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

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, 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.

• Authors: 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
• Journal: Nature medicine (Nat Med) Vol. 10 Issue 3 Pg. 268-74 (Mar 2004) ISSN: 1078-8956 [Print] United States
• PMID: 14770177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Acyl Coenzyme A
• Dietary Fats
• Insulin
• Triglycerides
• acylcarnitine
• Carboxy-Lyases
• malonyl-CoA decarboxylase
• Carnitine

Topics

• Acyl Coenzyme A (metabolism)
• Adenoviridae (genetics, metabolism)
• Animals
• Carboxy-Lyases (genetics, metabolism)
• Carnitine (analogs & derivatives, chemistry, metabolism)
• Cells, Cultured
• Dietary Fats
• Hepatocytes (cytology, metabolism)
• Insulin (metabolism)
• Insulin Resistance (physiology)
• Lipid Metabolism
• Liver (cytology, metabolism)
• Male
• Muscle, Skeletal (metabolism)
• Rats
• Rats, Wistar
• Triglycerides (metabolism)