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Molecular and Cellular Biology, June 2007, p. 4317-4327, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.02222-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Leptin Stimulates Fatty Acid Oxidation and Peroxisome Proliferator-Activated Receptor Gene Expression in Mouse C2C12 Myoblasts by Changing the Subcellular Localization of the 2 Form of AMP-Activated Protein Kinase ^,

Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan

Received 28 November 2006/ Returned for modification 22 January 2007/ Accepted 14 March 2007

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 (PPAR). We now show that leptin stimulates fatty acid oxidation and PPAR gene expression in the C2C12 muscle cell line through the activation of AMPK containing the 2 subunit (2AMPK) and through changes in the subcellular localization of this enzyme. Activated 2AMPK containing the ß1 subunit was shown to be retained in the cytoplasm, where it phosphorylated acetyl coenzyme A carboxylase and thereby stimulated fatty acid oxidation. In contrast, 2AMPK containing the ß2 subunit transiently increased fatty acid oxidation but underwent rapid translocation to the nucleus, where it induced PPAR gene transcription. A nuclear localization signal and Thr¹⁷² phosphorylation of 2 were found to be essential for nuclear translocation of 2AMPK, whereas the myristoylation of ß1 anchors 2AMPK in the cytoplasm. The prevention of 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 2AMPK are required for leptin-induced stimulation of fatty acid oxidation and PPAR gene expression in muscle cells.

Published ahead of print on 9 April 2007.

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