When examining substrate usage by cellular systems it is important that there be a match between rates of substrate uptake and rates of substrate metabolism. Therefore, an increased rate of fatty-acid uptake may be a potential mechanism responsible for IMTG accumulation in obese skeletal muscle. We and others have reported that obesity is associated with hyperlipidemia.71 As a result, fatty-acid uptake may be increased in obese skeletal muscle due to oversupply and increased rates of fatty-acid uptake.
It was once thought that fatty acids entered the muscle cell solely through passive diffusion. It is now apparent that fatty acids can also enter through a protein-mediated mechanism.21112 The proteins involved in the process include: fatty-acid-binding protein-plasma membrane (FABPpm), which is associated with the plasma membrane,102 and fatty-acid translocase (FAT/CD36), which is found both at the sarco-lemma and in intracellular pools.2 In addition, a third protein, fatty-acid transporter protein 1 (FATP1), is thought to be involved in the process, but it is less understood and may act as an acyl-CoA synthase.2,91
Transport of fatty acids into the cell is a dynamic process upregulated by both contraction and insulin stimulation. Contraction and insulin both activate the translocation of FAT/CD36 from intracellular stores to the plasma membrane.11,70 During the same conditions, rates of fatty-acid uptake are elevated, demonstrating that FAT/CD36 is the primary protein involved in facilitated transport. Stimulation of fatty-acid transport by insulin and muscle contraction occur through different mechanisms and are additive.11 Therefore, there are two mechanisms regulating fatty-acid transport in muscle: acute regulation through translocation of FAT/CD36 (following insulin and contraction) and chronic regulation through increased expression of transporter proteins.11
There is ample evidence suggesting that muscle fatty-acid transport is altered with insulin resistance. Studies examining aging and insulin resistance have shown that skeletal muscle from older animals has increased rates of palmitate uptake in response to insulin compared to young animals.105 Obese, insulin-resistant Zucker rats have also been shown to have elevated rates of fatty-acid transport.106 Although expression of transporter proteins was not elevated in obese Zucker rats, sarcolemmal concentrations of FAT/CD36 are elevated, and translocation of FAT/CD36 back to intracellular stores is seemingly impaired. A recent study from Bonen et al.13 examined fatty-acid transport in skeletal muscle from human subjects who were obese, type 2 diabetic, and healthy controls. They showed that fatty-acid transport was fourfold higher in obese and type 2 diabetic skeletal muscle, which was associated with increased IMTG content. They also found that increased fatty-acid transport was not associated with an increased expression of FAT/CD36 or FABPpm. However, they did find that sarcolemmal content of FAT/CD36, but not FABPpm, were higher in the muscle of obese and type 2 diabetic patients compared to controls. So, as with the muscle from obese Zucker rats, human obesity and type 2 diabetes is associated with increased FAT/CD36 at the sarcolemma, which forces rapid entry of fatty acids into muscle. This provides an interesting complexity in insulin-resistant muscle where GLUT4 (glucose transporters) are unable to readily translocate from intracellular pools to the sarcolemma, and FAT/CD36 (fatty-acid transporters) are unable to leave the sarcolemma and return to intracellular pools. As suggested by Bonen et al.,13 this results in a juxtaposed relationship between glucose and fatty-acid transporters, creating an environment for insulin resistance and increased stores of IMTGs and other lipid metabolites.
We can only speculate on the series of events that leads to insulin resistance in skeletal muscle. However, it is certain that increased levels of IMTG and concurrent lipid metabolites trigger skeletal-muscle insulin resistance. Why lipids accumulate in skeletal muscle of obese/insulin-resistant individuals is not completely understood. However, there is ample evidence demonstrating that increased rates of fatty-acid uptake alone or in combination with decreased rates of fatty-acid oxidation play a significant role.
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