Rosiglitazone increases fatty acid oxidation and fatty acid translocase (FAT/CD36) but not carnitine palmitoyltransferase I in rat muscle mitochondria

Abstract

Peroxisome proliferator-activated receptors (PPARs) alter the expression of genes involved in regulating lipid metabolism. Rosiglitazone, a PPARgamma agonist, induces tissue-specific effects on lipid metabolism; however, its mode of action in skeletal muscle remains unclear. Since fatty acid translocase (FAT/CD36) was recently identified as a possible regulator of skeletal muscle fatty acid transport and mitochondrial fatty acid oxidation, we examined in this tissue the effects of rosiglitazone infusion (7 days, 1 mg day(-1)) on FAT/CD36 mRNA and protein, its plasmalemmal content and fatty acid transport. In addition, in isolated subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria we examined rates of fatty acid oxidation, FAT/CD36 and carnitine palmitoyltransferase I (CPTI) protein, and CPTI and beta-hydroxyacyl CoA dehydrogenase (beta-HAD) activities. Rosiglitazone did not alter FAT/CD36 mRNA or protein expression, FAT/CD36 plasmalemmal content, or the rate of fatty acid transport into muscle (P > 0.05). In contrast, rosiglitazone increased the rates of fatty acid oxidation in both SS (+21%) and IMF mitochondria (+36%). This was accompanied by concomitant increases in FAT/CD36 in subsarcolemmal (SS) (+43%) and intermyofibrillar (IMF) mitochondria (+46%), while SS and IMF CPTI protein content, and CPTI submaximal and maximal activities (P > 0.05) were not altered. Similarly, citrate synthase (CS) and beta-HAD activities were also not altered by rosiglitazone in SS and IMF mitochondria (P > 0.05). These studies provide another example whereby changes in mitochondrial fatty oxidation are associated with concomitant changes in mitochondrial FAT/CD36 independent of any changes in CPTI. Moreover, these studies identify for the first time a mechanism by which rosiglitazone stimulates fatty acid oxidation in skeletal muscle, namely the chronic, subcellular relocation of FAT/CD36 to mitochondria.

Figure 1. Effects of 7 days rosiglitazone infusion

Effects of 7 days rosiglitazone infusion on FAT/CD36 mRNA, FAT/CD36 protein and plasmalemmal FAT/CD36 (A), and on the rates of palmitate transport into giant sarcolemmal vesicles (B) (mean ± s.e.m.). N = 8–16 muscles. P > 0.05 for all parameters.

Figure 2. The effect of rosiglitazone treatment on the palmitate oxidation rate

The effect of rosiglitazone treatment on the palmitate oxidation rate in isolated IMF and SS mitochondria (mean ± s.e.m.). N = 7–12 animals. *P < 0.05, control versus rosiglitazone treatment.

Figure 3. FAT/CD36 and CPTI protein

FAT/CD36 (A) and CPTI protein (B) in isolated IMF and SS mitochondria from control and rosiglitazone-treated muscle (mean ± s.e.m.). N = 7–12 animals. *P < 0.05, control versus rosiglitazone.

Figure 4. β-HAD, citrate synthase and CPT1 activity

β-HAD activity (A), citrate synthase activity (B) and CPT1 submaximal (75 μm palmitoyl-CoA) and maximal activity (300 μm palmitoyl-CoA) (C) in isolated IMF and SS mitochondria from control and rosiglitazone-treated muscle (mean ± s.e.m.). N = 7–12 animals. P > 0.05 for all parameters.