A new leptin-mediated mechanism for stimulating fatty acid oxidation A pivotal role for sarcolemmal FAT/CD36
Abstract
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. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.
Keywords
CD36 antigen
hydroxymethylglutaryl coenzyme A reductase kinase
Cd36 protein
fatty acid
oleic acid
succinimide derivative
sulfo-N-succinimidyl oleate
animal cell
Article
cardiac muscle cell
cell membrane
controlled study
energy yield
enzyme activation
enzyme active site
fatty acid oxidation
fatty acid transport
male
mouse
nonhuman
priority journal
protein phosphorylation
rat
skeletal muscle
Western blotting
animal
drug effects
genetics
knockout mouse
metabolism
oxidation reduction reaction
AMP-Activated Protein Kinases
Animals
Antigens
CD36
Cell Line
Fatty Acids
Leptin
Mice
Knockout
Muscle
Skeletal
Myocytes
Cardiac
Oleic Acids
Oxidation-Reduction
Phosphorylation
Protein Transport
Rats
Sarcolemma
Succinimides
Vidarabine