Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resi
Author: ["Jie An","Deborah M Muoio","Masakazu Shiota","Yuka Fujimoto","Gary W Cline","Gerald I Shulman","Timothy R Koves","Robert Stevens","David Millington","Christopher B Newgard"]
Publication: Nature Medicine
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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.
Cite this article
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
