Divergent effects of rosiglitazone on protein-mediated fatty acid uptake in adipose and in muscle tissues of Zucker rats

Abstract

Thiazolidinediones (TZDs) increase tissue insulin sensitivity in diabetes. Here, 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. 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.-Coort, S. L. M., W.

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

“…Despite the stronger antilipolytic effect of insulin on WAT lipolysis, explants of rosiglitazone-treated rats exposed to insulin concentrations approximating those found in vivo under fasting and postprandial conditions maintained a higher rate of NEFA release than controls. The apparent contradiction between this observation and the lower in vivo serum NEFA levels can be explained by the fact that, while reducing liver and muscle NEFA uptake, thiazolidinediones augment the ability of WAT to clear systemic NEFA through stimulation of protein-mediated NEFA uptake [3,38]. The rosiglitazone-induced increase in FABP4 and FATP expression observed in the present study confirms previous studies [39,40] and supports this notion.…”

Modest PGC-1α Overexpression in Muscle in Vivo Is Sufficient to Increase Insulin Sensitivity and Palmitate Oxidation in Subsarcolemmal, Not Intermyofibrillar, Mitochondria

“…It is still unknown whether the PPARs, and subsequently PGC-1␣, directly regulate FABPpm expression, particularly because there is some conflict in the literature as to whether the PPAR␥ activator rosiglitazone induces an up-regulation of FABPpm (55,57). A further complication with interpreting data for FABPpm is its apparent dual function depending on its subcellular location.…”

Fatty acid metabolism in adipocytes: functional analysis of fatty acid transport proteins 1 and 4

“…Role of FATPs in adipocyte fatty acid uptake and effluxnull for FATP1 exhibit reduced skeletal muscle LCFA uptake and resistance to high-fat diet-induced insulin resistance (15,35). In fat cells, rosiglitazone, a PPARg agonist, increases the expression of both CD36 and FATP1, suggesting that the lipid-lowering effects of this insulinsensitizing drug may be exerted at the level of adipose LCFA influx (36). Thus, the identification of a precise role for FATP1 in fatty acid influx may be crucial to understanding the mechanism of the beneficial insulin-sensitizing effects of this widely used class of drugs.…”