Rosiglitazone increases fatty acid oxidation and fatty acid translocase (FAT/CD36) but not carnitine palmitoyltransferase I in rat muscle mitochondria.
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.
Benton
Carley R
CR
Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada. abonen@uoguelph.ca
Holloway
Graham P
GP
Campbell
S E
SE
Yoshida
Yuko
Y
Tandon
Narendra N
NN
Glatz
Jan F C
JF
Luiken
Joost J J F P
JJ
Spriet
Lawrence L
LL
Bonen
Arend
A
D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage*; D014665:Vasodilator Agents / Q000008:administration & dosage
D018955:CD36 Antigens; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D002334:Carnitine O-Palmitoyltransferase