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

Nature Medicine volume 10, pages 268–274 (2004)Cite this article

Abstract

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, β-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 β-OH-butyrate levels and improvement of insulin sensitivity.

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Figure 1: Metabolic impact of MCD overexpression in primary hepatocytes and liver.
Figure 2: Metabolic variables in rats during hyperinsulinemic-euglycemic clamp.
Figure 3: Effect of MCD overexpression on muscle and liver insulin sensitivity.
Figure 4: Muscle triglyceride and LC-CoA levels.
Figure 5: Tandem mass spectrometry–based analysis of acylcarnitine species in muscle samples.

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Acknowledgements

These studies were supported by grants from Takeda Chemicals Industries, the Donald W. Reynolds Foundation and the National Institutes of Health (P01 DK58398). We are grateful to P. Anderson, K. Ross and H. Winfield for outstanding technical assistance.

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Authors and Affiliations

  1. Sarah W. Stedman Nutrition and Metabolism Center and Departments of Pharmacology & Cancer Biology, Pediatrics, Medicine and Biochemistry, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Jie An, Deborah M Muoio, Timothy R Koves, Robert Stevens, David Millington & Christopher B Newgard

  2. Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, 37232, Tennessee, USA

    Masakazu Shiota & Yuka Fujimoto

  3. Department of Internal Medicine, Yale University School of Medicine, New Haven, 06536, Connecticut, USA

    Gary W Cline & Gerald I Shulman

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Correspondence to Christopher B Newgard.

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An, J., Muoio, D., Shiota, M. et al. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat Med 10, 268–274 (2004). https://doi.org/10.1038/nm995

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