Adenosine Monophosphate Kinase Activation Research Articles

RAGE signaling mediates post-injury arterial neointima formation by suppression of liver kinase B1 and AMPK activity

ObjectiveIntima formation involves smooth muscle cell (SMC) proliferation and migration that ultimately drives arterial stenosis, thrombosis, and ischemia in atherosclerosis, hypertension, and arterial revascularization. Receptor for advanced glycation endproducts (RAGE) is a transmembrane signaling receptor implicated in diabetic renal and vascular complications, and post-injury intima formation, partly via Signal transducer and activator of transcription 3 (STAT3) activation. The metabolic super-regulator Adenosine monophosphate kinase (AMPK) inhibits SMC proliferation and intima formation. AMPK activation is promoted by liver kinase B1 (LKB1), and LKB1 inhibits STAT3 activation. Here, we tested the hypothesis that RAGE promotes arterial intima formation by modulating both LKB1 and AMPK. Methods and resultsRAGE ligands (the calgranulin S100A11, and glycated albumin) suppressed AMPK activation in conjunction with increased proliferation and migration of cultured SMCs. These effects were inhibited both by RAGE deficiency and by prior AMPK activation. In SMCs, RAGE ligands decreased LKB1 activity. Moreover, knockdown of both LKB1 and AMPK were associated with increased STAT3 phosphorylation levels. In response to murine carotid artery ligation, expression of RAGE and S100A11 increased, whereas AMPK and LKB1 activity decreased in situ. Conversely, LKB1 and AMPK activity increased in situ, and neointima formation was attenuated in Rage−/− mice. ConclusionThe linkage of decreased LKB1 and AMPK activity with increased STAT3 in SMCs mediates the capacity of RAGE ligand-induced signaling to promote neointima formation in response to arterial injury.

Obesity and energy balance: is the tail wagging the dog?

The scientific study of obesity has been dominated throughout the twentieth century by the concept of energy balance. This conceptual approach, based on fundamental thermodynamic principles, states that energy cannot be destroyed, and can only be gained, lost or stored by an organism. Its application in obesity research has emphasised excessive appetite (gluttony), or insufficient physical activity (sloth), as the primary determinants of excess weight gain, reflected in current guidelines for obesity prevention and treatment. This model cannot explain why weight accumulates persistently rather than reaching a plateau, and underplays the effect of variability in dietary constituents on energy and intermediary metabolism. An alternative model emphasises the capacity of fructose and fructose-derived sweeteners (sucrose, high-fructose corn syrup) to perturb cellular metabolism via modification of the adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio, activation of AMP kinase and compensatory mechanisms, which favour adipose tissue accretion and increased appetite while depressing physical activity. This conceptual model implicates chronic hyperinsulinaemia in the presence of a paradoxical state of 'cellular starvation' as a key driver of the metabolic modifications inducing chronic weight gain. We combine evidence from in vitro and in vivo experiments to formulate a perspective on obesity aetiology that emphasises metabolic flexibility and dietary composition rather than energy balance. Using this model, we question the direction of causation of reported associations between obesity and sleep duration or childhood growth. Our perspective generates new hypotheses, which can be tested to improve our understanding of the current obesity epidemic, and to identify novel strategies for prevention or treatment.

Resveratrol prevents norepinephrine induced hypertrophy in adult rat cardiomyocytes, by activating NO-AMPK pathway

Increased adrenergic drive is a major factor influencing the development of pathological cardiac hypertrophy, a stage which precedes overt heart failure. We examined the effect of resveratrol, a polyphenol (found predominantly in grapes), in preventing norepinephrine induced hypertrophy of adult cardiomyocyte, and the role of nitric oxide (NO) and adenosine monophosphate kinase (AMPK) in the effects of resveratrol. Cardiomyocytes isolated from adult rats were pretreated, or not, with resveratrol and then exposed to norepinephrine for 24h. In other experiments cardiomyocytes were also treated with different pharmacological inhibitors of NO synthase, AMPK and sirtuin for elucidating the signaling pathways underlying the effect of resveratrol. In order to validate the role of these signaling molecules in the in vivo settings, we also examined hearts from resveratrol treated spontaneously hypertensive rats (SHR), a genetic model of essential hypertension. Cardiomyocyte hypertrophy was determined by morphometry and 3H-phenylalanine incorporation assay. NO levels and AMPK activity were measured using a specific assay kit and western blot analysis respectively. In vitro, resveratrol prevented the norepinephrine-induced increase in cardiomyocytes size and protein synthesis. Pharmacological inhibition of NO-AMPK signaling abolished the anti-hypertrophic action of resveratrol. Consistent with the in vitro findings, the anti-hypertrophic effect of resveratrol in the SHR model was associated with increases in NO and AMPK activity. This study demonstrates that NO-AMPK signaling is linked to the anti-hypertrophic effect of resveratrol in adult cardiomyocytes in vitro, and in the SHR model in vivo.

