Leptin Stimulates Fatty Acid Oxidation and Peroxisome Proliferator-Activated Receptorα Gene Expression in Mouse C2C12 Myoblasts by Changing the Subcellular 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 α (PPAR α). We now show that leptin stimulates fatty acid oxidation and PPAR α gene expression in the C2C12 muscle cell line through the activation of AMPK containing the α 2 subunit (α 2AMPK) and through changes in the subcellular localization of this enzyme. Activated α 2AMPK containing the β1 subunit was shown to be retained in the cytoplasm, where it phosphorylated acetyl coenzyme A carboxylase and thereby stimulated fatty acid oxidation. In contrast, α 2AMPK containing the β2 subunit transiently increased fatty acid oxidation but underwent rapid translocation to the nucleus, where it induced PPAR α gene transcription. A nuclear localization signal and Thr172 phosphorylation of α 2 were found to be essential for nuclear translocation of α 2AMPK, whereas the myristoylation of β1 anchors α 2AMPK in the cytoplasm. The prevention of α 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 subcellular localization of α 2AMPK are required for leptin-induced stimulation of fatty acid oxidation and PPAR α gene expression in muscle cells. [ABSTRACT FROM AUTHOR]