Increased Rates of Fatty Acid Uptake and Plasmalemmal Fatty Acid Transporters in Obese Zucker Rats

Luiken, Joost J. F. P.; Arumugam, Y.; Dyck, David J.; Bell, Rhonda C.; Pelsers, Maurice M.L.; Turcotte, Lorraine P.; Tandon, Narendra N.; Glatz, Jan F. C.; Bonen, Arend

doi:10.1074/jbc.m100052200

Cited by 247 publications

(312 citation statements)

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“…It is worth noting that Man et al found that insulin repressed the expression of FATP1 mRNA by 66% after 24 h (t 1/2 ϭ 4 h) in 3T3-L1 adipocytes, although neither the effects on protein expression nor the effects on LCFA transport were examined. It is important to do so, because there seems to be little relationship between LCFA transporter mRNAs and their protein products and between LCFA transporter mRNAs and rates of LCFA transport (1,2,16,17). In contrast to the studies showing that insulin repressed FATP1 mRNA expression in 3T3-L1 adipocytes (21), we observed in cardiac myocytes that insulin markedly stimulated the protein expression of the LCFA transporter FAT/CD36, but not the LCFA transporter FABPpm.…”

Section: Fig 4 Effects Of Insulin On Fat/cd36 (A)contrasting

confidence: 53%

“…In obese Zucker rats (17) and streptozotocin (STZ)-induced diabetes (16), LCFA transport into heart and muscle is increased through the subcellular redistribution of FAT/CD36 to the plasma membrane [obesity (17)] and through the increased expression of FAT/CD36 and FABPpm, resulting in their increased sarcolemmal content [type 1 diabetes (16)]. Because of the many alterations in circulating substrates and hormones in these animal models, it was not possible to determine which factor(s) accounted for the changes in LCFA transporters.…”

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confidence: 99%

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Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm

Chabowski

Coort²,

Callés-Escandon³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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Because insulin has been shown to stimulate long-chain fatty acid (LCFA) esterification in skeletal muscle and cardiac myocytes, we investigated whether insulin increased the rate of LCFA transport by altering the expression and the subcellular distribution of the fatty acid transporters FAT/CD36 and FABPpm. In cardiac myocytes, insulin very rapidly increased the expression of FAT/CD36 protein in a time-and dose-dependent manner. During a 2-h period, insulin (10 nM) increased cardiac myocyte FAT/CD36 protein by 25% after 60 min and attained a maximum after 90 -120 min (ϩ40 -50%). There was a dose-dependent relationship between insulin (10 Ϫ12 to 10 Ϫ7 M) and FAT/CD36 expression. The half-maximal increase in FAT/CD36 protein occurred at 0.5 ϫ 10 Ϫ9 M insulin, and the maximal increase occurred at 10 Ϫ9 to 10 Ϫ8 M insulin (ϩ40 -50%). There were similar insulin-induced increments in FAT/CD36 protein in cardiac myocytes (ϩ43%) and in Langendorff-perfused hearts (ϩ32%). In contrast to FAT/CD36, insulin did not alter the expression of FABPpm protein in either cardiac myocytes or the perfused heart. By use of specific inhibitors of insulin-signaling pathways, it was shown that insulin-induced expression of FAT/CD36 occurred via the PI 3-kinase/Akt insulin-signaling pathway. Subcellular fractionation of cardiac myocytes revealed that insulin not only increased the expression of FAT/CD36, but this hormone also targeted some of the FAT/CD36 to the plasma membrane while concomitantly lowering the intracellular depot of FAT/ CD36. At the functional level, the insulin-induced increase in FAT/ CD36 protein resulted in an increased rate of palmitate transport into giant vesicles (ϩ34%), which paralleled the increase in plasmalemmal FAT/CD36 (ϩ29%). The present studies have shown that insulin regulates protein expression of FAT/CD36, but not FABPpm, via the PI 3-kinase/Akt insulin-signaling pathway. fatty acid translocase; plasma membrane-associated fatty acid-binding protein; cardiac myocytes; transport; plasma membrane; low-density microsomes; perfusion; heart LONG-CHAIN FATTY ACIDS (LCFAs) are taken up into cells by passive diffusion and by protein-mediated mechanisms involving a number of fatty acid-binding proteins (12,25). Overexpression of fatty acid transporters, including fatty acid translocase (FAT/CD36) and plasma membrane-associated fatty acid-binding protein (FABPpm), increase LCFA uptake (13,14). In recent years, it has been shown that rates of LCFA transport can be regulated acutely and chronically. In heart and skeletal muscle exposed briefly to insulin (15 min) and in contracting muscle (Ͻ30 min), rates of LCFA transport are increased due to the translocation of FAT/CD36 from an intracellular depot to the plasma membrane (4, 18, 19). Expression of FAT/CD36 mRNA is upregulated by LCFAs in neonatal cardiac myocytes (30), although the functional metabolic consequences of these changes on LCFA transport and metabolism have not been determined. In more detailed studies, FAT/CD36 mRNA and protein expression and plasma...

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Section: Fig 4 Effects Of Insulin On Fat/cd36 (A)contrasting

confidence: 53%

mentioning

confidence: 99%

Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm

Chabowski

Coort²,

Callés-Escandon³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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“…93,96 In addition to the PPARa-mediated increases in fatty acid oxidation, cardiac myocytes from Zucker obese rats have a larger proportion of FAT/CD36 97,98 located at the plasma membrane when compared with Zucker lean rats. 99 Normal insulin-mediated translocation of FAT/CD36 is not seen in Zucker obese rats, supporting the notion that a substantial portion of the FAT/CD36 pool is permanently relocated to the sarcolemma in the heart in obesity, and that this enables triglyceride accumulation via increased fatty acid uptake. 100 GLUT4 expression is also altered by excessive nutrient intake.…”

Section: Mitochondrial Metabolism and Lipotoxicity In Obesitysupporting

confidence: 49%

Myocardial substrate metabolism in obesity

et al. 2012

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Obesity is linked to a wide variety of cardiac changes, from subclinical diastolic dysfunction to end-stage systolic heart failure. Obesity causes changes in cardiac metabolism, which make ATP production and utilization less efficient, producing functional consequences that are linked to the increased rate of heart failure in this population. As a result of the increases in circulating fatty acids and insulin resistance that accompanies excess fat storage, several of the proteins and genes that are responsible for fatty acid uptake and metabolism are upregulated, and the metabolic machinery responsible for glucose utilization and oxidation are inhibited. The resultant increase in fatty acid metabolism, and the inherent alterations in the proteins of the electron transport chain used to create the gradient needed to drive mitochondrial ATP production, results in a decrease in efficiency of cardiac work and a relative increase in oxygen usage. These changes in cardiac mitochondrial metabolism are potential therapeutic targets for the treatment and prevention of obesity-related heart failure. (2013) Keywords: myocardial metabolism; review; obese INTRODUCTION Cardiac energy metabolism is essentially a four-step process involving the following: (1) myocellular substrate uptake/selection, (2) mitochondrial ATP production and (3) ATP transfer from the site of production (mitochondrion) to (4) the site of ATP utilization (cardiac myofibril; Figure 1). 1 Although glycolysis is an ATP generator, the overall ATP production is controlled largely by the rate at which the Krebs (tricarboxylic acid) cycle operates. 2 Acetyl co-enzyme A (CoA), which is produced from the oxidation of fatty acids, ketone bodies, or glucose via glycolysis, and the pyruvate dehydrogenase (PDH) enzyme complex 3 enters the Krebs cycle for complete oxidation. During oxidative phosphorylation, electrons, primarily obtained from oxidative metabolism of carbohydrates and fats, are transferred through the electron transport chain, a fourcomplex protein system embedded within the inner membrane of the mitochondria. The major function of the electron transport chain is to produce a proton electrochemical potential difference between two compartments that powers ATP synthase to generate ATP, which is used for all cardiac cellular processes. 4 ATP is the heart's only immediate source of energy for contraction, and as both systole and diastole are ATP-consuming processes, 5,6 cardiac ATP demand is very high. To keep up with this demand for continuous and efficient contraction and relaxation, the heart needs to produce around 20 times its own weight in ATP per day. 1 As a result of this large energy requirement, any impairment in ATP production, transfer or utilization can have detrimental effects on cardiac function. 7 Cardiac metabolism and ATP production is altered in obesity and has emerged as a candidate mechanism to explain the increase in heart failure in this population. 8 Indeed, it has recently been shown that obesity, in the absence of co-morbiditie...