The Role of Adenosine Monophosphate Kinase in Remodeling White Adipose Tissue Metabolism

Recent evidence indicates that the enzyme adenosine monophosphate (AMP) kinase exerts important fat-reducing effects in the adipose tissue, which has created great interest in this enzyme as a potential target for obesity treatment. This review summarizes our findings that chronic AMP kinase activation remodels adipocyte glucose and lipid metabolism and enhances the ability of adipose tissue to dissipate energy within itself and reduce adiposity.

Cerebral metabolism after forced or voluntary physical exercise

The pathophysiology of stroke, a leading cause of morbidity and mortality, is still in the process of being understood. Pre-ischemic exercise has been known to be beneficial in reducing the severity of stroke-induced brain injury in animal models. Forced exercise with a stressful component, rather than voluntary exercise, was better able to induce neuroprotection. This study further determined the changes in cerebral metabolism resulting from the two methods of exercise (forced versus voluntary).Adult male Sprague–Dawley rats were randomly assigned to 3 groups: the control group (no exercise), the forced treadmill exercise group, and the voluntary running wheel exercise group. In order to measure the extent of cerebral metabolism in animals with different exercise regimens, mRNA levels and protein expression of glucose transporter 1 and glucose transporter 3 (GLUT-1 and GLUT-3), phosphofructokinase (PFK), lactate dehydrogenase (LDH), and adenosine monophosphate kinase (AMPK) were measured utilizing real-time reverse transcription polymerase chain reaction (PCR) analysis as well as Western blot analysis. Phosphorylated AMPK activity was also measured using an ELISA activity kit, and hypoxic inducible factor (HIF)-1α was measured at transcription and translation levels.The data show that the forced exercise group had a significant (p < 0.05) increase in cerebral glycolysis, including expressions of GLUT-1, GLUT-3, PFK, LDH, phosphorylated AMPK activity and HIF-1α, when compared to the voluntary exercise and the control groups. Our results suggest that the effects of different exercise on HIF-1α expression and cerebral glycolysis may provide a possible reason for the discrepancy in neuroprotection, with forced exercise faring better than voluntary exercise through increased cerebral metabolism.

The Physiological Deadlock between AMPK and Gluconeogenesis: SOGA, a Novel Protein, May Provide the Key

This Commentary discusses how suppressor of glucose by autophagy (SOGA) contributes to adiponectin-mediated insulin-dependent inhibition of autophagy during the activation of adenosine monophosphate kinase (AMPK).

Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation

Most cancer cells exhibit increased glycolysis for generation of their energy supply. This specificity could be used to preferentially kill these cells. In this study, we identified the signaling pathway initiated by glycolysis inhibition that results in sensitization to death receptor (DR)-induced apoptosis. We showed, in several human cancer cell lines (such as Jurkat, HeLa, U937), that glucose removal or the use of nonmetabolizable form of glucose (2-deoxyglucose) dramatically enhances apoptosis induced by Fas or by tumor necrosis factor-related apoptosis-inducing ligand. This sensitization is controlled through the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is the central energy-sensing system of the cell. We established the fact that AMPK is activated upon glycolysis block resulting in mammalian target of rapamycin (mTOR) inhibition leading to Mcl-1 decrease, but no other Bcl-2 anti-apoptotic members. Interestingly, we determined that, upon glycolysis inhibition, the AMPK-mTOR pathway controlled Mcl-1 levels neither through transcriptional nor through posttranslational mechanism but rather by controlling its translation. Therefore, our results show a novel mechanism for the sensitization to DR-induced apoptosis linking glucose metabolism to Mcl-1 downexpression. In addition, this study provides a rationale for the combined use of DR ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers.

