A new leptin-mediated mechanism for stimulating fatty acid oxidation: a pivotal role for sarcolemmal FAT/CD36.
Leptin stimulates fatty acid oxidation in muscle and heart; but, the mechanism by which these tissues provide additional intracellular fatty acids for their oxidation remains unknown. We examined, in isolated muscle and cardiac myocytes, whether leptin, via AMP-activated protein kinase (AMPK) activation, stimulated fatty acid translocase (FAT/CD36)-mediated fatty acid uptake to enhance fatty acid oxidation. In both mouse skeletal muscle and rat cardiomyocytes, leptin increased fatty acid oxidation, an effect that was blocked when AMPK phosphorylation was inhibited by adenine 9-β-d-arabinofuranoside or Compound C. In wild-type mice, leptin induced the translocation of FAT/CD36 to the plasma membrane and increased fatty acid uptake into giant sarcolemmal vesicles and into cardiomyocytes. In muscles of FAT/CD36-KO mice, and in cardiomyocytes in which cell surface FAT/CD36 action was blocked by sulfo-N-succinimidyl oleate, the leptin-stimulated influx of fatty acids was inhibited; concomitantly, the normal leptin-stimulated increase in fatty acid oxidation was also prevented, despite the normal leptin-induced increase in AMPK phosphorylation. Conversely, in muscle of AMPK kinase-dead mice, leptin failed to induce the translocation of FAT/CD36, along with a failure to stimulate fatty acid uptake and oxidation. Similarly, when siRNA was used to reduce AMPK in HL-1 cardiomyocytes, leptin failed to induce the translocation of FAT/CD36. Our studies have revealed a novel mechanism of leptin-induced fatty acid oxidation in muscle tissue; namely, this process is dependent on the activation of AMPK to induce the translocation of FAT/CD36 to the plasma membrane, thereby stimulating fatty acid uptake. Without increasing this leptin-stimulated, FAT/CD36-dependent fatty acid uptake process, leptin-stimulated AMPK phosphorylation does not enhance fatty acid oxidation.
Integrated Biology Unit for Adaptations to Exercise (UBIAE-EA7362), University of Evry Val Essonne, Boulevard François Mitterrand, 91025 Evry, France.
Iman
I
Momken
Department of Physiology, Medical University of Bialystok, 15-089 Bialystok, Poland.
Adrian
A
Chabowski
Department of Molecular Genetics, Maastricht University, 6200-MD Maastricht, The Netherlands.
Ellen
E
Dirkx
Department of Molecular Genetics, Maastricht University, 6200-MD Maastricht, The Netherlands.
Miranda
M
Nabben
Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
Swati S
SS
Jain
Jay T
JT
McFarlan
Department of Molecular Genetics, Maastricht University, 6200-MD Maastricht, The Netherlands.
Jan F C
JF
Glatz
Department of Molecular Genetics, Maastricht University, 6200-MD Maastricht, The Netherlands.
Joost J F P
JJ
Luiken
Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada arend.bonen@gmail.com.
Arend
A
Bonen
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009829:Oleic Acids / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D012508:Sarcolemma / Q000235:genetics / Q000378:metabolism*; D013388:Succinimides / Q000494:pharmacology; D014740:Vidarabine / Q000494:pharmacology
D018955:CD36 Antigens; C008132:Cd36 protein, rat; D005227:Fatty Acids; D020738:Leptin; D009829:Oleic Acids; D013388:Succinimides; C120556:sulfo-N-succinimidyl oleate; D055372:AMP-Activated Protein Kinases; D014740:Vidarabine
AMPK; cardiac metabolism; fatty acid oxidation; fatty acid uptake; fatty acid-binding proteins; muscle metabolism