a-Lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle q Woo Je Lee a,1 , Kee-Ho Song c,1 , Eun Hee Koh a , Jong Chul Won a , Hyoun Sik Kim b , Hye-Sun Park b , Min-Seon Kim a , Seung-Whan Kim a,b , Ki-Up Lee a , Joong-Yeol Park a, * a Division of Endocrinology and Metabolism, 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 Endocrinology and Metabolism, Department of Internal Medicine, University of Konkuk College of Medicine, Seoul, Republic of Korea Received 6 May 2005 Available online 16 May 2005 Abstract Triglyceride accumulation in skeletal muscle contributes to insulin resistance in obesity. We recently showed that a-lipoic acid (ALA) reduces body weight and prevents the development of diabetes in diabetes-prone obese rats by reducing triglyceride accu- mulation in non-adipose tissues. AMP-activated protein kinase (AMPK) is a major regulator of cellular energy metabolism. We examined whether ALA lowers triglyceride accumulation in skeletal muscle by activating AMPK. a2-AMPK activity was decreased in obese rats compared to control rats. Administration of ALA to obese rats increased insulin-stimulated glucose disposal in whole body and in skeletal muscle. ALA also increased fatty acid oxidation and activated AMPK in skeletal muscle. Adenovirus-mediated administration of dominant negative AMPK into skeletal muscle prevented the ALA-induced increases in fatty acid oxidation and insulin-stimulated glucose uptake. These results suggest that ALA-induced improvement of insulin sensitivity is mediated by acti- vation of AMPK and reduced triglyceride accumulation in skeletal muscle. Ó 2005 Published by Elsevier Inc. Keywords: a-Lipoic acid; Insulin sensitivity; AMPK; Fatty acid oxidation; Skeletal muscle; Obesity Previous studies have shown that triglyceride accu- mulation is increased in skeletal muscle of obese subjects and of animal models of obesity [1,2]. In addition, stor- age of excess triglyceride and long chain fatty acyl CoA (LCAC) was shown to impair insulin signaling [2,3]. This has led to the hypothesis that, in obesity, increased lipid accumulation in skeletal muscle contributes to insulin resistance, leading to the development of type 2 diabetes mellitus [1,3–6]. AMP-activated protein kinase (AMPK) is an enzyme that is activated when the cellular energy is depleted [7]. When activated, AMPK increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis [8–12]. We recently reported that a-lipoic acid (ALA), a naturally occurring antioxidant and a cofactor of mitochondrial respiratory enzymes, reduces body weight [13] and pre- vents the development of diabetes in diabetes-prone obese rats by reducing triglyceride accumulation in non-adipose tissues [14]. We also found that ALA sup- presses hypothalamic AMPK, and that this is responsi- ble for anti-obesity effect of this drug [13]. Interestingly, Minokoshi et al. recently reported that leptin suppresses AMPK in the hypothalamus [15] but activates it in skel- etal muscle [16]. Thus, it is quite possible that ALA also activates AMPK in skeletal muscle while suppressing it in the hypothalamus. In this study, we examined 0006-291X/$ - see front matter Ó 2005 Published by Elsevier Inc. doi:10.1016/j.bbrc.2005.05.035 q Portions of this work were presented in abstract form at the 63rd Scientific Sessions of American Diabetes Association in New Orleans, Louisiana, USA, on June 13–17, 2003 (Diabetes 52 (Suppl. 1) (2003) A123). * 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 332 (2005) 885–891 BBRC