title: Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice.
abstract: Impaired skeletal muscle fatty acid oxidation has been suggested to contribute to insulin resistance and glucose intolerance. However, increasing muscle fatty acid oxidation may cause a reciprocal decrease in glucose oxidation, which might impair insulin sensitivity and glucose tolerance. We therefore investigated what effect inhibition of mitochondrial fatty acid uptake has on whole-body glucose tolerance and insulin sensitivity in obese insulin-resistant mice. C57BL/6 mice were fed a high-fat diet (60% calories from fat) for 12 weeks to develop insulin resistance. Subsequent treatment of mice for 4 weeks with the carnitine palmitoyltransferase-1 inhibitor, oxfenicine (150 mg/kg i.p. daily), resulted in improved whole-body glucose tolerance and insulin sensitivity. Exercise capacity was increased in oxfenicine-treated mice, which was accompanied by an increased respiratory exchange ratio. In the gastrocnemius muscle, oxfenicine increased pyruvate dehydrogenase activity, membrane GLUT4 content, and insulin-stimulated Akt phosphorylation. Intramyocellular levels of lipid intermediates, including ceramide, long-chain acyl CoA, and diacylglycerol, were also decreased. Our results demonstrate that inhibition of mitochondrial fatty acid uptake improves insulin sensitivity in diet-induced obese mice. This is associated with increased carbohydrate utilization and improved insulin signaling in the skeletal muscle, suggestive of an operating Randle Cycle in muscle.
authors.affiliation: Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Wendy
authors.initials: W
authors.lastname: Keung
authors.forename: John R
authors.initials: JR
authors.lastname: Ussher
authors.forename: Jagdip S
authors.initials: JS
authors.lastname: Jaswal
authors.forename: Monique
authors.initials: M
authors.lastname: Raubenheimer
authors.forename: Victoria H M
authors.initials: VH
authors.lastname: Lam
authors.forename: Cory S
authors.initials: CS
authors.lastname: Wagg
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000627:therapeutic use*; D050260:Carbohydrate Metabolism / Q000187:drug effects; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D018149:Glucose Intolerance / Q000209:etiology / Q000517:prevention & control; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000627:therapeutic use; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D004791:Enzyme Inhibitors; D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; C023010:4-hydroxyphenylglycine; D002334:Carnitine O-Palmitoyltransferase; D005998:Glycine