Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor α gene expression in mouse C2C12 myoblasts localization of the α2 form of AMP-activated protein kinase

Leptin stimulates fatty acid oxidation in skeletal muscle through the activation of AMP-activated protein kinase (AMPK) and the induction of gene expression, such as that for peroxisome proliferator-activated receptor alpha (PPAR alpha). We now show that leptin stimulates fatty acid oxidation and PPAR alpha gene expression in the C2C12 muscle cell line through the activation of AMPK containing the alpha 2 subunit (alpha 2AMPK) and through changes in the subcellular localization of this enzyme. Activated alpha 2AMPK containing the beta 1 subunit was shown to be retained in the cytoplasm, where it phosphorylated acetyl coenzyme A carboxyllase and thereby stimulated fatty acid oxidation. In contrast, alpha 2AMPK containing the beta 2 subunit transiently increased fatty acid oxidation but underwent rapid translocation to the nucleus, where it induced PPAR alpha gene transcription. A nuclear localization signal and Thr(172) phosphoryllation of alpha 2 were found to be essential for nuclear translocation of alpha 2AMPK, whereas the myristoylation of beta 1 anchors alpha 2AMPK in the cytoplasm. The prevention of alpha 2AMPK activation and the change in its subcellular localization inhibited the metabolic effects of leptin. Our data thus suggest that the activation of and changes in the subcellullar localization of alpha 2AMPK are required for leptin-induced stimulation of fatty acid oxidation and PPARa gene expression in muscle cells.