Effects of adenosine on myocardial glucose and palmitate metabolism after transient ischemia: role of 5′-AMP-activated protein kinase

2006 ◽  
Vol 291 (4) ◽  
pp. H1883-H1892 ◽  
Author(s):  
Jagdip S. Jaswal ◽  
Manoj Gandhi ◽  
Barry A. Finegan ◽  
Jason R. B. Dyck ◽  
Alexander S. Clanachan
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Glycogen Synthesis ◽  
Transient Ischemia ◽  
Palmitate Oxidation ◽  
Adrenoceptor Antagonist ◽  
Ampk Phosphorylation ◽  
Proton Production ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

Loss of cardioprotection by adenosine in hearts stressed by transient ischemia may be due to its effects on glucose metabolism. In the absence of transient ischemia, adenosine inhibits glycolysis, whereas it accelerates glycolysis after transient ischemia. Inasmuch as 5′-AMP-activated protein kinase (AMPK) is implicated as a regulator of glucose and fatty acid utilization, this study determined whether a differential alteration of AMPK activity contributes to acceleration of glycolysis by adenosine in hearts stressed by transient ischemia. Studies were performed in working rat hearts perfused aerobically under normal conditions or after transient ischemia (two 10-min periods of ischemia followed by 5 min of reperfusion). LV work was not affected by adenosine. AMPK phosphorylation was not affected by transient ischemia; however, phosphorylation and activity were increased nine- and threefold, respectively, by adenosine in stressed hearts. Phosphorylation of acetyl-CoA carboxylase and rates of palmitate oxidation were unaltered. Glycolysis and calculated proton production were increased 1.8- and 1.7-fold, respectively, in hearts with elevated AMPK activity. Elevated AMPK activity was associated with inhibition of glycogen synthesis and unchanged rates of glucose uptake and glycogenolysis. Phentolamine, an α-adrenoceptor antagonist, which prevents adenosine-induced activation of glycolysis in stressed hearts, prevented AMPK phosphorylation. These data demonstrate that adenosine-induced activation of AMPK after transient ischemia is not sufficient to alter palmitate oxidation or glucose uptake. Rather, activation of AMPK alters partitioning of glucose away from glycogen synthesis; the increase in glycolysis may in part contribute to loss of adenosine-induced cardioprotection in hearts subjected to transient ischemia.

AMPK activation with AICAR provokes an acute fall in plasma [K+]

2008 ◽  
Vol 294 (1) ◽  
pp. C126-C135 ◽  
Author(s):  
Dan Zheng ◽  
Anjana Perianayagam ◽  
Donna H. Lee ◽  
M. Douglas Brannan ◽  
Li E. Yang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Infusion Rate ◽  
Extracellular Fluid ◽  
Ampk Activation ◽  
Conscious Rats ◽  
Significant Fall ◽  
Ampk Phosphorylation ◽  
Atp Levels ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK), activated by an increase in intracellular AMP-to-ATP ratio, stimulates pathways that can restore ATP levels. We tested the hypothesis that AMPK activation influences extracellular fluid (ECF) K+ homeostasis. In conscious rats, AMPK was activated with 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) infusion: 38.4 mg/kg bolus then 4 mg·kg−1·min−1 infusion. Plasma [K+] and [glucose] both dropped at 1 h of AICAR infusion and [K+] dropped to 3.3 ± 0.04 mM by 3 h, linearly related to the increase in muscle AMPK phosphorylation. AICAR treatment did not increase urinary K+ excretion. AICAR lowered [K+] whether plasma [K+] was chronically elevated or lowered. The K+ infusion rate needed to maintain baseline plasma [K+] reached 15.7 ± 1.3 μmol K+·kg−1·min−1 between 120 and 180 min AICAR infusion. In mice expressing a dominant inhibitory form of AMPK in the muscle (Tg-KD1), baseline [K+] was not different from controls (4.2 ± 0.1 mM), but the fall in plasma [K+] in response to AICAR (0.25 g/kg) was blunted: [K+] fell to 3.6 ± 0.1 in controls and to 3.9 ± 0.1 mM in Tg-KD1, suggesting that ECF K+ redistributes, at least in part, to muscle ICF. In summary, these findings illustrate that activation of AMPK activity with AICAR provokes a significant fall in plasma [K+] and suggest a novel mechanism for redistributing K+ from ECF to ICF.

