Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.27 (AMPK)
 6,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increasing evidence suggests that reduced adipose tissue mitochondrial content is associated with the pathogenesis of type 2 diabetes. These investigations have utilized severely insulin-resistant rodent models. Thus, it is difficult to ascertain the potential mechanisms that initiate these changes and whether reductions in adipose mitochondria are an initiating event in the development of impaired glucose homeostasis. Thus, we sought to determine the time course of high-fat diet-induced reductions of mitochondrial content in epididymal adipose tissue in relation to changes in purported mediators of mitochondrial biogenesis and the development of impaired glucose homeostasis. Male Wistar rats were fed a high-fat diet ( approximately 59% of kcals from fat) for 2, 4, or 6 wk. Six weeks of high-fat feeding resulted in reductions in CORE I, COX IV, cytochrome c, HSP60, relative mtDNA copy number, and PGC-1alpha expression. These changes were not associated with decreases in eNOS and AMPK or increases in markers of oxidative stress. Interestingly, ex vivo treatment of adipose tissue cultures with palmitate led to decreases in PGC-1alpha expression and COX IV and CORE I protein content as observed in vivo. Thus, the high-fat diet-induced reductions in adipose tissue mitochondrial proteins may be mediated by increases in plasma fatty acids. Importantly, reductions in adipose tissue mitochondrial content occurred after the development of impaired glucose homeostasis. Thus, reductions in adipose tissue mitochondrial proteins are most likely not a causal event in the development of impaired glucose homeostasis.
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PMID:Time course of high-fat diet-induced reductions in adipose tissue mitochondrial proteins: potential mechanisms and the relationship to glucose intolerance. 1878 Jul 75

The mechanisms by which PGC-1alpha gene expression is controlled in skeletal muscle remains largely undefined. Thus, we sought to investigate the transcriptional regulation of PGC-1alpha using AICAR, an activator of AMPK, that is known to increase PGC-1alpha expression. A 2.2 kb fragment of the human PGC-1alpha promoter was cloned and sequence analysis revealed that this TATA-less sequence houses putative consensus sites including a GC-box, a CRE, several IRSs, a SRE, binding sites for GATA, MEF2, p 53, NF-kappaB, and EBox binding proteins. AMPK activation for 24 hours increased PGC-1alpha promoter activity with concomitant increases in mRNA expression. The effect of AICAR on transcriptional activation was mediated by an overlapping GATA/EBox binding site at -495 within the PGC-1alpha promoter based on gel shift analyses that revealed increases in GATA/EBox DNA binding. Mutation of the EBox within the GATA/EBox binding site in the promoter reduced basal promoter activity and completely abolished the AICAR effect. Supershift analyses identified USF-1 as a DNA binding transcription factor potentially involved in regulating PGC-1alpha promoter activity, which was confirmed in vivo by ChIP. Overexpression of either GATA-4 or USF-1 alone increased the p851 PGC-1alpha promoter activity by 1.7- and 2.0-fold respectively, while co-expression of GATA-4 and USF-1 led to an additive increase in PGC-1alpha promoter activity. The USF-1-mediated increase in PGC-1alpha promoter activation led to similar increases at the mRNA level. Our data identify a novel AMPK-mediated regulatory pathway that regulates PGC-1alpha gene expression. This could represent a potential therapeutic target to control PGC-1alpha expression in skeletal muscle.
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PMID:AMP-activated protein kinase-regulated activation of the PGC-1alpha promoter in skeletal muscle cells. 1897 83

