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J. Biol. Chem., Vol. 282, Issue 27, 19313-19320, July 6, 2007

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Role of AMP Kinase and PPAR in the Regulation of Lipid and Glucose Metabolism in Human Skeletal Muscle^*

David Kitz Krämer, Lubna Al-Khalili, Bruno Guigas¹, Ying Leng², Pablo M. Garcia-Roves, and Anna Krook^¶3

From the Departments of Molecular Medicine and Surgery and ^¶Physiology and Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden and Hormone and Metabolic Research Unit, School of Medicine, Université Catholique de Louvain and Institute of Cellular Pathology, B-1200 Brussels, Belgium

The peroxisome proliferator-activated receptor (PPAR) has been implicated in the regulation of lipid metabolism in skeletal muscle. Furthermore, activation of PPAR has been proposed to improve insulin sensitivity and reduce glucose levels in animal models of type 2 diabetes. We recently demonstrated that the PPAR agonist GW501516 activates AMP-activated protein kinase (AMPK) and stimulates glucose uptake in skeletal muscle. However, the underlying mechanism remains to be clearly identified. In this study, we first confirmed that incubation of primary cultured human muscle cells with GW501516 induced AMPK phosphorylation and increased fatty acid transport and oxidation and glucose uptake. Using small interfering RNA, we have demonstrated that PPAR expression is required for the effect of GW501516 on the intracellular accumulation of fatty acids. Furthermore, we have shown that the subsequent increase in fatty acid oxidation induced by GW501516 is dependent on both PPAR and AMPK. Concomitant with these metabolic changes, we provide evidence that GW501516 increases the expression of key genes involved in lipid metabolism (FABP3, CPT1, and PDK4) by a PPAR-dependent mechanism. Finally, we have also demonstrated that the GW501516-mediated increase in glucose uptake requires AMPK but not PPAR. In conclusion, the PPAR agonist GW501516 promotes changes in lipid/glucose metabolism and gene expression in human skeletal muscle cells by PPAR- and AMPK-dependent and -independent mechanisms.

Received for publication, March 19, 2007 , and in revised form, May 11, 2007.

^* This study was supported by grants from the Swedish Research Council, Swedish Medical Association, the Novo-Nordisk Foundation, the Swedish Diabetes Association, the Swedish Animal Welfare Agency and the Swedish Fund for Research without Animal Experiments, the Swedish National Centre for Research in Sports, the Hedlund Foundation, and the European Union Framework 6 Integrated Project EXGENESIS LSHM-CT-2004-005272 and Network of Excellence EUGENE2 LSHM-CT-2004-512013. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of the ICP-"Michel de Visscher" Fellowship.

² Current address: Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

³ To whom correspondence should be addressed: Integrative Physiology, Dept. of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden. Tel.: 46-8-524-8-7824; Fax: 46-8-335-436; E-mail: Anna.Krook{at}ki.se.

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