Abstract
Thiazolidinediones (TZDs) increase tissue insulin sensitivity in diabetes. Here, we hypothesize that, in adipose tissue, skeletal muscle, and heart, alterations in protein-mediated FA uptake are involved in the effect of TZDs. As a model, we used obese Zucker rats, orally treated for 16 days with 5 mg rosiglitazone (Rgz)/kg body mass/day. In adipose tissue from Rgz-treated rats, FA uptake capacity increased by 2.0-fold, coinciding with increased total contents of fatty acid translocase (FAT/CD36; 2.3-fold) and fatty acid transport protein 1 (1.7-fold) but not of plasmalemmal fatty acid binding protein, whereas only the plasmalemmal content of FAT/CD36 was changed (increase of 1.7-fold). The increase in FA uptake capacity of adipose tissue was associated with a decline in plasma FA and triacylglycerols (TAGs), 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, suggesting enhanced insulin sensitivity. Also, in skeletal muscle, the FA transport system was not changed. However, the TAG content remained unaltered in skeletal muscle, which coincided with increased cytoplasmic adipose-type FABP content, suggesting that increased extramyocellular TAGs mask the decline of intracellular TAG in muscle. In conclusion, our study implicates FAT/CD36 in the mechanism by which Rgz increases tissue insulin sensitivity.
Highlights
IntroductionWe hypothesize that, in adipose tissue, skeletal muscle, and heart, alterations in proteinmediated FA uptake are involved in the effect of TZDs. As a model, we used obese Zucker rats, orally treated for 16 days with 5 mg rosiglitazone (Rgz)/kg body mass/day
Thiazolidinediones (TZDs) increase tissue insulin sensitivity in diabetes
In response to the Rgz treatment, plasma cholesterol levels increased significantly by 1.7-fold in obese Zucker rats (P Ͻ 0.05; Table 1). This increased plasma cholesterol was distributed among the three different lipoprotein fractions (i.e., VLDL, LDL, and HDL). These effects of Rgz are characteristic of the treatment of insulin resistance with PPAR␥ agonists in rodent and human studies [2, 3, 25,26,27]
Summary
We hypothesize that, in adipose tissue, skeletal muscle, and heart, alterations in proteinmediated FA uptake are involved in the effect of TZDs. As a model, we used obese Zucker rats, orally treated for 16 days with 5 mg rosiglitazone (Rgz)/kg body mass/day. Several studies with insulinresistant rodent models and type 2 diabetic patients have demonstrated that TZD treatment reduces both hyperinsulinemia and hyperlipidemia [1,2,3,4,5] Another important effect of TZDs is the normalization of insulin-stimulated whole-body glucose disposal, as reflected by an improved insulin action on skeletal muscle [2] and heart [4]. Activation of PPAR␥ by TZDs regulates the transcription of genes involved in the differentiation of preadipocytes and the remodeling of adipose tissue, resulting in smaller, more insulin-sensitive adipocytes [3, 10]. Intracellular FAT/CD36 translocates to the plasma membrane upon a variety of stimuli, such as by contractile stimuli that activate AMP kinase [16] and by insulin via the activation of phosphatidylinositol 3-kinase [17]
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