scholarly journals Resveratrol Ameliorates High-Fat-Diet-Induced Abnormalities in Hepatic Glucose Metabolism in Mice via the AMP-Activated Protein Kinase Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Caiping Lu ◽  
Hanying Xing ◽  
Linquan Yang ◽  
Kaiting Chen ◽  
Linyi Shu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
High Fat Diet ◽  
Blood Glucose Concentration ◽  
Glycogen Synthesis ◽  
Liver Fat ◽  
High Fat ◽  
Amp Activated Protein Kinase

Diabetes mellitus is highly prevalent worldwide. High-fat-diet (HFD) consumption can lead to liver fat accumulation, impair hepatic glycometabolism, and cause insulin resistance and the development of diabetes. Resveratrol has been shown to improve the blood glucose concentration of diabetic mice, but its effect on the abnormal hepatic glycometabolism induced by HFD-feeding and the mechanism involved are unknown. In this study, we determined the effects of resveratrol on the insulin resistance of high-fat-diet-fed mice and a hepatocyte model by measuring serum biochemical indexes, key indicators of glycometabolism, glucose uptake, and glycogen synthesis in hepatocytes. We found that resveratrol treatment significantly ameliorated the HFD-induced abnormalities in glucose metabolism in mice, increased glucose absorption and glycogen synthesis, downregulated protein phosphatase 2A (PP2A) and activated Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ), and increased the phosphorylation of AMP-activated protein kinase (AMPK). In insulin-resistant HepG2 cells, the administration of a PP2A activator or CaMKKβ inhibitor attenuated the effects of resveratrol, but the administration of an AMPK inhibitor abolished the effects of resveratrol. Resveratrol significantly ameliorates abnormalities in glycometabolism induced by HFD-feeding and increases glucose uptake and glycogen synthesis in hepatocytes. These effects are mediated through the activation of AMPK by PP2A and CaMKKβ.

scholarly journals AMP-activated protein kinase phosphorylation of the R domain inhibits PKA stimulation of CFTR

2009 ◽  
Vol 297 (1) ◽  
pp. C94-C101 ◽  
Author(s):  
J Darwin King ◽  
Adam C. Fitch ◽  
Jeffrey K. Lee ◽  
Jill E. McCane ◽  
Don-On Daniel Mak ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Dominant Negative ◽  
Ampk Phosphorylation ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase ◽  
Stimulation Of ◽  
In Cells ◽  
R Domain

The metabolic sensor AMP-activated protein kinase (AMPK) has emerged as an important link between cellular metabolic status and ion transport activity. We previously found that AMPK binds to and phosphorylates CFTR in vitro and inhibits PKA-dependent stimulation of CFTR channel gating in Calu-3 bronchial serous gland epithelial cells. To further characterize the mechanism of AMPK-dependent regulation of CFTR, whole cell patch-clamp measurements were performed with PKA activation in Calu-3 cells expressing either constitutively active or dominant-negative AMPK mutants (AMPK-CA or AMPK-DN). Baseline CFTR conductance in cells expressing AMPK-DN was substantially greater than controls, suggesting that tonic AMPK activity in these cells inhibits CFTR under basal conditions. Although baseline CFTR conductance in cells expressing AMPK-CA was comparable to that of controls, PKA stimulation of CFTR was completely blocked in AMPK-CA-expressing cells, suggesting that AMPK activation renders CFTR resistant to PKA activation in vivo. Phosphorylation studies of CFTR in human embryonic kidney-293 cells using tetracycline-inducible expression of AMPK-DN demonstrated AMPK-dependent phosphorylation of CFTR in vivo. However, AMPK activity modulation had no effect on CFTR in vivo phosphorylation in response to graded doses of PKA or PKC agonists. Thus, AMPK-dependent CFTR phosphorylation renders the channel resistant to activation by PKA and PKC without preventing phosphorylation by these kinases. We found that Ser768, a CFTR R domain residue considered to be an inhibitory PKA site, is the dominant site of AMPK phosphorylation in vitro. Ser-to-Ala mutation at this site enhanced baseline CFTR activity and rendered CFTR resistant to inhibition by AMPK, suggesting that AMPK phosphorylation at Ser768 is required for its inhibition of CFTR. In summary, our findings indicate that AMPK-dependent phosphorylation of CFTR inhibits CFTR activation by PKA, thereby tuning the PKA-responsiveness of CFTR to metabolic and other stresses in the cell.