Mitochondrial DNA: An Up‐and‐coming Actor in White Adipose Tissue Pathophysiology

Mitochondrial DNA: An Up‐and‐coming Actor in White Adipose Tissue Pathophysiology

2020 Is 18F-FDG a surrogate tracer to measure tumor hypoxia? Comparison with the hypoxic tracer 14C-EF3 in animal tumour models

The pathophysiology of stroke, a leading cause of morbidity and mortality, is still in the process of being understood. Pre-ischemic exercise has been known to be beneficial in reducing the severity of stroke-induced brain injury in animal models. Forced exercise with a stressful component, rather than voluntary exercise, was better able to induce neuroprotection. This study further determined the changes in cerebral metabolism resulting from the two methods of exercise (forced versus voluntary).Adult male Sprague–Dawley rats were randomly assigned to 3 groups: the control group (no exercise), the forced treadmill exercise group, and the voluntary running wheel exercise group. In order to measure the extent of cerebral metabolism in animals with different exercise regimens, mRNA levels and protein expression of glucose transporter 1 and glucose transporter 3 (GLUT-1 and GLUT-3), phosphofructokinase (PFK), lactate dehydrogenase (LDH), and adenosine monophosphate kinase (AMPK) were measured utilizing real-time reverse transcription polymerase chain reaction (PCR) analysis as well as Western blot analysis. Phosphorylated AMPK activity was also measured using an ELISA activity kit, and hypoxic inducible factor (HIF)-1α was measured at transcription and translation levels.The data show that the forced exercise group had a significant (p < 0.05) increase in cerebral glycolysis, including expressions of GLUT-1, GLUT-3, PFK, LDH, phosphorylated AMPK activity and HIF-1α, when compared to the voluntary exercise and the control groups. Our results suggest that the effects of different exercise on HIF-1α expression and cerebral glycolysis may provide a possible reason for the discrepancy in neuroprotection, with forced exercise faring better than voluntary exercise through increased cerebral metabolism.

Kochujang, a Korean fermented red pepper plus soybean paste, improves glucose homeostasis in 90% pancreatectomized diabetic rats

Objectives Red pepper and soybeans have been reported to modulate energy and glucose metabolism. However, the antidiabetic effect of kochujang, the fermented product of red pepper plus soybeans, has not been studied. We examined whether kochujang affected insulin secretion from β-cells and/or peripheral insulin resistance in 90% pancreatectomized diabetic rats fed high-fat diets. Methods Diabetic rats consumed a high-fat diet containing two different kinds of 5% kochujang powder or the equivalent amount of nutrients for 8 wk. Two types of kochujang were made through the fermentation of two different kinds of meju (soybeans), red peppers, glutinous rice, and malts. Meju was produced by fermenting soybeans in a traditional method (TMK) or in a more modern method in which soybeans are inoculated with Bacillus subtilus and Aspergillus sojae (MMK). Results TMK and MMK decreased body weight, visceral fat, and serum leptin levels without modulating caloric intake in diabetic rats compared with the control. TMK and MMK also improved glucose tolerance by enhancing insulin sensitivity but did not potentiate glucose-stimulated insulin secretion. The improvement in hepatic insulin sensitivity caused by TMK and MMK was explained by the potentiated phosphorylation of signal transducer and activator of transcription-3 → adenosine monophosphate kinase → acetyl-coenzyme A carboxylase and decreased phosphoenolpyruvate carboxykinase expression. Kochujang diets reduced hepatic glucose output and triacylglycerol accumulation and increased glycogen storage. Conclusion The combination of red pepper and fermented soybeans in kochujang improves glucose homeostasis by reducing insulin resistance, not by enhancing β-cell function, in diabetic rats. The improvement is associated with decreased hepatic fat storage by the activation of adenosine monophosphate kinase.

Adenosine monophosphate kinase (AMPK) expression and activity in the lung

AMPK activity has been implicated in endothelial cell death and vascular smooth muscle proliferation in hypoxia, suggesting that this metabolic sensor participates in vascular pathology. However, molecular mechanisms of AMPK signaling in the lung are poorly understood. Initial studies revealed that the 2 isoforms of AMPK (AMPKα1 and AMPKα2) are expressed at low levels in the rat lung but that hypoxia induces AMPK expression in an isoform‐ and location‐dependent manner. AMPKα1 expression is predominantly induced in the lung periphery and is associated with capillaries while AMPKα2 is expressed in larger vessels. Selective expression of AMPK isoforms extends to distinct pulmonary cell types: pulmonary artery endothelial cells (PAECs) express AMPKα2 while pulmonary microvascular endothelial cells (PMVECs) express AMPKα1. Smooth muscle cells (SMCs) and columnar epithelia express both isoforms. Studies using PAEC, PMVEC, and SMC cultures revealed that AMPK inhibition increases SMC growth and attenuates PMVEC growth. Immunochemical staining indicated that AMPK α1 co‐localizes with the cell adhesion molecule N‐cadherin near regions of cell‐cell contact in PMVECs, results confirmed in co‐immunoprecipitation assays. In conclusion, AMPK expression and function in the lung exhibits both isoform and cell‐type specificity. Supported by research and training grants from NIH.