The Roots of Atractylodes macrocephala Koidzumi Enhanced Glucose and Lipid Metabolism in C2C12 Myotubes via Mitochondrial Regulation

Hindawi Publishing Corporation Evidence-Based Complementary and Alternative Medicine Volume 2015, Article ID 643654, 10 pages http://dx.doi.org/10.1155/2015/643654 Research Article The Roots of Atractylodes macrocephala Koidzumi Enhanced Glucose and Lipid Metabolism in C2C12 Myotubes via Mitochondrial Regulation Mi Young Song,1,2 Seok Yong Kang,2,3 Tae Woo Oh,2 Rethineswaran Vinoth Kumar,3 Hyo Won Jung,2,3 and Yong-Ki Park2,3 1 Department of Rehabilitation Medicine of Korean Medicine, College of Korean Medicine, Dongguk University, Gyeongju 707, Republic of Korea 2 Korean Medicine R&D Center, College of Korean Medicine, Dongguk University, Gyeongju 707, Republic of Korea 3 Department of Herbology, College of Korean Medicine, Dongguk University, Gyeongju 707, Republic of Korea Correspondence should be addressed to Yong-Ki Park; Received 27 May 2015; Revised 18 September 2015; Accepted 18 October 2015 Academic Editor: Evan P. Cherniack Copyright © 2015 Mi Young Song et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The root of Atractylodes macrocephala Koidzumi (Atractylodis Rhizoma Alba, ARA) is a Traditional Korean Medicine and has been commonly used for weight control. Mitochondrial dysfunction appears to be a key contributor to insulin resistance, and therefore mitochondrial targeting drugs represent an important potential strategy for the treatment of insulin resistance and obesity. In this study, the authors investigated the regulatory effects of ARA on mitochondrial function with respect to the stimulation of glucose and lipid metabolism in C2C12 myotubes. After differentiating C2C12 myotubes, cells were treated with or without different concentrations (0.2, 0.5, and 1.0 mg/mL) of ARA extract. ARA extract significantly increased the expression of peroxisome proliferator-activated receptor coactivator 1 alpha (PGC1𝛼) and the downregulations of its targets, nuclear respiratory factor-1 (NRF1), transcription factor A (TFAM), and total ATP content in C2C12 myotubes. ARA extract also increased the expressions of PGC1𝛼 activator and of the metabolic sensors, AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase and sirtuin (SIRT) 1. Furthermore, it significantly increased glucose uptake by enhancing glucose consumption and subsequently decreased FFA contents and increased carnitine palmitoyltransferase (CPT) 1b expression. Our study indicates that ARA has a potential for stimulating mitochondrial function and energy metabolism in muscle. 1. Introduction Mitochondria play an important role in energy metabolism by activating glucose transport and fatty acid oxidation. Imbalance between energy intake and expenditure leads to mitochondrial dysfunction, which contributes to the pathogeneses of age-associated diseases, such as obesity, insulin resistance, and type 2 (T2) diabetes [1]. Skeletal muscle is a crucial tissue from the perspectives of mitochondrial dysfunction and insulin resistance. Cumulative evidence strongly suggests that changes in mitochondrial function in skeletal muscle are closely related with both insulin resistance and T2 diabetes [2–5]. Furthermore, insulin resistance is highly associated with myocellular lipid accumulation [6, 7] and impaired oxidative capacity of skeletal muscle (caused by mitochondrial dysfunction induced impairment of fatty acid oxidation) and accelerates or directly causes insulin resistance. Peroxisome proliferator-activated receptor coactivator 1 alpha (PGC1𝛼) is a key factor of mitochondrial function. PGC1𝛼 is considered a master regulator of mitochondrial biogenesis and a potent coactivator of a plethora of transcription factors that impact whole body energy expenditure. Furthermore, PGC1𝛼 is a coactivator of nuclear transcription factors, such as nuclear respiratory factor-1 (NRF-1) and transcription factor A (TFAM), which are crucially required for 2 Evidence-Based Complementary and Alternative Medicine mitochondrial gene expression and replication of the mitochondrial genome [8, 9]. In skeletal muscle, two metabolic sensors, AMP-activated protein kinase (AMPK) and sirtuin (SIRT) 1, are known to affect the activity of PGC-1𝛼 directly via the phosphorylation of AMPK and deacetylation of SIRT1 [8]. The AMPK system is a key player in the regulation of energy balance at both the cellular and whole body levels and is placed centre stage in studies on obesity, diabetes, and metabolic syndrome. In particular, the activation of AMPK in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing the expressions of genes involved in these pathways [8, 10]. SIRT1, an enzyme that mediates the NAD+ -dependent deacetylation of target substrates, is a well-known activator of PGC-1𝛼, and the two molecules, AMPK and SIRT1, have similar effects on cellular fuel metabolism and mitochondrial function because they regulate each other and share many common target molecules [11]. Recently, the developments of mitochondrial targeting drugs or nutrients for the treatment of insulin resistance, obesity, and type 2 diabetes have opened up new avenues for enhancing health [12]. Several drugs and a handful of natural and nutritional compounds, such as metformin, AMPK activator [13], thiazolidinedione (PPAR𝛾 agonist) [14], and resveratrol, SIRT1 activator [15], have been shown to regulate mitochondrial biogenesis and reduce insulin resistance. To date few medicinal plants have been investigated in this context, and, thus, natural products are viewed optimistically as a means of providing agents for the treatment of insulin resistance and its related metabolic diseases. The roots of Atractylodes macrocephala Koidzumi (Atractylodis Rhizoma Alba, ARA, Compositae) are used in Traditional Korean Medicine (TKM) for the treatment of gastrointestinal diseases, abdominal pain, and obesity, and it has been shown that ARA extract has anti-inflammatory [16, 17], antiulcer [18], and antitumor effects [19, 20]. Furthermore, the administration of ARA extract to high fat-fed obese rats reduced body weight gain and plasma triglyceride levels [21], and ARA extract has been reported to activate insulin signaling pathways in 3T3-L1 adipocytes [22]. However, the underlying mechanisms responsible for its effects on obesity and insulin resistance have not been studied in depth. Therefore, in the present study, we investigated whether ARA extract has the ability to regulate glucose and lipid metabolism by regulating mitochondrial function in skeletal muscle cells. (ARA extract) was stored at −80∘ C and dissolved in distilled water prior to assays. The compositional analysis of ARA extracts was performed by a HPLC system (Agilent Technologies 1260 Infinity, USA). Atractylenolide III (SigmaAldrich, St. Louis, MO, USA) was used as a standard. Samp (...truncated)