Guillard R,Martin S,Michiels C,Sulpice T,Daugan A

doi

10.1016/j.ejphar.2009.07.004

subject

Has Abstract

pub_date

2009-09-15 00:00:00

pages

28-36

issue

1-3

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(09)00596-2

journal_volume

618

pub_type

杂志文章

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