scholarly journals Effect of acute activation of 5′-AMP-activated protein kinase on glycogen regulation in isolated rat skeletal muscle

2007 ◽  
Vol 102 (3) ◽  
pp. 1007-1013 ◽  
Author(s):  
Licht Miyamoto ◽  
Taro Toyoda ◽  
Tatsuya Hayashi ◽  
Shin Yonemitsu ◽  
Masako Nakano ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Muscle Glycogen ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycolytic Flux ◽  
Ampk Activation ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase ◽  
Isolated Rat

5′-AMP-activated protein kinase (AMPK) has been implicated in glycogen metabolism in skeletal muscle. However, the physiological relevance of increased AMPK activity during exercise has not been fully clarified. This study was performed to determine the direct effects of acute AMPK activation on muscle glycogen regulation. For this purpose, we used an isolated rat muscle preparation and pharmacologically activated AMPK with 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside (AICAR). Tetanic contraction in vitro markedly activated the α1- and α2-isoforms of AMPK, with a corresponding increase in the rate of 3- O-methylglucose uptake. Incubation with AICAR elicited similar enhancement of AMPK activity and 3- O-methylglucose uptake in rat epitrochlearis muscle. In contrast, whereas contraction stimulated glycogen synthase (GS), AICAR treatment decreased GS activity. Insulin-stimulated GS activity also decreased after AICAR treatment. Whereas contraction activated glycogen phosphorylase (GP), AICAR did not alter GP activity. The muscle glycogen content decreased in response to contraction but was unchanged by AICAR. Lactate release was markedly increased when muscles were stimulated with AICAR in buffer containing glucose, indicating that the glucose taken up into the muscle was catabolized via glycolysis. Our results suggest that AMPK does not mediate contraction-stimulated glycogen synthesis or glycogenolysis in skeletal muscle and also that acute AMPK activation leads to an increased glycolytic flux by antagonizing contraction-stimulated glycogen synthesis.

scholarly journals Hydrogen Sulfide Impairs Glucose Utilization and Increases Gluconeogenesis in Hepatocytes

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 114-126 ◽  
Author(s):  
Ling Zhang ◽  
Guangdong Yang ◽  
Ashley Untereiner ◽  
Youngjun Ju ◽  
Lingyun Wu ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Hepg2 Cells ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Glucose Utilization ◽  
Glycogen Content ◽  
Glycogen Synthesis ◽  
Primary Mouse ◽  
Amp Activated Protein Kinase

Mounting evidence has established hydrogen sulfide (H2S) as an important gasotransmitter with multifaceted physiological functions. The aim of the present study was to investigate the role of H2S on glucose utilization, glycogen synthesis, as well as gluconeogenesis in both HepG2 cells and primary mouse hepatocytes. Incubation with NaHS (a H2S donor) impaired glucose uptake and glycogen storage in HepG2 cells via decreasing glucokinase activity. Adenovirus-mediated cystathionine γ-lyase (CSE) overexpression increased endogenous H2S production and lowered glycogen content in HepG2 cells. Glycogen content was significantly higher in liver tissues from CSE knockout (KO) mice compared to that from wild type (WT) mice in fed condition. Glucose consumption was less in primarily cultured hepatocytes isolated from WT mice than those from CSE KO mice, but more glucose was produced by hepatocytes via gluconeogenesis and glycogenolysis pathways in WT mice than in CSE KO mice. NaHS treatment reduced the phosphorylation of AMP-activated protein kinase, whereas stimulation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside reversed H2S-impaired glucose uptake. H2S-increased glucose production was likely through increased phosphoenolpyruvate carboxykinase activity. In addition, insulin at the physiological range inhibited CSE expression, and H2S decreased insulin-stimulated phosphorylation of Akt in HepG2 cells. CSE expression was increased, however, in insulin-resistant state induced by exposing cells to high levels of insulin (500 nm) and glucose (33 mm) for 24 h. Taken together, these data suggest that the interaction of H2S and insulin in liver plays a pivotal role in regulating insulin sensitivity and glucose metabolism.

Additive effect of contraction and insulin on glucose uptake and glycogen synthase in muscle with different glycogen contents

2010 ◽  
Vol 108 (5) ◽  
pp. 1106-1115 ◽  
Author(s):  
Yu-Chiang Lai ◽  
Elham Zarrinpashneh ◽  
Jørgen Jensen
Keyword(s):  
Protein Kinase ◽  
Glucose Uptake ◽  
Skeletal Muscles ◽  
Glycogen Content ◽  
Glycogen Synthase ◽  
Additive Effect ◽  
Insulin Stimulation ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase ◽  
Pkb Phosphorylation

Insulin and contraction regulate glucose uptake and glycogen synthase (GS) via distinct mechanisms in skeletal muscles, and an additive effect has been reported. Glycogen content is known to influence both contraction- and insulin-stimulated glucose uptake and GS activity. Our study reports that contraction and insulin additively stimulate glucose uptake in rat epitrochlearis muscles with normal (NG) and high (HG) glycogen contents, but the additive effect was only partial. In muscles with low glycogen (LG) content no additive effect was seen, but glucose uptake was higher in LG than in NG and HG during contraction, insulin stimulation, and when the two stimuli were combined. In LG, contraction-stimulated AMP-activated protein kinase (AMPK) activity and insulin-stimulated PKB phosphorylation were higher than in NG and HG, but phosphorylation of Akt substrate of 160 kDa was not elevated correspondingly. GLUT4 content was 50% increased in LG (rats fasted 24 h), which may explain the increased glucose uptake. Contraction and insulin also additively increased GS fractional activity in NG and HG but not in LG. GS fractional activity correlated most strongly with GS Ser641 phosphorylation ( R −0.94, P < 0.001). GS fractional activity also correlated with GS Ser7,10 phosphorylation, but insulin did not reduce GS Ser7,10 phosphorylation. In conclusion, an additive effect of contraction and insulin on glucose uptake and GS activity occurs in muscles with normal and high glycogen content but not in muscles with low glycogen content. Furthermore, contraction, insulin, and glycogen content all regulate GS Ser641 phosphorylation and GS fractional activity in concert.

p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5′-AMP-activated protein kinase

2007 ◽  
Vol 292 (4) ◽  
pp. H1978-H1985 ◽  
Author(s):  
Jagdip S. Jaswal ◽  
Manoj Gandhi ◽  
Barry A. Finegan ◽  
Jason R. B. Dyck ◽  
Alexander S. Clanachan
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Glucose Utilization ◽  
Glycogen Synthesis ◽  
Mitogen Activated Protein Kinase ◽  
Transient Ischemia ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitors ◽  
Ampk Activity ◽  
Mapk Inhibitors

Adenosine-induced acceleration of glycolysis in hearts stressed by transient ischemia is accompanied by suppression of glycogen synthesis and by increases in activity of adenosine 5′-monophosphate-activated protein kinase (AMPK). Because p38 mitogen-activated protein kinase (MAPK) may regulate glucose metabolism and may be activated downstream of AMPK, this study determined the effects of the p38 MAPK inhibitors SB202190 and SB203580 on adenosine-induced alterations in glucose utilization and AMPK activity. Studies were performed in working rat hearts perfused aerobically following stressing by transient ischemia (2 × 10-min ischemia followed by 5-min reperfusion). Phosphorylation of AMPK and p38 MAPK each were increased fourfold by adenosine, and these effects were inhibited by either SB202190 or SB203580. Neither of these inhibitors directly affected AMPK activity. Attenuation of the adenosine-induced increase in AMPK and p38 MAPK phosphorylation by SB202190 and SB203580 occurred independently of any change in tissue ATP-to-AMP ratio and did not alter glucose uptake, but it was accompanied by an increase in glycogen synthesis and glycogen content and by inhibition of glycolysis and proton production. There was a significant inverse correlation between the rate of glycogen synthesis and AMPK activity and between AMPK activity and glycogen content. These data demonstrate that AMPK is likely downstream of p38 MAPK in mediating the effects of adenosine on glucose utilization in hearts stressed by transient ischemia. The ability of p38 MAPK inhibitors to relieve the inhibition of glycogen synthesis and to inhibit glycolysis and proton production suggests that these agents may restore adenosine-induced cardioprotection in stressed hearts.

