Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance.
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 beta-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 beta-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.
Koves
Timothy R
TR
Sarah W. Stedman Nutrition and Metabolism Center, Department of Medicine, Duke University, Durham, NC 27710, USA.
Ussher
John R
JR
Noland
Robert C
RC
Slentz
Dorothy
D
Mosedale
Merrie
M
Ilkayeva
Olga
O
Bain
James
J
Stevens
Robert
R
Dyck
Jason R B
JR
Newgard
Christopher B
CB
Lopaschuk
Gary D
GD
Muoio
Deborah M
DM
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004041:Dietary Fats / Q000008:administration & dosage; D005227:Fatty Acids / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D051381:Rats
D001786:Blood Glucose; D004041:Dietary Fats; D005227:Fatty Acids; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase