Rosiglitazone increases fatty acid oxidation and fatty acid translocase (FAT/CD36) but not carnitine palmitoyltransferase I in rat muscle mitochondria

Peroxisome proliferator‐activated receptors (PPARs) alter the expression of genes involved in regulating lipid metabolism. Rosiglitazone, a PPARγ agonist, induces tissue‐specific effects on lipid metabolism; however, its mode of action in skeletal muscle remains unclear. Since fatty acid translocase (FAT/CD36) was recently identified as a possible regulator of skeletal muscle fatty acid transport and mitochondrial fatty acid oxidation, we examined in this tissue the effects of rosiglitazone infusion (7 days, 1 mg day−1) on FAT/CD36 mRNA and protein, its plasmalemmal content and fatty acid transport. In addition, in isolated subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria we examined rates of fatty acid oxidation, FAT/CD36 and carnitine palmitoyltransferase I (CPTI) protein, and CPTI and β‐hydroxyacyl CoA dehydrogenase (β‐HAD) activities. Rosiglitazone did not alter FAT/CD36 mRNA or protein expression, FAT/CD36 plasmalemmal content, or the rate of fatty acid transport into muscle (P > 0.05). In contrast, rosiglitazone increased the rates of fatty acid oxidation in both SS (+21%) and IMF mitochondria (+36%). This was accompanied by concomitant increases in FAT/CD36 in subsarcolemmal (SS) (+43%) and intermyofibrillar (IMF) mitochondria (+46%), while SS and IMF CPTI protein content, and CPTI submaximal and maximal activities (P > 0.05) were not altered. Similarly, citrate synthase (CS) and β‐HAD activities were also not altered by rosiglitazone in SS and IMF mitochondria (P > 0.05). These studies provide another example whereby changes in mitochondrial fatty oxidation are associated with concomitant changes in mitochondrial FAT/CD36 independent of any changes in CPTI. Moreover, these studies identify for the first time a mechanism by which rosiglitazone stimulates fatty acid oxidation in skeletal muscle, namely the chronic, subcellular relocation of FAT/CD36 to mitochondria.

[1]  M. Danson,et al.  Citrate synthase. , 2020, Current topics in cellular regulation.

[2]  C. Hoppel,et al.  Fatty acid oxidation in cardiac and skeletal muscle mitochondria is unaffected by deletion of CD36. , 2007, Archives of biochemistry and biophysics.

[3]  Hideo Hatta,et al.  Negligible direct lactate oxidation in subsarcolemmal and intermyofibrillar mitochondria obtained from red and white rat skeletal muscle , 2007, Journal of Physiology.

[4]  J. Callés-Escandon,et al.  Metabolic challenges reveal impaired fatty acid metabolism and translocation of FAT/CD36 but not FABPpm in obese Zucker rat muscle. , 2007, American journal of physiology. Endocrinology and metabolism.

[5]  M. Febbraio,et al.  Tissue-Specific Effects of Rosiglitazone and Exercise in the Treatment of Lipid-Induced Insulin Resistance , 2007, Diabetes.

[6]  J. Callés-Escandon,et al.  Fatty acid binding protein facilitates sarcolemmal fatty acid transport but not mitochondrial oxidation in rat and human skeletal muscle , 2007, The Journal of physiology.

[7]  G. Heigenhauser,et al.  Skeletal muscle mitochondrial FAT/CD36 content and palmitate oxidation are not decreased in obese women. , 2007, American journal of physiology. Endocrinology and metabolism.

[8]  A. Bonen,et al.  A null mutation in skeletal muscle FAT/CD36 reveals its essential role in insulin- and AICAR-stimulated fatty acid metabolism. , 2007, American journal of physiology. Endocrinology and metabolism.

[9]  A. Bonen,et al.  AMPK-mediated increase in myocardial long-chain fatty acid uptake critically depends on sarcolemmal CD36. , 2007, Biochemical and biophysical research communications.

[10]  A. Hevener,et al.  Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance. , 2007, American journal of physiology. Endocrinology and metabolism.

[11]  A. Kleinfeld,et al.  Is membrane transport of FFA mediated by lipid, protein, or both? An unknown protein mediates free fatty acid transport across the adipocyte plasma membrane. , 2007, Physiology.

[12]  A. Bonen,et al.  Is membrane transport of FFA mediated by lipid, protein, or both? Mechanisms and regulation of protein-mediated cellular fatty acid uptake: molecular, biochemical, and physiological evidence. , 2007, Physiology.

[13]  B. Kemp,et al.  Rosiglitazone Treatment Enhances Acute AMP-Activated Protein Kinase–Mediated Muscle and Adipose Tissue Glucose Uptake in High-Fat–Fed Rats , 2006, Diabetes.

