AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARa and PGC-1 Woo Je Lee a,1 , Mina Kim b,1 , Hye-Sun Park b , Hyoun Sik Kim b , Min Jae Jeon b , Ki Sook Oh b , Eun Hee Koh a , Jong Chul Won a , Min-Seon Kim a , Goo Taeg Oh c , Michung Yoon d , Ki-Up Lee a , Joong-Yeol Park a, * a Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea b Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea c Division of Molecular Life Sciences, Center for Cell Signaling Research, Ewha Womans University, Seoul, Republic of Korea d Department of Life Sciences, Mokwon University, Taejon, Republic of Korea Received 20 November 2005 Available online 12 December 2005 Abstract AMP-activated protein kinase (AMPK) activation increases fatty acid oxidation in skeletal muscle by decreasing malonyl CoA con- centrations. However, this may not explain the long-term effects of AMPK activation. Here we show that AMPK activation by 5-amino- imidazole-4-carboxamide ribonucleoside (AICAR) increases mRNA expression of PPARa target genes and PGC-1 in cultured muscle cells and mouse skeletal muscle, and that inhibition of PPARa and PGC-1 by siRNAs prevents AICAR-stimulated increase in fatty acid oxidation. These data suggest that a novel transcriptional regulatory mechanism involving PPARa and PGC-1 exists that is responsible for long-term stimulation of fatty acid oxidation in skeletal muscle by AICAR. Ó 2005 Elsevier Inc. All rights reserved. Keywords: AICAR; AMPK; PPARa; PGC-1; Fatty acid oxidation; Muscle AMP-activated protein kinase (AMPK) is an enzyme that is activated when cellular energy is depleted [1,2]. When activated, AMPK increases glucose uptake and fatty acid oxidation in skeletal muscle cells to increase ATP pro- duction [3–6]. The adenosine analog 5-aminoimidazole-4- carboxamide ribonucleoside (AICAR) is a well-known activator of AMPK [7]. Activation of AMPK by AICAR has been shown to decrease intracellular malonyl CoA con- centrations by inhibiting acetyl CoA carboxylase (ACC), the rate-limiting enzyme of malonyl CoA synthesis [4,8], and by stimulating malonyl CoA decarboxylase (MCD), the enzyme responsible for malonyl CoA degradation [8,9]. Malonyl CoA is an allosteric inhibitor of carnitine palmitoyltransferase (CPT)-1, the enzyme that controls the transfer of long-chain fatty acyl CoA into the mito- chondria. Thus, decreased malonyl CoA concentrations triggered by AMPK activation may account for the increased fatty acid oxidation that is observed in these cells. However, these processes are relatively transient and may not be sufficient to explain the long-term effects of AMPK activation. In fact, sustained activation of AMPK has been shown not to be associated with inactivation of ACC dur- ing prolonged exercise [10]. The peroxisome proliferator-activated receptors (PPARs), which constitute a subfamily of the nuclear receptor superfamily, regulate gene expression in response to ligand binding [11–13]. Among them, PPARa is expressed predominantly in the liver, heart, and skeletal muscle, and up-regulates the expression of genes involved in fatty acid metabolism [12–16], particularly when coacti- vated by PPARc coactivator (PGC)-1 [17]. In fact, endur- ance training, a condition that chronically activates 0006-291X/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2005.12.011 * Corresponding author. Fax: +82 2 3010 6962. E-mail address: jypark@amc.seoul.kr (J.-Y. Park). 1 These authors contributed equally to this work. www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 340 (2006) 291–295 BBRC