Regulation of Lipid Metabolism by Glucocorticoids and 11β-HSD1 in Skeletal Muscle

被引:22
作者
Morgan, Stuart A. [1 ]
Gathercole, Laura L. [1 ]
Simonet, Claire [1 ]
Hassan-Smith, Zaki K. [1 ]
Bujalska, Iwona [1 ]
Guest, Phil [1 ]
Abrahams, Lianne [1 ]
Smith, Dave M. [2 ]
Stewart, Paul M. [1 ]
Lavery, Gareth G. [1 ]
Tomlinson, Jeremy W. [1 ]
机构
[1] Univ Birmingham, Ctr Endocrinol Diabet & Metab, Sch Clin & Expt Med, Inst Biomed Res, Birmingham B15 2TT, W Midlands, England
[2] AstraZeneca, Diabet & Obes Drug Discovery, Macclesfield SK10 4TF, Cheshire, England
基金
英国惠康基金; 英国医学研究理事会; 英国生物技术与生命科学研究理事会;
关键词
FATTY-ACID OXIDATION; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; INSULIN-RESISTANCE; ADIPOSE-TISSUE; MICE; EXPRESSION; MECHANISM; CELLS; COA; ACYLTRANSFERASE;
D O I
10.1210/en.2012-2214
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta -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 beta-oxidation. Selective 11 beta-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 beta-oxidative gene expression increased in corticosterone (CORT)and 11DHC-treated wild-type mice and CORT (but not 11DHC)-treated 11 beta-HSD1(-/-) mice. Furthermore, CORT-and 11DHC-treated wild-type mice and CORT (but not 11DHC)-treated 11 beta-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. (Endocrinology 154: 2374-2384, 2013)
引用
收藏
页码:2374 / 2384
页数:11
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