Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance.
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.
An
Jie
J
Sarah W. Stedman Nutrition and Metabolism Center and Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Muoio
Deborah M
DM
Shiota
Masakazu
M
Fujimoto
Yuka
Y
Cline
Gary W
GW
Shulman
Gerald I
GI
Koves
Timothy R
TR
Stevens
Robert
R
Millington
David
D
Newgard
Christopher B
CB
D000214:Acyl Coenzyme A / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism*; D002331:Carnitine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D004041:Dietary Fats; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000378:metabolism
D000214:Acyl Coenzyme A; D004041:Dietary Fats; D007328:Insulin; D014280:Triglycerides; C116917:acylcarnitine; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D002331:Carnitine