Acute exercise performance represents a major metabolic challenge for the skeletal muscle, but also for the liver as the most important source of energy. However the molecular adaptation of the liver to one single bout of exercise is largely unknown. C57BL/6 mice performed a 60 min treadmill run at high aerobic intensity. Liver, soleus and white gastrocnemius muscle were removed immediately after exercise. The single bout of exercise resulted in a very rapid and pronounced induction of hepatic metabolic enzymes and regulators of metabolism or transcription: glucose-6-phosphatase (G6Pase; 3-fold), pyruvate dehydrogenase kinase-4 (PDK4; 4.8-fold), angiopoietin-like 4 (2.1-fold), insulin receptor substrate (IRS)-2 (5.1-fold), peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-1alpha; 3-fold). In soleus and white gastrocnemius muscle the up-regulation of IRS-2 and PDK4 was less pronounced compared with the liver and no significant induction of PGC-1alpha could be detected at this early time point. Activation of AMPK was found in both liver and white gastrocnemius muscle as phosphorylation of Thr-172. The induction of endogenous insulin secretion by a glucose load directly after the exercise bout resulted in a significantly higher PKB/Akt phosphorylation in the liver of exercised mice. The markedly enhanced IRS-2 protein amount, and presumably reduced serine/threonine phosphorylation of the IRS proteins induced by the acute exercise could be responsible for this enhanced action of insulin. In conclusion, acute exercise induced a rapid and pronounced transcriptional adaptation in the liver, and regulated hepatic IRS proteins leading to improved cellular insulin signal transduction.
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PMID:Acute regulation of metabolic genes and insulin receptor substrates in the liver of mice by one single bout of treadmill exercise. 1900 Oct 47

Reactive oxygen species (ROS) play an important role in cellular function via the activation of signaling cascades. ROS have been shown to affect mitochondrial biogenesis, morphology, and function. Their beneficial effects are likely mediated via the upregulation of transcriptional regulators such as peroxisome proliferator-activated receptor-gamma coactivator-1 protein-alpha (PGC-1alpha). However, the ROS signals that regulate PGC-1alpha transcription in skeletal muscle are not understood. Here we examined the effect of H2O2 on the regulation of PGC-1alpha expression, and its relationship to AMPK activation. We demonstrate that 24 h of exogenous H2O2 treatment increased PGC-1alpha promoter activity and mRNA expression. Both effects were blocked with the addition of N-acetylcysteine, a ROS scavenger. These effects were mediated, in part, via upstream stimulatory factor-1/Ebox DNA binding and involved 1) interactions with downstream sequences and 2) the activation of AMPK. Elevated ROS led to the activation of AMPK, likely via a decline in ATP levels. The activation of AMPK using 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside increased PGC-1alpha promoter activity and mRNA levels but reduced ROS production. Thus the net effect of AMPK activation on PGC-1alpha expression was a result of increased transcriptional activation, counterbalanced by reduced ROS production. The effects of H2O2 on PGC-1alpha expression differed depending on the level of ROS within the cell. Low levels of ROS result in reduced PGC-1alpha mRNA in the absence of an effect on PGC-1alpha promoter activation. In contrast, elevated levels of H2O2 induce PGC-1alpha transcription indirectly, via AMPK activation. These data identify unique interactions between ROS and AMPK activation on the expression of PGC-1alpha in muscle cells.
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PMID:Interactions between ROS and AMP kinase activity in the regulation of PGC-1alpha transcription in skeletal muscle cells. 1900 63

The NAD(+)-dependent deacetylase SIRT1 controls metabolic processes in response to low nutrient availability. We report the metabolic phenotype of mice treated with SRT1720, a specific and potent synthetic activator of SIRT1 that is devoid of direct action on AMPK. SRT1720 administration robustly enhances endurance running performance and strongly protects from diet-induced obesity and insulin resistance by enhancing oxidative metabolism in skeletal muscle, liver, and brown adipose tissue. These metabolic effects of SRT1720 are mediated by the induction of a genetic network controlling fatty acid oxidation through a multifaceted mechanism that involves the direct deacetylation of PGC-1alpha, FOXO1, and p53 and the indirect stimulation of AMPK signaling through a global metabolic adaptation mimicking low energy levels. Combined with our previous work on resveratrol, the current study further validates SIRT1 as a target for the treatment of metabolic disorders and characterizes the mechanisms underlying the therapeutic potential of SIRT1 activation.
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PMID:Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. 1904 67

