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

J An, DM Muoio, M Shiota, Y Fujimoto, GW Cline… - Nature medicine, 2004 - nature.com
J An, DM Muoio, M Shiota, Y Fujimoto, GW Cline, GI Shulman, TR Koves, R Stevens
Nature medicine, 2004nature.com
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 …
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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