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“…Notably, an increased amount of FAT/CD36 was detectable at the sarcolemma in the obese rat heart. These findings indicate that in cardiac myocytes from obese Zucker rats, a portion of the intracellular FAT/CD36 pool is permanently relocated to the sarcolemma (23). However, it is not known whether this permanent relocation is due to an impaired FAT/CD36 translocation from intracellular pools toward the sarcolemma in response to insulin or due to cellular contractions.…”

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confidence: 59%

“…Insulin predominantly directs intracellular LCFAs toward esterification (21), whereas during cellular contractions LCFAs are efficiently used for energy production via mitochondrial ␤-oxidation (22). Recently, we unmasked a pivotal role of FAT/CD36 in the altered cardiac LCFA uptake in obese Zucker rats (23). It appears that in giant membrane vesicles isolated from the heart of obese Zucker rats, LCFA uptake was elevated, whereas neither the total abundance of FAT/CD36 mRNA nor the total amount of protein was different in the heart of obese rats compared with that of lean Zucker rats.…”

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Enhanced Sarcolemmal FAT/CD36 Content and Triacylglycerol Storage in Cardiac Myocytes From Obese Zucker Rats

et al. 2004

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In obesity, the development of cardiomyopathy is associated with the accumulation of myocardial triacylglycerols (TAGs), possibly stemming from elevation of myocardial long-chain fatty acid (LCFA) uptake. Because LCFA uptake is regulated by insulin and contractions, we examined in cardiac myocytes from lean and obese Zucker rats the effects of insulin and the contraction-mimetic agent oligomycin on the initial rate of LCFA uptake, subcellular distribution of FAT/CD36, and LCFA metabolism. In cardiac myocytes from obese Zucker rats, under basal conditions, FAT/CD36 was relocated to the sarcolemma at the expense of intracellular stores. In addition, the LCFA uptake rate, LCFA esterification rate into TAGs, and the intracellular unesterified LCFA concentration each were significantly increased. All these metabolic processes were normalized by the FAT/CD36 inhibitor sulfo-N-succinimidyloleate, indicating its antidiabetic potential. In cardiac myocytes isolated from lean rats, in vitro administration of insulin induced the translocation of FAT/ CD36 to the sarcolemma and stimulated initial rates of LCFA uptake and TAG esterification. In contrast, in myocytes from obese rats, insulin failed to alter the subcellular localization of FAT/CD36 and the rates of LCFA uptake and TAG esterification. In cardiac myocytes from lean and obese animals, oligomycin stimulated the initial rates of LCFA uptake and oxidation, although oligomycin only induced the translocation of FAT/CD36 to the sarcolemma in lean rats. The present results indicate that in cardiac myocytes from obese Zucker rats, a permanent relocation of FAT/CD36 to the sarcolemma is responsible for myocardial TAG accumulation. Furthermore, in vitro these cardiac myocytes, although sensitive to contraction-like stimulation, were completely insensitive to insulin, as the basal conditions in hyperinsulinemic, obese animals resemble the insulin-stimulated condition in lean littermates.

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Increased Rates of Fatty Acid Uptake and Plasmalemmal Fatty Acid Transporters in Obese Zucker Rats

Cited by 247 publications

References 46 publications

Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm

Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm

Myocardial substrate metabolism in obesity

Enhanced Sarcolemmal FAT/CD36 Content and Triacylglycerol Storage in Cardiac Myocytes From Obese Zucker Rats

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