Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

The prevalences of insulin resistance and type 2 diabetes mellitus are rising dramatically, and, as a consequence, there is an urgent need to understand the pathogenesis underpinning these conditions to develop new and more efficacious treatments. We have tested the hypothesis that glucocorticoid (GC)-mediated changes in insulin sensitivity may be associated with changes in lipid flux. Furthermore, prereceptor modulation of GC availability by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may represent a critical regulatory step. Dexamethasone (DEX) decreased lipogenesis in both murine C2C12 and human LHC-NM2 myotubes. Inactivating p-Ser-79/218 of acetyl-CoA carboxylase 1/2 and activating p-Thr-172 of AMP-activated protein kinase were both increased after DEX treatment in C2C12 myotubes. In contrast, DEX increased β-oxidation. Selective 11β-HSD1 inhibition blocked the 11-dehydrocorticosterone (11DHC)-mediated decrease in lipogenic gene expression and increase in lipolytic gene expression. Lipogenic gene expression was decreased, whereas lipolytic and β-oxidative gene expression increased in corticosterone (CORT)- and 11DHC-treated wild-type mice and CORT (but not 11DHC)-treated 11β-HSD1(-/-) mice. Furthermore, CORT- and 11DHC-treated wild-type mice and CORT (but not 11DHC)-treated 11β-HSD1(-/-) mice had increased p-Ser-79/218 acetyl-CoA carboxylase 1/2, p-Thr-172 AMP-activated protein kinase and intramyocellular diacylglyceride content. In summary, we have shown that GCs have potent actions on intramyocellular lipid homeostasis by decreasing lipid storage, increasing lipid mobilization and utilization, and increasing diacylglyceride content. It is plausible that dysregulated intramyocellular lipid metabolism may underpin GC-induced insulin resistance of skeletal muscle.

Original publication

DOI

10.1210/en.2012-2214

Type

Journal article

Journal

Endocrinology

Publication Date

07/2013

Volume

154

Pages

2374 - 2384

Keywords

11-beta-Hydroxysteroid Dehydrogenase Type 1, Acetyl-CoA Carboxylase, Animals, Cell Line, Dexamethasone, Glucocorticoids, Humans, Lipid Metabolism, Lipogenesis, Mice, Mice, Knockout, Muscle Fibers, Skeletal, Muscle, Skeletal