Projects per year
Abstract
The prevalence 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-mediated changes in insulin sensitivity may be associated with changes in lipid flux. Furthermore, pre-receptor modulation of glucocorticoid availability by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may represent a critical regulatory step.Dexamethasone decreased lipogenesis in both murine C2C12 and human LHC-NM2 myotubes. Inactivating p-Ser-79/218 of acetyl-CoA carboxylase 1/2 (ACC1/2) and activating p-Thr-172 of AMP-activated protein kinase (AMPK) were both increased following dexamethasone treatment in C2C12 myotubes. By contrast, dexamethasone increased β-oxidation. Selective 11β-HSD1 inhibition blocked the 11-dehydrocorticosterone (11DHC)-mediated decrease in lipogenic, and increase in lipolytic gene expression. Lipogenic gene expression was decreased, whilst lipolytic and β-oxidative genes 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 ACC1/2, p-Thr-172 AMPK and intramyocellular diacylglyderide content.In summary, we have shown that glucocorticoids have potent actions upon intramyocellular lipid homeostasis by decreasing lipid storage, increasing lipid mobilisation and utilisation and increasing diacylglyderide content. It is plausible that dysregulated intramyocellular lipid metabolism may underpin GC-induced insulin resistance of skeletal muscle.
Original language | English |
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Pages (from-to) | 2374-2384 |
Number of pages | 11 |
Journal | Endocrinology |
Volume | 154 |
Issue number | 7 |
DOIs | |
Publication status | Published - 30 Apr 2013 |
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Dive into the research topics of 'Regulation of Lipid Metabolism by Glucocorticoids and 11β-HSD1 in Skeletal Muscle'. Together they form a unique fingerprint.Projects
- 3 Finished
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Centre for Musculoskeletal Ageing Research (linked to 18289 & 19482)
Lord, J., Buckley, C., Duda, J., Dunn, W., Miall, C. & Greig, C.
1/08/12 → 31/07/17
Project: Research Councils
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Glucocorticoid Metabolism and the Control of Metabolic Phenotype
Tomlinson, J.
1/10/09 → 30/09/14
Project: Research Councils
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Investigating Hexose-6-Phosphate Dehydrogenase in the Control of Skeletal Muscle Function and Carbohydrate Metabolism
Lavery, G.
Biotechnology & Biological Sciences Research Council
1/09/09 → 31/08/14
Project: Research Councils