Suzuki A, Okamoto S, Lee S, Saito K, Shiuchi T, Minokoshi Y. Leptin Stimulates Fatty Acid Oxidation and PPARα Gene Expression in Mouse C2C12 Myoblasts by Changing the Subcellular Localization of α2AMP-Activated Protein Kinase. Mol Cell Biol 27: 4317-4327, 2007.
Leptin stimulates fatty acid oxidation in skeletal muscle via AMP-activated protein kinase (AMPK) and expression of fatty acid oxidation-related genes, including peroxisome proliferator-activated receptor-α(PPARα). Here we report that leptin stimulates fatty acid oxidation and PPARα gene expression in the C2C12 muscle cell line through activation of α2AMPK and changing the subcellular localization of the enzyme. Activated α2AMPK containing β1 retains in the cytoplasm and phosphorylates acetyl-CoA carboxylase, thereby stimulating fatty acid oxidation. In contrast, α2AMPK containing β2, transiently increases fatty acid oxidation, but immediately translocates into the nucleus and induces PPARα gene transcription. The nuclear localization signal (NLS) and Thr172 phosphorylation of α2 are essential for nuclear translocation of α2AMPK, whereas myristoylation of β1 anchors the AMPK in the cytoplasm. Blocking both α2AMPK activation and changes in its subcellular localization, inhibits the metabolic effects of leptin. Thus, our data suggest that activation and changes in the subcellular localization of α2AMPK are required for stimulating fatty acid oxidation and PPARα gene expression in muscle cells.
Leptin translocates α2AMPK to the nucleus at 1 hr, depending β1-subunit. Nuclear α2AMPK stimulates PPARα gene expression. Six hours after treatment, leptin increases β1 expression. Active α2AMPK containing β1 retains in the cytoplasm and stimulates ACC phosphophorylation and fatty acid oxidation in mitochondria.
