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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 {alpha} Gene Expression in Mouse C2C12 Myoblasts by Changing the Subcellular Localization of the {alpha}2 Form of AMP-Activated Protein Kinase{triangledown} ,{dagger}

Atsushi Suzuki, Shiki Okamoto, Suni Lee, Kumiko Saito, Tetsuya Shiuchi, and Yasuhiko Minokoshi*

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 {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 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, {alpha}2AMPK containing the ß2 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 Thr172 phosphorylation of {alpha}2 were found to be essential for nuclear translocation of {alpha}2AMPK, whereas the myristoylation of ß1 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 subcellular localization of {alpha}2AMPK are required for leptin-induced stimulation of fatty acid oxidation and PPAR{alpha} gene expression in muscle cells.

* Corresponding author. Mailing address: Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan. Phone: 81-564-55-7745. Fax: 81-564-55-7741. E-mail: minokosh{at}nips.ac.jp

{triangledown} Published ahead of print on 9 April 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

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.



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