Short-term adenosine monophosphate–activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside treatment increases the sirtuin 1 protein expression in skeletal muscle

Suwa, Masataka; Nakano, Hiroshi; Radák, Zsolt; Kumagai, Shuzo

doi:10.1016/j.metabol.2010.03.003

Cited by 35 publications

(33 citation statements)

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“…The ability of ALA to increase NAD + and the NAD + /NADH ratio may explain, at least in part, how ALA treatment increases SIRT1 activity. On the other hand, activation of AMPK was linked to SIRT1 protein production in skeletal muscle cells [29]. As ALA activates AMPK, another possibility is that ALA induces SIRT1 production through AMPK activation.…”

Section: Discussionmentioning

confidence: 99%

α-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase

et al. 2012

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Aims/hypothesis Sirtuin 1 (SIRT1) is a longevity-associated protein, which regulates energy metabolism and lifespan in response to nutrient deprivation. It has been proposed to be a therapeutic target for obesity and metabolic syndrome. We investigated whether α-lipoic acid (ALA) exerts a lipidlowering effect through regulation of SIRT1 activation and production in C 2 C 12 myotubes. Methods ALA-stimulated AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), adipose triacylglycerol lipase (ATGL) and fatty acid synthase (FAS) production, as well as intracellular triacylglycerol accumulation and fatty acid β-oxidation were analysed in the absence or presence of a SIRT1 inhibitor (nicotinamide), SIRT1 small interfering (si) RNA and an AMPK inhibitor (compound C) in C 2 C 12 myotubes. Mice with streptozotocin/nicotinamideinduced diabetes and db/db mice fed on a high-fat diet were used to study the ALA-mediated lipid-lowering effects in vivo.Results ALA increased the NAD + /NADH ratio to enhance SIRT1 activity and production in C 2 C 12 myotubes. ALA subsequently increased AMPK and ACC phosphorylation, leading to increased palmitate β-oxidation and decreased intracellular triacylglycerol accumulation in C 2 C 12 myotubes. In cells treated with nicotinamide or transfected with SIRT1 siRNA, ALA-mediated AMPK/ACC phosphorylation, intracellular triacylglycerol accumulation and palmitate β-oxidation were reduced, suggesting that SIRT1 is an upstream regulator of AMPK. ALA increased ATGL and suppressed FAS protein production in C 2 C 12 myotubes. Oral administration of ALA in diabetic mice fed on a high-fat diet and db/db mice dramatically reduced the body weight and visceral fat content. Conclusions/interpretation ALA activates both SIRT1 and AMPK, which leads to lipid-lowering effects in vitro and in vivo. These findings suggest that ALA may have beneficial effects in the treatment of dyslipidaemia and obesity.

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Section: Discussionmentioning

confidence: 99%

α-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase

et al. 2012

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“…LDH facilitates the pyruvate uptake of mitochondria (52) that further influences the NAD/NADH ratio, and one can expect decreased SIRT1 activity right after intensive exercise bouts, due to the increased lactate/pyruvate ratio, which, in turn, decreases the NAD/NADH ratio. However, exercise bouts increase the activity of SIRT1 (188,308,383), indicating that within a certain range, SIRT1 activity is independent from the NAD/NADH ratio (9). On the other hand, significant oxidative stress could down-regulate SIRT1 (7).…”

Section: A Sirtuins As Redox-sensitive Energy Sensors Of Exercisementioning

confidence: 99%

Oxygen Consumption and Usage During Physical Exercise: The Balance Between Oxidative Stress and ROS-Dependent Adaptive Signaling

Radák

Zhao

Koltai

et al. 2013

Antioxidants & Redox Signaling

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The complexity of human DNA has been affected by aerobic metabolism, including endurance exercise and oxygen toxicity. Aerobic endurance exercise could play an important role in the evolution of Homo sapiens, and oxygen was not important just for survival, but it was crucial to redox-mediated adaptation. The metabolic challenge during physical exercise results in an elevated generation of reactive oxygen species (ROS) that are important modulators of muscle contraction, antioxidant protection, and oxidative damage repair, which at moderate levels generate physiological responses. Several factors of mitochondrial biogenesis, such as peroxisome proliferator-activated receptor-c coactivator 1a (PGC-1a), mitogen-activated protein kinase, and SIRT1, are modulated by exercise-associated changes in the redox milieu. PGC-1a activation could result in decreased oxidative challenge, either by upregulation of antioxidant enzymes and/or by an increased number of mitochondria that allows lower levels of respiratory activity for the same degree of ATP generation. Endogenous thiol antioxidants glutathione and thioredoxin are modulated with high oxygen consumption and ROS generation during physical exercise, controlling cellular function through redox-sensitive signaling and proteinprotein interactions. Endurance exercise-related angiogenesis, up to a significant degree, is regulated by ROSmediated activation of hypoxia-inducible factor 1a. Moreover, the exercise-associated ROS production could be important to DNA methylation and post-translation modifications of histone residues, which create heritable adaptive conditions based on epigenetic features of chromosomes. Accumulating data indicate that exercise with moderate intensity has systemic and complex health-promoting effects, which undoubtedly involve regulation of redox homeostasis and signaling. Antioxid. Redox Signal. 18, 1208Signal. 18, -1246

