Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance

被引:371
作者
An, J
Muoio, DM
Shiota, M
Fujimoto, Y
Cline, GW
Shulman, GI
Koves, TR
Stevens, R
Millington, D
Newgard, CB [1 ]
机构
[1] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Dept Pharmacol, Durham, NC 27710 USA
[3] Duke Univ, Med Ctr, Dept Canc Biol, Durham, NC 27710 USA
[4] Vanderbilt Univ, Med Ctr, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA
[5] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06536 USA
关键词
D O I
10.1038/nm995
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Lipid infusion or ingestion of a high-fat diet results in insulin resistance, but the mechanism underlying this phenomenon remains unclear. Here we show that, in rats fed a high-fat diet, whole-animal, muscle and liver insulin resistance is ameliorated following hepatic overexpression of malonyl-coenzyme A (CoA) decarboxylase (MCD), an enzyme that affects lipid partitioning. MCD overexpression decreased circulating free fatty acid (FFA) and liver triglyceride content. In skeletal muscle, levels of triglyceride and long-chain acyl-CoA (LC-CoA)-two candidate mediators of insulin resistance-were either increased or unchanged. Metabolic profiling of 36 acylcarnitine species by tandem mass spectrometry revealed a unique decrease in the concentration of one lipid-derived metabolite, beta-OH-butyrate, in muscle of MCD-overexpressing animals. The best explanation for our findings is that hepatic expression of MCD lowered circulating FFA levels, which led to lowering of muscle beta-OH-butyrate levels and improvement of insulin sensitivity.
引用
收藏
页码:268 / 274
页数:7
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