[14]  J. Horowitz,et al.  Coimmunoprecipitation of FAT/CD36 and CPT I in skeletal muscle increases proportionally with fat oxidation after endurance exercise training. , 2006, American journal of physiology. Endocrinology and metabolism.

[15]  J. Olefsky,et al.  Increased Malonyl-CoA Levels in Muscle From Obese and Type 2 Diabetic Subjects Lead to Decreased Fatty Acid Oxidation and Increased Lipogenesis; Thiazolidinedione Treatment Reverses These Defects , 2006, Diabetes.

[16]  H. Pilegaard,et al.  Higher skeletal muscle α2AMPK activation and lower energy charge and fat oxidation in men than in women during submaximal exercise , 2006, The Journal of physiology.

[17]  J. Callés-Escandon,et al.  Differential effects of contraction and PPAR agonists on the expression of fatty acid transporters in rat skeletal muscle , 2006, The Journal of physiology.

[18]  A. Bonen,et al.  Identification of fatty acid translocase on human skeletal muscle mitochondrial membranes: essential role in fatty acid oxidation. , 2006, American journal of physiology. Endocrinology and metabolism.

[19]  M. Febbraio,et al.  Chronic rosiglitazone treatment restores AMPKalpha2 activity in insulin-resistant rat skeletal muscle. , 2006, American journal of physiology. Endocrinology and metabolism.

[20]  A. Bonen,et al.  Mitochondrial long chain fatty acid oxidation, fatty acid translocase/CD36 content and carnitine palmitoyltransferase I activity in human skeletal muscle during aerobic exercise , 2006, The Journal of physiology.

[21]  Ping Li,et al.  Peroxisome Proliferator-activated Receptor-γ Co-activator 1α-mediated Metabolic Remodeling of Skeletal Myocytes Mimics Exercise Training and Reverses Lipid-induced Mitochondrial Inefficiency* , 2005, Journal of Biological Chemistry.

[22]  A. Bonen,et al.  Divergent effects of rosiglitazone on protein-mediated fatty acid uptake in adipose and in muscle tissues of Zucker rats Published, JLR Papers in Press, March 16, 2005. DOI 10.1194/jlr.M400426-JLR200 , 2005, Journal of Lipid Research.

[23]  M. Raney,et al.  ERK1/2 inhibition prevents contraction-induced increase in plasma membrane FAT/CD36 content and FA uptake in rodent muscle. , 2005, Acta physiologica Scandinavica.

[24]  D. Muoio,et al.  Subsarcolemmal and intermyofibrillar mitochondria play distinct roles in regulating skeletal muscle fatty acid metabolism. , 2005, American journal of physiology. Cell physiology.

[25]  J. Callés-Escandon,et al.  The subcellular compartmentation of fatty acid transporters is regulated differently by insulin and by AICAR , 2005, FEBS letters.

[26]  M. Febbraio,et al.  Rosiglitazone enhances glucose tolerance by mechanisms other than reduction of fatty acid accumulation within skeletal muscle. , 2004, Endocrinology.

[27]  A. Bonen,et al.  Monocarboxylate transporters in subsarcolemmal and intermyofibrillar mitochondria. , 2004, Biochemical and biophysical research communications.

[28]  A. Bonen,et al.  A Novel Function for Fatty Acid Translocase (FAT)/CD36 , 2004, Journal of Biological Chemistry.

[29]  G. Cooney,et al.  Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin , 2004, Diabetologia.

[30]  M. Lazar,et al.  Peroxisome proliferator-activated receptor γ in diabetes and metabolism , 2004 .

[31]  G. Heigenhauser,et al.  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 , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[32]  A. Zorzano,et al.  Regulation of cardiac long-chain fatty acid and glucose uptake by translocation of substrate transporters , 2004, Pflügers Archiv.

[33]  S. Mudaliar,et al.  Thiazolidinediones upregulate impaired fatty acid uptake in skeletal muscle of type 2 diabetic subjects. , 2003, American journal of physiology. Endocrinology and metabolism.

[34]  A. Bonen,et al.  Contraction-induced fatty acid translocase/CD36 translocation in rat cardiac myocytes is mediated through AMP-activated protein kinase signaling. , 2003, Diabetes.

[35]  J. Leszyk,et al.  Mitochondrial Biogenesis and Remodeling during Adipogenesis and in Response to the Insulin Sensitizer Rosiglitazone , 2003, Molecular and Cellular Biology.

[36]  J. Bruce German,et al.  Lipid metabolome-wide effects of the PPARγ agonist rosiglitazones⃞s The online version of this article (available at http://www.jlr.org) contains an additional 4 tables. Published, JLR Papers in Press, August 16, 2002. DOI 10.1194/jlr.M200169-JLR200 , 2002, Journal of Lipid Research.

