Atractylenolide III Enhances Energy Metabolism by Increasing the SIRT-1 and PGC1α Expression with AMPK Phosphorylation in C2C12 Mouse Skeletal Muscle Cells

Abstract

Targeting energy expenditure provides a potential alternative strategy for achieving energy balance to combat obesity and the development of type 2 diabetes mellitus (T2DM). In the present study, we investigated whether atractylenolide III (AIII) regulates energy metabolism in skeletal muscle cells. Differentiated C2C12 myotubes were treated with AIII (10, 20, or 50 µM) or metformin (2.5 mM) for indicated times. The levels of glucose uptake, the expressions of key mitochondrial biogenesis-related factors and their target genes were measured in C2C12 myotubes. AIII significantly increased the glucose uptake levels, and significantly increased the expressions of peroxisome proliferator-activated receptor coactivator-1α (PGC1α) and mitochondrial biogenesis-related markers, such as, nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TFAM) and mitochondrial mass and total ATP contents. In addition, AIII significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of sirtuin1 (SIRT1). These results suggest that AIII may have beneficial effects on obesity and T2DM by improving energy metabolism in skeletal muscle.Key words atractylenolide III; mitochondrial biogenesis; AMP-activated protein kinase; peroxisome proliferator-activated receptor coactivator-1α; sirtuin1; C2C12 cellThe prevalence of obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM) has increased over past decades, 1) and it is estimated over 1.9 billion adults worldwide are overweight, and that more than 600 million are clinically obese. 2)Obesity, T2DM, and metabolic syndrome are among the most frequent pathological consequences of chronic energy metabolism imbalance.3) The maintenance of energy balance depends on the regulations of energy intake and expenditure. However, the long-term efficacies of reduced energy intake, such as, by calorific restriction, are problematic, and thus, the targeting of energy expenditure could provide a more effective means of promoting energy balance and combating obesity and T2DM. 4)Skeletal muscle is regarded a target organ in the context of cellular bioenergetics, and is known to play an important role in the maintenance of glucose homeostasis and insulin sensitivity. Insulin resistance is associated with myocellular lipid accumulation, and it has been shown that insulin resistance is caused or accelerated by impaired oxidative capacity of skeletal muscle.5,6) One study conducted under euglycemic conditions showed that skeletal muscle is responsible for ca. 80% of total body glucose uptake. 7)Peroxisome proliferator-activated receptor coactivator 1α (PGC1α), AMP-activated protein kinase (AMPK) and sirtuin1 (SIRT1) compose an energy sensing network that controls energy expenditure in skeletal muscle.8) PGC1α plays a central role in the regulation of cellular energy metabolism, which results from the up-regulation of oxidative metabolism and the stimulation of mitochondrial biogenesis. 9) Furthermore, it is known metabolic sensors, such as A...

The Root of Atractylodes macrocephala Koidzumi Prevents Obesity and Glucose Intolerance and Increases Energy Metabolism in Mice

“…Interestingly, in the present study, ARA increased PGC1α and phosphorylated AMPK protein levels and the protein levels of NRF1 and TFAM, which are both downstream transcription factors of PGC1α [ 18 ]. Furthermore, these findings are consistent with those that we previously reported for C2C12 skeletal muscle cells [ 15 , 16 ]. In addition, PGC1α has been shown to regulate the expressions of endogenous antioxidant proteins [ 19 ], and, in the present study, we observed that ARA also increased levels of antioxidant enzymes, such as HO-1 and catalase.…”

“…ARA or fermented ARA have been reported to reduce body weights and serum lipid levels in high fat diet (HFD) induced animal models of obesity [ 13 , 14 ], but the mechanisms responsible for these anti-obesity effects have not been elucidated. In a previous study, we found ARA increased lipid and glucose metabolism by enhancing the activities of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) and adenosine monophosphate-activated protein kinase (AMPK) in C2C12 skeletal muscle cells [ 15 ], and, in a following study, we showed that atractylenolide III (the primary bioactive component in ARA) also enhanced PGC1α and AMPK activities in C2C12 cells [ 16 ]. However, no reports have been previously issued on the regulation of energy metabolism by ARA in an obese animal model.…”

AMPK: a balancer of the renin–angiotensin system

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Systematic integrative analysis of gene expression identifies HNF4A as the central gene in pathogenesis of non-alcoholic steatohepatitis

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