Triacylglycerol accumulation in human obesity and type 2 diabetes is associated with increased rates of skeletal muscle fatty acid transport and increased sarcolemmal FAT/CD36

Abstract

We examined whether, in human obesity and type 2 diabetes, long chain fatty acid (LCFA) transport into skeletal muscle is upregulated and contributes to an excess intramuscular triacylglycerol accumulation. In giant sarcolemmal vesicles prepared from human skeletal muscle, LCFA transport rates were upregulated approximately 4-fold and were associated with an increased intramuscular triacylglycerol content in obese individuals and in type 2 diabetics. In these individuals, the increased sarcolemmal LCFA transport rate was not associated with an altered expression of FAT/CD36 or FABPpm. Instead, the increase in the LCFA transport rate was associated with an increase in sarcolemmal FAT/CD36 but not sarcolemmal FABPpm. Rates of fatty acid esterification were increased threefold in isolated human muscle strips obtained from obese subjects, while concomitantly rates of fatty acid oxidation were not altered. Thus, the increased rate of fatty acid transport may contribute to the increased rates of triacylglycerol accumulation in human skeletal muscle. The altered FAT/CD36 trafficking in muscle from obese subjects and type 2 diabetics juxtaposes the known alterations in GLUT4 trafficking, i.e., GLUT4 is known to be retained in its intracellular depots while FAT/CD36 is retained at the sarcolemma. This redistribution of FAT/CD36 to the sarcolemma may contribute to the etiology of insulin resistance in human muscle, and hence, FAT/CD36 provides another potential therapeutic target for the prevention and/or treatment of insulin resistance.

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients

“…This is in accordance with another study showing that IMCL content in myotubes from lean control and obese non-diabetic participants was significantly related to BMI of the donor [5]. However, we and others [10] have shown that type 2 diabetes alone, in the absence of whole-body indicators of obesity, is also associated with skeletal muscle lipid accumulation. Our study provides evidence that this finding is limited to fresh skeletal muscle and is not observed in primary myotubes.…”

“…Myotubes were incubated with antibody raised against desmin and visualised using a secondary antibody conjugated to Alexa 546 (red). Nuclei in cells were stained by DAPI (blue [28,29] and obese participants [10] compared with controls. In Fig.…”

“…The molecular mechanisms leading to excessive IMCL accumulation in skeletal muscle could result from reduced fatty acid oxidation [8,9] and/or an increased rate of fatty acid uptake across the plasma membrane [10]. Several studies have provided evidence of mitochondrial dysfunction in skeletal muscle of type 2 diabetic and prediabetic participants [1,8,9,11,12].…”

“…The principal muscle fatty acid transporter, fatty acid translocase (FAT)/CD36, is involved in regulating uptake of long-chain fatty acids into skeletal muscle [17,18]. Sarcolemmal FAT/CD36 relocation was observed in obese and type 2 diabetic participants [10]. In obese rats, increased IMCL accumulation was associated with an increased rate of fatty acid transport (mainly by FAT/CD36) that exceeded the concurrently increased capacity for mitochondrial fatty acid oxidation [19].…”

Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats

“…Excessive PGC-1α production induces many undesirable consequences, including abnormal mitochondrial proliferation, disruption of myofibrillar architecture, displacement of nuclei [12], obesity, intramuscular lipid accumulation and insulin resistance [10,11]. We [3,13] have suggested that insulin resistance in PGC-1α transgenic mice [10,11] may stem from a large, PGC-1α-induced increase in the fatty acid transporter, fatty acid translocase (FAT), which has been associated with increases in intramuscular lipids and insulin resistance in humans and in animals [14,15]. Viewed in this light, PGC-1α-induced insulin resistance in transgenic mice is less of a paradox than has been suggested [11].…”