Metabolic challenges reveal impaired fatty acid metabolism and translocation of FAT/CD36 but not FABPpm in obese Zucker rat muscle

Abstract

Han X-X, Chabowski A, Tandon NN, Calles-Escandon J, Glatz JF, Luiken JJ, Bonen A. Metabolic challenges reveal impaired fatty acid metabolism and translocation of FAT/CD36 but not FABPpm in obese Zucker rat muscle. Am J Physiol Endocrinol Metab 293: E566-E575, 2007. First published May 22, 2007; doi:10.1152/ajpendo.00106.2007.-We examined, in muscle of lean and obese Zucker rats, basal, insulin-induced, and contractioninduced fatty acid transporter translocation and fatty acid uptake, esterification, and oxidation. In lean rats, insulin and contraction induced the translocation of the fatty acid transporter FAT/CD36 (43 and 41%, respectively) and plasma membrane-associated fatty acid binding protein (FABPpm; 19 and 60%) and increased fatty acid uptake (63 and 40%, respectively). Insulin and contraction increased lean muscle palmitate esterification and oxidation 72 and 61%, respectively. In obese rat muscle, basal levels of sarcolemmal FAT/CD36 (ϩ33%) and FABPpm (ϩ14%) and fatty acid uptake (ϩ30%) and esterification (ϩ32%) were increased, whereas fatty acid oxidation was reduced (Ϫ28%). Insulin stimulation of obese rat muscle increased plasmalemmal FABPpm (ϩ15%) but not plasmalemmal FAT/CD36, blunted fatty acid uptake and esterification, and failed to reduce fatty acid oxidation. In contracting obese rat muscle, the increases in fatty acid uptake and esterification and FABPpm translocation were normal, but FAT/CD36 translocation was impaired and fatty acid oxidation was blunted. There was no relationship between plasmalemmal fatty acid transporters and palmitate partitioning. In conclusion, fatty acid metabolism is impaired at several levels in muscles of obese Zucker rats; specifically, they are 1) insulin resistant with respect to FAT/CD36 translocation and fatty acid uptake, esterification, and oxidation and 2) contraction resistant with respect to fatty acid oxidation and FAT/CD36 translocation, but, conversely, 3) obese muscles are neither insulin nor contraction resistant at the level of FABPpm. Finally, 4) there is no evidence that plasmalemmal fatty acid transporters contribute to the channeling of fatty acids to specific metabolic destinations within the muscle.

Subcellular lipid droplet distribution in red and white muscles in the obese Zucker rat

“…However, this literature is based on in vitro measurements that are optimised to determine the capacity of mitochondrial function and therefore may not represent the in vivo oxidative flux. In support of this, in the obese Zucker rat, despite increased mitochondrial density as shown here and elsewhere [9,38], and despite increased in vitro mitochondrial function [9], we (present study) and others [41] found that rates of total muscle fatty acid oxidation were decreased, while, as found here, rates of triacylglycerol esterification were increased. It should be noted that the notion that fatty acid oxidation is reduced in obese Zucker rats [15,42,43] is controversial.…”

“…The increase in subsarcolemmal mitochondrial density and fatty acid oxidation may represent compensatory mechanisms designed to prevent lipid droplet accumulation in the subsarcolemmal region. Therefore, reduced mitochondrial fatty acid oxidation apparently cannot account for the observed intramuscular lipid accumulation, a notion that is consistent with contemporary mitochondrial literature [37][38][39][40][41]. However, this literature is based on in vitro measurements that are optimised to determine the capacity of mitochondrial function and therefore may not represent the in vivo oxidative flux.…”

“…The results with this approach suggest that fewer lipids are transported into intermyofibrillar mitochondria in the in vivo situation. This finding is somewhat surprising, given the now wellrecognised observation that rates of fatty acid transport in the obese Zucker rat are substantially increased [9,15,41]. Nevertheless, it appears that less [ 3 H]palmitate was transported into intermyofibrillar mitochondria, despite a greater delivery of fatty acids into the muscle's interior, suggesting that lipids were trafficked away from the mitochondria.…”

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

“…Muscle Triacylglycerol-Concentrations of intramuscular triacylglycerol were determined using thin layer chromatography, as outlined elsewhere (38). Briefly, muscle (50 mg) was homogenized (Polytron, Kinematica AG, Brinkmann, LittauLucerne, Switzerland) in 2 ml of 1:1 chloroform/methanol on ice.…”

Greater Transport Efficiencies of the Membrane Fatty Acid Transporters FAT/CD36 and FATP4 Compared with FABPpm and FATP1 and Differential Effects on Fatty Acid Esterification and Oxidation in Rat Skeletal Muscle

“…1). Some fatty acid transporters have now also been implicated in the dysregulation of fatty acid metabolism in heart and skeletal muscle in models of insulin resistance and type 1 and 2 diabetes, including FAT/CD36 (5-9), FATP1 (10,11), and possibly FATP4 (11,12) but not FABPpm (5)(6)(7). Thus, in recent years, it has become widely accepted that (a) long chain fatty acids traverse the plasma membrane via a protein-mediated mechanism and (b) some of the fatty acid transporters are central to the dysregulation in skeletal muscle fatty acid metabolism in obesity and type 2 diabetes.…”