From a cell signaling perspective, short-duration intense muscular work is typically associated with resistance training and linked to pathways that stimulate growth. However, brief repeated sessions of sprint or high-intensity interval exercise induce rapid phenotypic changes that resemble traditional endurance training. We tested the hypothesis that an acute session of intense intermittent cycle exercise would activate signaling cascades linked to mitochondrial biogenesis in human skeletal muscle. Biopsies (vastus lateralis) were obtained from six young men who performed four 30-s "all out" exercise bouts interspersed with 4 min of rest (<80 kJ total work). Phosphorylation of AMP-activated protein kinase (AMPK; subunits alpha1 and alpha2) and the p38 mitogen-activated protein kinase (MAPK) was higher (P <or= 0.05) immediately after bout 4 vs. preexercise. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) mRNA was increased approximately twofold above rest after 3 h of recovery (P <or= 0.05); however, PGC-1alpha protein content was unchanged. In contrast, phosphorylation of protein kinase B/Akt (Thr(308) and Ser(473)) tended to decrease, and downstream targets linked to hypertrophy (p70 ribosomal S6 kinase and 4E binding protein 1) were unchanged after exercise and recovery. We conclude that signaling through AMPK and p38 MAPK to PGC-1alpha may explain in part the metabolic remodeling induced by low-volume intense interval exercise, including mitochondrial biogenesis and an increased capacity for glucose and fatty acid oxidation.
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PMID:Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1alpha in human skeletal muscle. 1911 61

The aim of the present study was to test the hypothesis that PGC-1alpha is required for exercise-induced VEGF expression in both young and old mice and that AMPK activation leads to increased VEGF expression through a PGC-1alpha-dependent mechanism. Whole body PGC-1alpha knockout (KO) and littermate wild-type (WT) mice were submitted to either 1) 5 wk of exercise training, 2) lifelong (from 2 to 13 mo of age) exercise training in activity wheel, 3) a single exercise bout, or 4) 4 wk of daily subcutaneous AICAR or saline injections. In skeletal muscle of PGC-1alpha KO mice, VEGF protein expression was approximately 60-80% lower and the capillary-to-fiber ratio approximately 20% lower than in WT. Basal VEGF mRNA expression was similar in WT and PGC-1alpha KO mice, but acute exercise and AICAR treatment increased the VEGF mRNA content in WT mice only. Exercise training of young mice increased skeletal muscle VEGF protein expression approximately 50% in WT mice but with no effect in PGC-1alpha KO mice. Furthermore, a training-induced prevention of an age-associated decline in VEGF protein content was observed in WT but not in PGC-1alpha KO muscles. In addition, repeated AICAR treatments increased skeletal muscle VEGF protein expression approximately 15% in WT but not in PGC-1alpha KO mice. This study shows that PGC-1alpha is essential for exercise-induced upregulation of skeletal muscle VEGF expression and for a training-induced prevention of an age-associated decline in VEGF protein content. Furthermore, the findings suggest an AMPK-mediated regulation of VEGF expression through PGC-1alpha.
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PMID:PGC-1alpha mediates exercise-induced skeletal muscle VEGF expression in mice. 1940 59

