Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve
High-Fat Diet–Induced Insulin Resistance
Clinton R. Bruce 1 2 ,
Andrew J. Hoy 2 ,
Nigel Turner 2 ,
Matthew J. Watt 3 4 ,
Tamara L. Allen 1 ,
Kevin Carpenter 5 6 ,
Gregory J. Cooney 2 ,
Mark A. Febbraio 1 and
Edward W. Kraegen 2
1 Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
2 Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
3 St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, Victoria, Australia
4 Department of Physiology, Monash University, Clayton, Victoria, Australia
5 Department of Biochemical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
6 Discipline of Genetic Medicine, University of Sydney, New South Wales, Australia
Corresponding author: Clinton R. Bruce, clinton.bruce{at}baker.edu.au
Abstract
OBJECTIVE— Skeletal muscle insulin resistance is associated with lipid accumulation, but whether insulin resistance is due to reduced
or enhanced flux of long-chain fatty acids into the mitochondria is both controversial and unclear. We hypothesized that skeletal
muscle–specific overexpression of the muscle isoform of carnitine palmitoyltransferase 1 (CPT1), the enzyme that controls
the entry of long-chain fatty acyl CoA into mitochondria, would enhance rates of fatty acid oxidation and improve insulin
action in muscle in high-fat diet insulin-resistant rats.
RESEARCH DESIGN AND METHODS— Rats were fed a standard (chow) or high-fat diet for 4 weeks. After 3 weeks, in vivo electrotransfer was used to overexpress
the muscle isoform of CPT1 in the distal hindlimb muscles (tibialis anterior and extensor digitorum longus [EDL]). Skeletal
muscle insulin action was examined in vivo during a hyperinsulinemic-euglycemic clamp.
RESULTS— In vivo electrotransfer produced a physiologically relevant increase of ∼20% in enzyme activity; and although the high-fat
diet produced insulin resistance in the sham-treated muscle, insulin action was improved in the CPT1-overexpressing muscle.
This improvement was associated with a reduction in triacylglycerol content, the membrane-to-cytosolic ratio of diacylglycerol,
and protein kinase C θ activity. Importantly, overexpression of CPT1 did not affect markers of mitochondrial capacity or function,
nor did it alter skeletal muscle acylcarnitine profiles irrespective of diet.
CONCLUSIONS— Our data provide clear evidence that a physiological increase in the capacity of long-chain fatty acyl CoA entry into mitochondria
is sufficient to ameliorate lipid-induced insulin resistance in muscle.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 December 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
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Overexpression of Carnitine Palmitoyltransferase-1 in Skeletal Muscle Is Sufficient to Enhance Fatty Acid Oxidation and Improve High-Fat Diet–Induced Insulin Resistance

10.2337/db08-1078