Nature Medicine10, 268 - 274 (2004)
Published online: 8 February 2004; | doi:10.1038/nm995
Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance
Jie An1, Deborah M Muoio1, Masakazu Shiota2, Yuka Fujimoto2, Gary W Cline3, Gerald I Shulman3, Timothy R Koves1, Robert Stevens1, David Millington1
& Christopher B Newgard1
1
Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology & Cancer Biology, Pediatrics, Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
2
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
3
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
Correspondence should be addressed to Christopher B Newgard newga002@mc.duke.edu
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, -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 -OH-butyrate levels and improvement of insulin sensitivity.
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-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 