Mitochondria are dynamic organelles that integrate environmental signals to regulate energy production, apoptosis and Ca(2+) homeostasis. Not surprisingly, mitochondrial dysfunction is associated with aging and the pathologies observed in age-related diseases. The vast majority of mitochondrial proteins are encoded in the nuclear genome, and so communication between the nucleus and mitochondria is essential for maintenance of appropriate mitochondrial function. Several proteins have emerged as major regulators of mitochondrial gene expression, capable of increasing transcription of mitochondrial genes in response to the physiological demands of the cell. In this review, we will focus on PGC-1alpha, SIRT1, AMPK and mTOR and discuss how these proteins regulate mitochondrial function and their potential involvement in aging, calorie restriction and age-related disease. We will also discuss the pathways through which mitochondria signal to the nucleus. Although such retrograde signaling is not well studied in mammals, there is growing evidence to suggest that it may be an important area for future aging research. Greater understanding of the mechanisms by which mitochondria and the nucleus communicate will facilitate efforts to slow or reverse the mitochondrial dysfunction that occurs during aging.
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PMID:The coordination of nuclear and mitochondrial communication during aging and calorie restriction. 1949 Oct 41

Caloric restriction (CR), reduced protein, methionine, or tryptophan diets; and reduced insulin and/or IGFI intracellular signaling can extend mean and/or maximum lifespan and delay deleterious age-related physiological changes in animals. Mice and flies can shift readily between the control and CR physiological states, even at older ages. Many health benefits are induced by even brief periods of CR in flies, rodents, monkeys, and humans. In humans and nonhuman primates, CR produces most of the physiologic, hematologic, hormonal, and biochemical changes it produces in other animals. In primates, CR provides protection from type 2 diabetes, cardiovascular and cerebral vascular diseases, immunological decline, malignancy, hepatotoxicity, liver fibrosis and failure, sarcopenia, inflammation, and DNA damage. It also enhances muscle mitochondrial biogenesis, affords neuroprotection; and extends mean and maximum lifespan. CR rapidly induces antineoplastic effects in mice. Most claims of lifespan extension in rodents by drugs or nutrients are confounded by CR effects. Transcription factors and co-activators involved in the regulation of mitochondrial biogenesis and energy metabolism, including SirT1, PGC-1alpha, AMPK and TOR may be involved in the lifespan effects of CR. Paradoxically, low body weight in middle aged and elderly humans is associated with increased mortality. Thus, enhancement of human longevity may require pharmaceutical interventions.
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PMID:Caloric restriction: from soup to nuts. 1985 62

Peroxisome proliferator-activated receptor gamma coactivator (PGC-1alpha) is a transcriptional coactivator that plays a key role in coordinating mitochondrial biogenesis. Recent evidence has linked p38 MAPK and AMPK with activation of PGC-1alpha. It was recently shown in rodent skeletal muscle that acute endurance exercise causes a shift in the subcellular localization of PGC-1alpha from the cytosol to the nucleus, allowing PGC-1alpha to coactivate transcription factors and increase mitochondrial gene expression, but human data are limited and equivocal in this regard. Our purpose was to examine p38 MAPK and AMPK activation, and PGC-1alpha protein content in whole muscle, cytosolic, and nuclear fractions of human skeletal muscle following an acute bout of endurance exercise. Eight trained men (29 +/- 3 yr; Vo(2peak) = 55 +/- 2 ml.kg(-1).min(-1)) cycled for 90 min at approximately 65% of Vo(2peak) and needle biopsy samples (vastus lateralis) were obtained before and immediately after exercise. At rest, the majority of PGC-1alpha was detected in cytosolic compared with the nuclear fractions. In response to exercise, nuclear PGC-1alpha protein increased by 54% (P < 0.05), yet whole muscle PGC-1alpha protein was unchanged compared with rest. Whole muscle and cytosolic p38 MAPK phosphorylation increased several-fold immediately after exercise compared with rest (P < 0.05). Acetyl CoA carboxylase (ACC) phosphorylation, a marker of AMPK activation, was increased by approximately 5-fold in cytosolic fractions following exercise (P < 0.05). These data provide evidence that, in human skeletal muscle, activation of cytosolic p38 MAPK and AMPK may be potential signals that lead to increased nuclear abundance and activation of PGC-1alpha in response to an acute bout of endurance exercise.
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PMID:Acute endurance exercise increases the nuclear abundance of PGC-1alpha in trained human skeletal muscle. 2010 91


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