西亚试剂:Mitochondrial Overload and Incomplete Fatty Acid Oxidation
发布时间:2025-10-20
Mitochondrial Overload and Incomplete Fatty Acid Oxidation Contribute to Skeletal Muscle Insulin Resistance
Timothy R. Koves,1,2 John R. Ussher,4 Robert C. Noland,1 Dorothy Slentz,1 Merrie Mosedale,1 Olga Ilkayeva,1 James Bain,1 Robert Stevens,1 Jason R.B. Dyck,4 Christopher B. Newgard,1,2,3 Gary D. Lopaschuk,4 and Deborah M. Muoio1,2,3,
1 Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC 27710, USA
2 Department of Medicine, Duke University, Durham, NC 27710, USA
3 Department of Pharmacology & Cancer Biology, Duke University, Durham, NC 27710, USA
4 Cardiovascular Research Group, University of Alberta, Edmonton, AB T6G 2S2, Canada
Corresponding author
Deborah M. Muoio
Summary
Previous studies have suggested that insulin resistance develops secondary to diminished fat oxidation and resultant accumulation of cytosolic lipid molecules that impair insulin signaling. Contrary to this model, the present study used targeted metabolomics to find that obesity-related insulin resistance in skeletal muscle is characterized by excessive β-oxidation, impaired switching to carbohydrate substrate during the fasted-to-fed transition, and coincident depletion of organic acid intermediates of the tricarboxylic acid cycle. In cultured myotubes, lipid-induced insulin resistance was prevented by manipulations that restrict fatty acid uptake into mitochondria. These results were recapitulated in mice lacking malonyl-CoA decarboxylase (MCD), an enzyme that promotes mitochondrial β-oxidation by relieving malonyl-CoA-mediated inhibition of carnitine palmitoyltransferase 1. Thus, mcd−/− mice exhibit reduced rates of fat catabolism and resist diet-induced glucose intolerance despite high intramuscular levels of long-chain acyl-CoAs. These findings reveal a strong connection between skeletal muscle insulin resistance and lipid-induced mitochondrial stress.
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