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“…The AMP-activated protein kinase is an intracellular energy sensor and plays an important role in maintaining energy homeostasis (7). Activation of AMPK has been reported to increase SIRT1 protein levels in skeletal muscle (40) and to activate NAMPT, thereby increasing intracellular NAD ϩ levels (5). We therefore studied whether AMPK is involved in regulation of SIRT1 signaling by leucine.…”

Section: Effect Of Dietary Leucine On Sirt1 Expression In Skeletal Mumentioning

confidence: 99%

Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice

Lee

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

125

106

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Li H, Xu M, Lee J, He C, Xie Z. Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice. Am J Physiol Endocrinol Metab 303: E1234 -E1244, 2012. First published September 11, 2012; doi:10.1152/ajpendo.00198.2012.-Leucine supplementation has been shown to prevent high-fat diet (HFD)-induced obesity, hyperglycemia, and dyslipidemia in animal models, but the underlying mechanisms are not fully understood. Recent studies suggest that activation of Sirtuin 1 (SIRT1) is an important mechanism to maintain energy and metabolic homeostasis. We therefore examined the involvement of SIRT1 in leucine supplementationprevented obesity and insulin resistance. To accomplish this goal, male C57BL/6J mice were fed normal diet or HFD, supplemented with or without leucine. After 2 mo of treatment, alterations in SIRT1 expression, insulin signaling, and energy metabolism were analyzed. Eight weeks of HFD induced obesity, fatty liver, mitochondrial dysfunction, hyperglycemia, and insulin resistance in mice. Addition of leucine to HFD correlated with increased expression of SIRT1 and NAMPT (nicotinamide phosphoribosyltransferase) as well as higher intracellular NAD ϩ levels, which decreased acetylation of peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC1␣) and forkhead box O1 (FoxO1). The deacetylation of PGC1␣ may contribute to upregulation of genes controlling mitochondrial biogenesis and fatty acid oxidation, thereby improving mitochondrial function and preventing HFD-induced obesity in mice. Moreover, decreased acetylation of FoxO1 was accompanied by decreased expression of pseudokinase tribble 3 (TRB3) and reduced the association between TRB3 and Akt, which enhanced insulin sensitivity and improved glucose metabolism. Finally, transfection of dominant negative AMPK prevented activation of SIRT1 signaling in HFD-Leu mice. These data suggest that increased expression of SIRT1 after leucine supplementation may lead to reduced acetylation of PGC1␣ and FoxO1, which is associated with attenuation of HFD-induced mitochondrial dysfunction, insulin resistance, and obesity. leucine supplementation; obesity; SIRT1; PGC1␣; FoxO1; insulin resistance OBESITY, THE MOST COMMON NUTRITIONAL DISORDER in Western countries, is primarily an imbalance between calorie intake and energy expenditure (17). Increasing evidence suggests that obesity and insulin resistance are associated with reduced mitochondrial biogenesis and impaired mitochondrial function (32), which can be triggered by adverse nutrition such as increased fatty acid exposure resulting from high-fat diet (HFD) or overfeeding. Impaired mitochondrial function leads to lipid accumulation in fat tissue, skeletal muscle, and liver, impairing insulin signaling and glucose metabolism (3). Interventions to increase mitochondrial biogenesis and improve mitochondrial function have been shown to correct insulin signaling and metabolic abnormalities (35).Traditionally, strategies for preventin...

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Short-term adenosine monophosphate–activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside treatment increases the sirtuin 1 protein expression in skeletal muscle

Cited by 35 publications

References 61 publications

α-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase

α-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase

Oxygen Consumption and Usage During Physical Exercise: The Balance Between Oxidative Stress and ROS-Dependent Adaptive Signaling

Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice

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