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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online May 7, 2004 as doi:10.1096/fj.03-1065fje. |
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Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada;
* Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada;
Section of Endocrinology and Metabolism, Wake Forest University School of Medicine & Baptist Medical Center, Winston-Salem North Carolina, USA;
Thrombosis and Vascular Biology Laboratory, Otsuka America Pharmaceutical Inc., Rockville, Maryland, USA;
Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands; and
|| Department of Medicine, McMaster University, Hamilton, Ontario, Canada
1Correspondence: Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, N1G 2W1, Canada. E-mail: abonen{at}uogulph.ca
SPECIFIC AIMS
We hypothesized that intramuscular triacylglycerol accumulation in human skeletal muscle was attributable to an increased rate of long chain fatty acid (LCFA) transport into the myocyte as a result of an increase in the fatty acid transporters FAT/CD36 and/or FABPpm. Thus, we compared in control, overweight, and obese individuals and in type 2 diabetics 1) the rates of palmitate transport into giant sarcolemmal vesicles prepared from human skeletal muscles, 2) the expression of fatty acid transport proteins in muscle homogenates and at the plasma membrane, 3) concentrations of intramuscular triacylglycerols, and 4) rates of palmitate oxidation and esterification in human muscle strips, in vitro.
PRINCIPAL FINDINGS
1. Increased rates of fatty acid transport into human muscle from obese subjects and type 2 diabetics
The participants included men and women who were lean (n=11; 51.3±4.5 years, body mass index (BMI) 21.8±0.6), overweight (n=10; 50.9±5.9 years, BMI 26.9±0.5), or obese (n=7; 59.6±5.2 years, BMI 34.7±1.7), or who had been diagnosed with type 2 diabetes (n=5; 69.5±9.2 years, BMI 25.6±1.1). Human muscle samples were obtained at the onset of abdominal surgery under general anesthesia. A portion of the sample was frozen immediately; the remainder was used to prepare giant sarcolemmal vesicles for LCFA transport studies. A portion of the vesicles was frozen for analyses of plasmalemmal LCFA transporters. In control and obese individuals, rates of palmitate esterification and esterification were determined in thin strips of abdominal muscle, in vitro.
Rates of palmitate transport into giant sarcolemmal vesicles were increased 
4-fold in obese individuals and type 2 diabetics (P<0.05) compared with lean and overweight individuals (Fig. 1
). No differences were observed between lean and overweight individuals or between obese individuals and type 2 diabetics (P>0.05, Fig. 1
).
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2. Expression of fatty acid transport proteins in muscle homogenates and their presence at the plasma membrane
No differences in homogenate FABPpm expression were observed among the groups, except in the obese subjects, in whom the total FABPpm in muscle homogenates was reduced by 30%. However, there were no differences in plasma membrane FABPpm content among the four groups (P>0.05). Similarly, homogenate FAT/CD36 did not differ among the four groups, but plasmalemmal FAT/CD36 was increased in the obese individuals (+28%, P<0.05) and in type 2 diabetics (+58%, P<0.05) compared with lean and overweight subjects.
3. Skeletal muscle triacylglycerols, fatty acid transport, and plasmalemmal FAT/CD36
Skeletal muscle triacylglycerol concentration were increased 2- and 3-fold in skeletal muscle of obese individuals and type 2 diabetics, respectively (P<0.05). The rates of palmitate incorporation into the intramuscular triacylglycerol depots in isolated muscle strips were tripled (lean 26.3±3.9; obese 76.1±18.5 nmol palmitate/g/h, P<0.05); concomitantly, rates of palmitate oxidation were not altered.
Rates of palmitate transport and plasma membrane FAT/CD36 were positively associated with the intramuscular triacylglycerol concentrations (Fig. 2
). Thus, increased plasmalemmal FAT/CD36 and the increased rates of palmitate influx into muscle, combined with the increased rates of LCFA esterification, are contributing factors to the large increase in the intramuscular triacylglycerol depots in skeletal muscle of obese individuals and type 2 diabetics.