scholarly journals Glucose regulates AMP-activated protein kinase activity and gene expression in clonal, hypothalamic neurons expressing proopiomelanocortin: additive effects of leptin or insulin

2007 ◽  
Vol 192 (3) ◽  
pp. 605-614 ◽  
Author(s):  
Fang Cai ◽  
Armen V Gyulkhandanyan ◽  
Michael B Wheeler ◽  
Denise D Belsham
Keyword(s):  
Protein Kinase ◽  
Energy Homeostasis ◽  
Cell Model ◽  
Neuronal Cell ◽  
Cell Types ◽  
Glucose Sensing ◽  
Protein Kinase Activity ◽  
Energy Status ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

The mammalian hypothalamus comprises an array of phenotypically distinct cell types that interpret peripheral signals of energy status and, in turn, elicits an appropriate response to maintain energy homeostasis. We used a clonal representative hypothalamic cell model expressing proopiomelanocortin (POMC; N-43/5) to study changes in AMP-activated protein kinase (AMPK) activity and glucose responsiveness. We have demonstrated the presence of cellular machinery responsible for glucose sensing in the cell line, including glucokinase, glucose transporters, and appropriate ion channels. ATP-sensitive potassium channels were functional and responded to glucose. The N-43/5 POMC neurons may therefore be an appropriate cell model to study glucose-sensing mechanisms in the hypothalamus. In N-43/5 POMC neurons, increasing glucose concentrations decreased phospho-AMPK activity. As a relevant downstream effect, we found that POMC transcription increased with 2.8 and 16.7 mM glucose. Upon addition of leptin, with either no glucose or with 5 mM glucose, we found that leptin decreased AMPK activity in N-43/5 POMC neurons, but had no significant effect at 25 mM glucose, whereas insulin decreased AMPK activity at only 5 mM glucose. These results demonstrate that individual hypothalamic neuronal cell types, such as the POMC neuron, can have distinct responses to peripheral signals that relay energy status to the brain, and will therefore be activated uniquely to control neuroendocrine function.

scholarly journals Adrenaline is a critical mediator of acute exercise-induced AMP-activated protein kinase activation in adipocytes

2007 ◽  
Vol 403 (3) ◽  
pp. 473-481 ◽  
Author(s):  
Ho-Jin Koh ◽  
Michael F. Hirshman ◽  
Huamei He ◽  
Yangfeng Li ◽  
Yasuko Manabe ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase Activity ◽  
Chronic Exercise ◽  
Rat Adipocytes ◽  
Compound C ◽  
Isolated Adipocytes ◽  
Ampk Activity ◽  
Exercise Induced ◽  
Amp Activated Protein Kinase

Exercise increases AMPK (AMP-activated protein kinase) activity in human and rat adipocytes, but the underlying molecular mechanisms and functional consequences of this activation are not known. Since adrenaline (epinephrine) concentrations increase with exercise, in the present study we hypothesized that adrenaline activates AMPK in adipocytes. We show that a single bout of exercise increases AMPKα1 and α2 activities and ACC (acetyl-CoA carboxylase) Ser79 phosphorylation in rat adipocytes. Similarly to exercise, adrenaline treatment in vivo increased AMPK activities and ACC phosphorylation. Pre-treatment of rats with the β-blocker propranolol fully blocked exercise-induced AMPK activation. Increased AMPK activity with exercise and adrenaline treatment in vivo was accompanied by an increased AMP/ATP ratio. Adrenaline incubation of isolated adipocytes also increased the AMP/ATP ratio and AMPK activities, an effect blocked by propranolol. Adrenaline incubation increased lipolysis in isolated adipocytes, and Compound C, an AMPK inhibitor, attenuated this effect. Finally, a potential role for AMPK in the decreased adiposity associated with chronic exercise was suggested by marked increases in AMPKα1 and α2 activities in adipocytes from rats trained for 6 weeks. In conclusion, both acute and chronic exercise are significant regulators of AMPK activity in rat adipocytes. Our findings suggest that adrenaline plays a critical role in exercise-stimulated AMPKα1 and α2 activities in adipocytes, and that AMPK can function in the regulation of lipolysis.

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