Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats.
Cross-sectional studies in human subjects have used 1H magnetic resonance spectroscopy (HMRS) to demonstrate that insulin resistance correlates more tightly with the intramyocellular lipid (IMCL) concentration than with any other identified risk factor. To further explore the interaction between these two elements in the rat, we used two strategies to promote the storage of lipids in skeletal muscle and then evaluated subsequent changes in insulin-mediated glucose disposal. Normal rats received either a low-fat or a high-fat diet (20% lard oil) for 4 weeks. Two additional groups (lowfat + etoxomir and lard + etoxomir) consumed diets containing 0.01% of the carnitine palmitoyltransferase-1 inhibitor, R-etomoxir, which produced chronic blockade of enzyme activity in liver and skeletal muscle. Both the high-fat diet and drug treatment significantly impaired insulin sensitivity, as measured with the hyperinsulinemic-euglycemic clamp. Insulin-mediated glucose disposal (IMGD) fell from 12.57 +/- 0.72 in the low-fat group to 9.79 +/- 0.59, 8.96 +/- 0.38, and 7.32 +/- 0.28 micromol x min(-1) x 100 g(-1) in the low-fat + etoxomir, lard, and lard + etoxomir groups, respectively. We used HMRS, which distinguishes between fat within the myocytes and fat associated with contaminating adipocytes located in the muscle bed, to assess the IMCL content of isolated soleus muscle. A tight inverse relationship was found between IMGD and IMCL, the correlation (R = 0.96) being much stronger than that seen between IMGD and either fat mass or weight. In conclusion, either a diet rich in saturated fat or prolonged inhibition of fatty acid oxidation impairs IMGD in rats via a mechanism related to the accumulation of IMCL.
Dobbins
R L
RL
Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 75235-9135, USA. rdobbi@mednet.swmed.edu
Szczepaniak
L S
LS
Bentley
B
B
Esser
V
V
Myhill
J
J
McGarry
J D
JD
D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D001835:Body Weight; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004435:Eating / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000503:physiopathology; D066298:In Vitro Techniques; D007333:Insulin Resistance / Q000502:physiology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D050356:Lipid Metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004041:Dietary Fats; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D007527:Isoenzymes; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose; C054207:etomoxir