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CONCLUSIONS
A number of studies in recent years have implicated changes in circulating fatty acids and fatty acid metabolism with impaired insulin sensitivity in skeletal muscle. This study demonstrates for the first time that in muscles from obese subjects and type 2 diabetics, rates of fatty acid transport are increased. This is associated with the increased plasmalemmal content of FAT/CD36, but not FABPpm. This greater influx of fatty acids contributes to the excess accumulation of intramuscular triacylglycerols, since we demonstrate that rates of LCFA esterification are increased in skeletal muscle from obese subjects, whereas rates of LCFA oxidation are not altered.
Although there has been some debate as to whether long chain fatty acids traverse the plasma membrane via unregulated diffusion or protein-mediated processes, modern molecular evidence indicates that both processes occur. Using animal models, we earlier reported that the fatty acid transporter FAT/CD36 can be translocated from an intracellular depot to the plasma membrane by muscle contraction and by insulin, and this increase in plasmalemmal FAT/CD36 increases the rates of fatty acid uptake into muscle tissue.
In the present studies in human muscle (obesity and type 2 diabetes), the increases in skeletal muscle fatty acid transport rates and plasmalemmal FAT/CD36, while the total available pool of FAT/CD36 (i.e., plasmalemmal FAT/CD36+intracellular FAT/CD36) is not altered, parallel completely our previously reported observations in muscle from obese Zucker rats. Changes in plasmalemmal FABPpm were not observed in either insulin-resistant animal muscle or human muscle from obese subjects and type 2 diabetics (present study).
FAT/CD36 cycling between the plasmalemma and intracellular depots has recently been reported in several studies from our laboratory. The increase in plasmalemmal FAT/CD36 in the absence of an altered expression of this protein in insulin-resistant animal muscle and human muscle from obese subjects and type 2 diabetics (present study) suggests that the normal cycling of this transporter between the sarcolemma and its intracellular depot has been altered chronically.
The impairment of FAT/CD36 cycling between subcellular compartments is reminiscent of a similar disturbance in the insulin-responsive glucose transport system. It is well known that GLUT4 cycling between the cell surface and intracellular depots is impaired in skeletal muscle in obesity and type 2 diabetes despite similar levels of total available GLUT4. The impairments in FAT/CD36 and GLUT4 cycling are juxtaposed. In obesity and type 2 diabetes, FAT/CD36 is retained at the cell surface while GLUT4 is retained within the intracellular depots. Given the strong association between fatty acid transport and intramuscular triacylglycerol, a marker of insulin resistance, it is tempting to speculate there may be cross-talk between the FAT/CD36 and GLUT4 signaling pathways.
The increase in rates of LCFA esterification and the positive association between fatty acid transport and triacylglycerol concentrations in skeletal muscle strongly suggest that the increased LCFAs transported into muscle contributes to the accumulation of intramuscular triacylglycerols. We propose (Fig. 3
) that the intramuscular triacylglycerol concentrations in obesity and type 2 diabetes are increased due to an increase in plasmalemmal FAT/CD36. This increase in plasmalemmal FAT/CD36 then serves to increase the rate of fatty acid transport into the muscle cell, where the excess LCFAs, that are taken up, are primarily stored as triacylglycerols. Excess intramuscular triacylglycerol accumulation has been associated with impairments in insulin signaling in human obesity and type 2 diabetes, although triacylglycerol depots are most likely a surrogate measure of other fatty acid metabolites that interfere with insulin signaling in muscle.
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The present study indicates that an increase in the fatty acid transport rate is another disturbance in lipid handling that can occur in skeletal muscle in humans. The key mechanism accounting for this increase is not altered expression of fatty acid transporters, but rather subcellular relocation of FAT/CD36 to the sarcolemma, indicating that FAT/CD36 cycling between the plasma membrane and its intracellular compartment has been altered in obesity and type 2 diabetes. The increased influx of fatty acids, along with their increased rate of esterification, contributes to the increased intramuscular accumulation of triacylglycerols. Thus, the increased rate of fatty acid transport may be a critical step in the LCFA-mediated development of insulin resistance, and FAT/CD36 provides another potential therapeutic target for the prevention and/or treatment of insulin resistance.
FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-1065fje; Doi: 10.1096/fj.03-1065fje
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