Curcumin Stimulates Glucose Uptake Through AMPK-p38 MAPK Pathways in L6 Myotube Cells JI HAE KIM, 1 JI MAN PARK, 2 EUNG-KYUN KIM, 2 JUNG OK LEE, 1 SOO KYUNG LEE, 1 JIN HEE JUNG, 1 GA YOUNG YOU, 1 SUN HWA PARK, 1 PANN-GHILL SUH, 2 ** AND HYEON SOO KIM 1 * 1 Department of Anatomy, Korea University College of Medicine, Seoul, South Korea 2 Division of Molecular and Life Science, POSTECH (Pohang University Science and Technology), Pohang, South Korea Curcumin has been shown to exert a variety of beneficial human health effects. However, mechanisms by which curcumin acts are poorly understood. In this study, we report that curcumin activated AMP-activated protein kinase (AMPK) and increased glucose uptake in rat L6 myotubes. In addition, curcumin activated the mitogen-activated protein kinase kinase (MEK)3/6-p38 mitogen-activated protein kinase (MAPK) signaling pathways in the downstream of the AMPK cascade. Moreover, inhibition of either AMPK or p38 MAPK resulted in blockage of curcumin-induced glucose uptake. Furthermore, the administration of curcumin to mice increased AMPK phosphorylation in the skeletal muscles. Taken together, these results indicate that the beneficial health effect of curcumin can be explained by its ability to activate AMPK-p38 MAPK pathways in skeletal muscles. J. Cell. Physiol. 223: 771–778, 2010. ß 2010 Wiley-Liss, Inc. Curcuma longa L., a member of the Zingiberaceae family, is a perennial herb that is distributed broadly throughout the tropical and subtropical regions of the world, and is widely cultivated in Asian countries, principally in India and China. It is the origin of the flavoring powder turmeric, a popular spice in both vegetarian and non-vegetarian foods, and it has also been shown to have favorable digestive properties (Govindarajan, 1980). Curcumin, the primary color component of turmeric, was isolated from the rhizomes of Curcuma longa L., which constitute the principal component of this plant. A number of previous studies have elucidated many of the biological functions of curcumin, including its anti-inflammatory (Srimal and Dhawan, 1973; Ammon et al., 1992; Huang et al., 1992), anti-oxidative (Reddy and Lokesh, 1992, 1994), anti-human immunodeficiency virus (HIV) (Mazumder et al., 1995), and anti-tumor properties (Huang et al., 1988). Recently, the hypoglycemic effect of turmeric was reported in a study involving diabetic mice (Kuroda et al., 2005), but the molecular mechanisms underlying this effect remain obscure. The AMP-activated protein kinase (AMPK) complex is an evolutionarily conserved cellular energy status sensor (Hardie, 2004; Kahn et al., 2005). AMPK is activated in response to an increase in the cellular AMP/ATP ratio, which occurs as the ATP levels decline (Hardie et al., 1998, 2003). Once activated, AMPK switches on ATP-generating pathways, and switches off ATP- consuming pathways. AMPK can also be activated via multiple AMPK regulatory pathways (Fryer et al., 2002; Hawley et al., 2002). The molecular mechanisms underlying AMPK activation have yet to be thoroughly elucidated, but it has been previously demonstrated that AMPK activation requires the phosphorylation of the catalytic a subunit on Thr-172 within the activation loop (Crute et al., 1998; Stein et al., 2000). Both LKB1 and calcium/calmodulin-dependent protein kinase (CaMKK) have also been associated with AMPK (Hawley et al., 2003; Woods et al., 2003; Hong et al., 2005; Hurley et al., 2005). Upon activation, AMPK causes an increase in glucose uptake, fatty acid oxidation, and mitochondrial biogenesis. The activation of p38 mitogen-activated protein kinase (MAPK) has been associated with AMPK activation (Jakobsen et al., 2001; Lemieux et al., 2003; Musi and Goodyear, 2003). It has also been suggested that p38 MAPK activation is essential for the stimulation of glucose uptake in response to insulin (Somwar et al., 2002) and muscle contraction (Somwar et al., 2000). Furthermore, p38 MAPK has been shown to be downstream of AMPK (Xi et al., 2001). Hypoxia, muscle contraction, and hyperosmolarity, all of which evoke metabolic stress, are known to increase glucose uptake and AMPK activity (Hayashi et al., 2000). Physiologic conditions also activate p38 MAPK (Conrad et al., 1999). Moreover, over-expression of constitutively active forms of p38 MAPK upstream regulatory kinases, MKK3 and MKK6, stimulates translocation of GLUT1 and GLUT4 transporters (Ryder et al., 2000). Therefore, it follows that AMPK and p38 MAPK share the similar signaling pathway. In order to more precisely characterize the metabolic effects of curcumin, we have conducted an investigation into the effects of curcumin on AMPK phosphorylation in muscle. In this study, Ji Hae Kim and Ji Man Park contributed equally to this work. Contract grant sponsor: Korea Science and Engineering Foundation (KOSEF); Contract grant number: R01-2008-000-11180-0. Contract grant sponsor: Korea Government (MEST: Ministry of Education, Science and Technology); Contract grant number: 2009-0077467. *Correspondence to: Hyeon Soo Kim, Department of Anatomy, Korea University College of Medicine, 126-1, 5-ga, Anam-dong, Seongbuk-gu, Seoul 136-701, South Korea. E-mail: anatomykim@korea.ac.kr **Correspondence to: Pann-Ghill Suh, Division of Molecular and Life Science, POSTECH, Pohang 790-784, South Korea. E-mail: pgs@postech.ac.kr Received 29 September 2009; Accepted 6 January 2010 Published online in Wiley InterScience (www.interscience.wiley.com.), 4 March 2010. DOI: 10.1002/jcp.22093 ORIGINAL ARTICLE 771 Journal of Journal of Cellular Physiology Cellular Physiology ß 2010 WILEY-LISS, INC.