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Papers In Press, published online ahead of print March 16, 2005
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Department of Molecular Genetics, Maastricht University, Maastricht 6200 MD
Corresponding Author: s.coort{at}gen.unimaas.nl
Thiazolidinediones (TZDs) increase tissue insulin sensitivity in type-2 diabetes, and enhance long-chain fatty acid (FA) deposition in adipocytes. Here, we hypothesize that, in adipose tissue, skeletal muscle and heart, alterations in the capacity to take up FA and in the total and plasmalemmal contents of membrane-associated FA transport proteins (FAT/CD36, FATP1 and FABPpm) are involved in the insulin sensitizing effect of TZDs. As a model we used insulin-resistant, obese Zucker rats, orally treated for 16 days with 5 mg rosiglitazone (Rgz)/kg body mass per day. In adipose tissue from Rgz-treated rats, FA uptake capacity increased by 2.0-fold, coinciding with increased total tissue contents of FAT/CD36 (2.3-fold) and FATP1 (1.7-fold), but not of FABPpm, whereas changes at the level of the plasmalemma were only observed for FAT/CD36 (increase of 1.7-fold). The increase in FA uptake capacity of adipose tissue was associated with a decline in plasma FA (-53%) and triacylglycerols (TAG, -56%), suggesting that Rgz-treatment enhanced plasma FA extraction by adipocytes. In obese hearts, Rgz-treatment had no effect on the FA transport system, yet the total TAG content decreased by 36%, suggesting enhanced cardiac insulin sensitivity. In skeletal muscle the FA transport system also remained unaltered, although, the overall TAG content in skeletal muscle did not decline. However, cytoplasmic adipose-type FABP content increased in skeletal muscle, suggesting that increased deposition of TAG in muscular adipose tissue masks the decline of TAG in muscle fibers. In conclusion, our study implicates FAT/CD36 in the mechanism by which rosiglitazone, in obese Zucker rats, redirects the FA flux from muscle towards adipose tissue, causing plasma FA and TAG concentrations to decline, and reducing intramyocellular lipid overload.
Revised on March 3, 2005
Accepted on March 10, 2005
Divergent effects of rosiglitazone on plasmalemmal fatty acid uptake capacity and transporter proteins in adipose and in muscle tissues of obese Zucker rats
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