[37]  David Carling,et al.  The Anti-diabetic Drugs Rosiglitazone and Metformin Stimulate AMP-activated Protein Kinase through Distinct Signaling Pathways* , 2002, The Journal of Biological Chemistry.

[38]  G. Dohm,et al.  Evidence of a malonyl-CoA-insensitive carnitine palmitoyltransferase I activity in red skeletal muscle. , 2002, American journal of physiology. Endocrinology and metabolism.

[39]  J. Fleckner,et al.  Novel genes regulated by the insulin sensitizer rosiglitazone during adipocyte differentiation. , 2002, Diabetes.

[40]  A. Bonen,et al.  Insulin induces the translocation of the fatty acid transporter FAT/CD36 to the plasma membrane. , 2002, American journal of physiology. Endocrinology and metabolism.

[41]  A. Bonen,et al.  Increased Rates of Fatty Acid Uptake and Plasmalemmal Fatty Acid Transporters in Obese Zucker Rats* , 2001, The Journal of Biological Chemistry.

[42]  P. Bugelski,et al.  Comparison of adipose tissue changes following administration of rosiglitazone in the dog and rat , 2001, Diabetes, obesity & metabolism.

[43]  S. Mudaliar,et al.  Peroxisome Proliferator-Activated Receptor (PPAR) γ and Retinoid X Receptor (RXR) agonists have complementary effects on glucose and lipid metabolism in human skeletal muscle , 2001, Diabetologia.

[44]  D. Hood.  Plasticity in Skeletal, Cardiac, and Smooth Muscle Invited Review: Contractile activity-induced mitochondrial biogenesis in skeletal muscle , 2001 .

[45]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[46]  A. Marette,et al.  Abundance and subcellular distribution of MCT1 and MCT4 in heart and fast-twitch skeletal muscles. , 2000, American journal of physiology. Endocrinology and metabolism.

[47]  A. Bonen,et al.  Acute Regulation of Fatty Acid Uptake Involves the Cellular Redistribution of Fatty Acid Translocase* , 2000, The Journal of Biological Chemistry.

[48]  F. Kamp,et al.  How are free fatty acids transported in membranes? Is it by proteins or by free diffusion through the lipids? , 1999, Diabetes.

[49]  A. Bonen,et al.  Protein-mediated palmitate uptake and expression of fatty acid transport proteins in heart giant vesicles. , 1999, Journal of lipid research.

[50]  A. Bonen,et al.  Muscle contractile activity increases fatty acid metabolism and transport and FAT/CD36. , 1999, American journal of physiology. Endocrinology and metabolism.

[51]  B. Kiens,et al.  Palmitate transport and fatty acid transporters in red and white muscles. , 1998, American journal of physiology. Endocrinology and metabolism.

[52]  J. Cregg,et al.  Functional studies of yeast-expressed human heart muscle carnitine palmitoyltransferase I. , 1997, Archives of biochemistry and biophysics.

[53]  J. McGarry,et al.  The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. , 1997, European journal of biochemistry.

[54]  M. Díaz-Ricart,et al.  Inhibition of platelet adhesion to collagen by monoclonal anti‐CD36 antibodies , 1996, British journal of haematology.

[55]  P. Grimaldi,et al.  Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36. , 1993, The Journal of biological chemistry.

[56]  D. Hood,et al.  Properties of skeletal muscle mitochondria isolated from subsarcolemmal and intermyofibrillar regions. , 1993, The American journal of physiology.

[57]  J. Veerkamp,et al.  Fatty acid oxidation in human and rat heart. Comparison of cell-free and cellular systems. , 1984, Biochimica et biophysica acta.

[58]  V. V. van Hinsbergh,et al.  Incomplete palmitate oxidation in cell-free systems of rat and human muscles. , 1983, Biochimica et biophysica acta.

[59]  C. Long,et al.  Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat. , 1983, The Biochemical journal.

[60]  W. Rutter,et al.  Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. , 1979, Biochemistry.

[61]  M. Lazar,et al.  Peroxisome proliferator-activated receptor gamma in diabetes and metabolism. , 2004, TIPS - Trends in Pharmacological Sciences.

[62]  S. Mudaliar,et al.  Peroxisome proliferator-activated receptor (PPAR) gamma and retinoid X receptor (RXR) agonists have complementary effects on glucose and lipid metabolism in human skeletal muscle. , 2001, Diabetologia.

[63]  A. Bonen,et al.  Muscle contractile activity increases fatty acid metabolism and transport and FAT/CD36. , 1999, The American journal of physiology.