Cardiac and skeletal muscle fatty acid transport and transporters and triacylglycerol and fatty acid oxidation in lean and Zucker diabetic fatty rats

Abstract

We examined fatty acid transporters, transport, and metabolism in hearts and red and white muscles of lean and insulin-resistant (week 6) and type 2 diabetic (week 24) Zucker diabetic fatty (ZDF) rats. Cardiac fatty acid transport was similar in lean and ZDF hearts at week 6 but was reduced at week 24 (Ϫ40%) in lean but not ZDF hearts. Red muscle of ZDF rats exhibited an early susceptibility to upregulation (ϩ66%) of fatty acid transport at week 6 that was increased by 50% in lean and ZDF rats at week 24 but remained 44% greater in red muscle of ZDF rats. In white muscle, no differences were observed in fatty acid transport between groups or from week 6 to week 24. In all tissues (heart and red and white muscle), FAT/CD36 protein and plasmalemmal content paralleled the changes in fatty acid transport. Triacylglycerol content in red and white muscles, but not heart, in lean and ZDF rats correlated with fatty acid transport (r ϭ 0.91) and sarcolemmal FAT/CD36 (r ϭ 0.98). Red and white muscle fatty acid oxidation by isolated mitochondria was not impaired in ZDF rats but was reduced by 18 -24% in red muscle of lean rats at week 24. Thus, in red, but not white, muscle of insulin-resistant and type 2 diabetic animals, a marked upregulation in fatty acid transport and intramuscular triacylglycerol was associated with increased levels of FAT/CD36 expression and plasmalemmal content. In heart, greater rates of fatty acid transport and FAT/CD36 in ZDF rats (week 24) were attributable to the inhibition of age-related reductions in these parameters. However, intramuscular triacylglycerol did not accumulate in hearts of ZDF rats. Thus insulin resistance and type 2 diabetes are accompanied by tissue-specific differences in FAT/CD36 and fatty acid transport and metabolism. Upregulation of fatty acid transport increased red muscle, but not cardiac, triacylglycerol accumulation. White muscle lipid metabolism dysregulation was not observed. plasma membrane-associated fatty acid-binding protein; FAT/CD36; GLUT4; mitochondria; giant vesicles INSULIN RESISTANCE IN HEART and skeletal muscle has been linked to intramuscular accumulation of fatty acids, the metabolites of which interfere with activation of the insulin signaling pathway involved in recruitment of GLUT4 to the cell surface (17,18,26,50,54). This excess lipid metabolite accumulation is thought to be due to a reduced fatty acid oxidation (36) and/or an altered rate of fatty acid uptake into tissues such as heart (19, 41) and skeletal muscle (9,19). Evidence for impaired fatty acid oxidation is not consistently supported by recent studies in insulin-resistant skeletal muscle (22,32,46), whereas the excess influx of fatty acids is gaining more credence (9,19,38).Fatty acid entry into many tissues occurs via a proteinmediated mechanism (6, 34, 35). The key fatty acid transporters include FAT/CD36 and plasma membrane-associated fatty acid-binding protein (FABPpm), which can be induced to translocate by muscle contraction (7,23,33,42,56) and by stimulation with insulin (23,33,4...

High muscle lipid content in obesity is not due to enhanced activation of key triglyceride esterification enzymes or the suppression of lipolytic proteins

“…Similarly, in vitro findings indicate that fatty acid transport into skeletal muscle obtained from obese adults was severalfold greater than that measured in muscle obtained from their nonobese counterparts (5). Fatty acid uptake into muscle is regulated largely by facilitated transport (39), and our current findings agree with previous data (4,5) indicating that the key fatty acid transporter FAT/CD36 is greater in the membrane fraction of skeletal muscle taken from obese compared with nonobese adults. Moreover, Holloway et al (22) suggest that the augmented fatty acid uptake due to the increased plasmalemmal FAT/CD36 content in muscle from obese compared with nonobese animals is directed largely toward the triglyceride synthesis pathway for esterification.…”

“…Amphipathic compounds span the neutral lipid/cytosol interface with the hydrophobic region embedding into the triglyceride and hydrophilic regions facing the aqueous cytosol. The most abundant proteins coating mammalian cytosolic triglycerides are the five perilipin family members (4,27). Perilipins are a component of the partition between insoluble triglycerides and the aqueous cytosol.…”

“…Fatty acid transport into skeletal muscle is largely a protein-mediated process (16,38). Several putative fatty acid transporter proteins have been identified, and among them, fatty acid translocase (FAT/CD36) is a major fatty acid transporter in human muscle (1,4). The abundance of FAT/CD36 on the muscle plasma membrane has been found to be directly proportional to the rate of fatty acid uptake (5), and therefore, it helps dictate the availability of substrate for IMTG synthesis.…”

Cardioprotective effect of the PPAR ligand tetradecylthioacetic acid in type 2 diabetic mice

“…This is also supported in the present study where increased FA oxidation in db/db hearts was associated with increased expression of several PPAR-␣ target genes including genes encoding proteins important for FA uptake and oxidation. The accompanying increase in protein-mediated FA uptake and FA oxidation has been suggested to play a central role in the development of ventricular dysfunction due to cardiac steatosis and lipotoxicity (9,20,41). Another hallmark of diabetic hearts (also demonstrated in the present study) is decreased cardiac efficiency (22,27), due to increased unloaded MV O 2 (8,22).…”

Overexpression of Vesicle-associated Membrane Protein (VAMP) 3, but Not VAMP2, Protects Glucose Transporter (GLUT) 4 Protein Translocation in an in Vitro Model of Cardiac Insulin Resistance

“…Interestingly, VAMP2 has been found to be up-regulated in skeletal muscle of Zucker diabetic fatty rats compared with their lean controls (44). In the same model, CD36 expression and presence at the sarcolemma of skeletal muscle cells and cardiomyocytes is elevated (7,45,46). Therefore, our observation that overexpression of VAMP2 in cardiomyocytes leads to an increased content of sarcolemmal CD36 links both observations in the Zucker diabetic fatty rat to a common mechanism, suggesting a novel function for VAMP2 in the accumulation of CD36 at the plasma membrane in the insulin-resistant heart.…”