Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor κB signalling in rat skeletal muscle cells by AMP-activated protein kinase

2011 ◽  
Vol 435 (2) ◽  
pp. 463-474 ◽  
Author(s):  
Charlotte J. Green ◽  
Katherine Macrae ◽  
Sarah Fogarty ◽  
D. Grahame Hardie ◽  
Kei Sakamoto ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Glucose Transport ◽  
P38 Mapk ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Amp Activated Protein Kinase ◽  
Inflammatory Signalling

Sustained over-supply of saturated non-esterified ‘free’ fatty acids has been shown to promote skeletal muscle insulin resistance, which may be driven, in part, by an increase in inflammatory signalling within this tissue. In the present manuscript we show that exposure of L6 myotubes to palmitate, a saturated fatty acid, induces activation of the NF-κB (nuclear factor κB) pathway {based on increased IKK [IκB (inhibitory κB) kinase] phosphorylation, IκBα loss and elevated interleukin-6 mRNA expression} and that this was associated with enhanced phosphorylation/activation of p38 MAPK (mitogen-activated protein kinase), JNK (c-Jun N-terminal kinase) and ERK (extracellular-signal-regulated kinase) as well as impaired insulin-dependent activation of PKB (protein kinase B)/Akt and glucose transport. NF-κB activation by palmitate was unaffected by pharmacological inhibition of p38 MAPK or JNK, but was suppressed significantly by inhibition of MEK (MAPK/ERK kinase)/ERK signalling. The importance of ERK with respect to downstream NF-κB signalling was underscored by the finding that PMA, a potent ERK activator, enhanced IKK phosphorylation. Strikingly, both palmitate- and PMA-induced activation of IKK/NF-κB were antagonized by AMPK (AMP-activated protein kinase) activators because of reduced ERK signalling. Although palmitate-induced activation of NF-κB was repressed by AMPK activation and by cellular overexpression of a mutated IκBα (S32A/S36A) super-repressor, this did not ameliorate the loss in insulin-stimulated PKB activation or glucose transport. Our results from the present study indicate that ERK plays a pivotal role in palmitate-induced activation of the IKK/NF-κB signalling axis and that AMPK can restrain the activity of this pro-inflammatory pathway. The finding that insulin resistance persists in myotubes in which NF-κB signalling has been repressed implies that palmitate and/or its lipid derivatives retain the capacity to impair insulin-regulated events independently of the increase in inflammatory signalling.

scholarly journals The Heme Oxygenase System Abates Hyperglycemia in Zucker Diabetic Fatty Rats by Potentiating Insulin-Sensitizing Pathways

Endocrinology ◽  
2008 ◽  
Vol 150 (5) ◽  
pp. 2098-2108 ◽  
Author(s):  
Joseph Fomusi Ndisang ◽  
Nina lane ◽  
Ashok Jadhav
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Protein Kinase ◽  
Insulin Signaling ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Antidiabetic Effect ◽  
Insulin Resistant ◽  
Aldolase B ◽  
Amp Activated Protein Kinase

Emerging evidence indicates that aldosterone causes oxidative stress by stimulating proinflammatory/oxidative mediators, including nuclear factor-κB, activating protein (AP-1), and c-Jun N-terminal kinase. Thus, in insulin-resistant type 2 diabetes (T2D), oxidative stress generated by hyperglycemia and aldosterone would potentiate the oxidative destruction of tissue and important regulators of glucose metabolism like adiponectin and insulin. Although heme oxygenase (HO)-1 is cytoprotective, its effects on T2D have not been fully characterized. Here we report an enduring antidiabetic effect of the HO inducer, hemin, on Zucker diabetic-fatty rat (ZDF), a model of insulin-resistant T2D. Chronically applied hemin to ZDF reduced and maintained significantly low fasting and postprandial hyperglycemia for 4 months after therapy. The antidiabetic effect was accompanied by enhanced HO activity, catalase, cyclic GMP, bilirubin, ferritin, total antioxidant capacity, and insulin. In contrast, reduced aldosterone alongside markers/mediators of oxidative stress, including 8-isoprostane, c-Jun N-terminal kinase, nuclear factor-κB, AP-1, and AP-2 were observed. Interestingly, in hemin-treated ZDF, inhibitory proteins of insulin-signaling, such as glycogen synthase kinase-3 and protein-tyrosine phosphastase-1B were reduced, whereas agents that promote insulin signaling including adiponectin, cAMP, AMP-activated protein kinase, aldolase-B, and glucose transporter-4 (GLUT4), were robustly increased. Correspondingly, hemin improved ip glucose tolerance, reduced insulin intolerance, and lowered insulin resistance (homeostasis model assessment of insulin resistance), and the inability of insulin to enhance GLUT4 was overturned. These results suggest that the suppression of hyperglycemia and aldosterone-induced oxidative stress alongside the potentiation of insulin-sensitizing pathways may account for the 4-month enduring antidiabetic effect. The synergistic interaction between the HO system, aldolase-B, adiponectin, AMP-activated protein kinase, and GLUT4 may be explored for novel strategies against postprandial/fasting hyperglycemia and insulin-resistant T2D.

Role of the AMP-activated protein kinase in regulating fatty acid metabolism during exerciseThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 315-322 ◽  
Author(s):  
Gregory R. Steinberg
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Moderate Intensity ◽  
Amp Activated Protein Kinase

During moderate-intensity exercise, fatty acids are the predominant substrate for working skeletal muscle. The release of fatty acids from adipose tissue stores, combined with the ability of skeletal muscle to actively fine tune the gradient between fatty acid and carbohydrate metabolism, depending on substrate availability and energetic demands, requires a coordinated system of metabolic control. Over the past decade, since the discovery that AMP-activated protein kinase (AMPK) was increased in accordance with exercise intensity, there has been significant interest in the proposed role of this ancient stress-sensing kinase as a critical integrative switch controlling metabolic responses during exercise. In this review, studies examining the role of AMPK as a regulator of fatty acid metabolism in both adipose tissue and skeletal muscle during exercise will be discussed. Exercise induces activation of AMPK in adipocytes and regulates triglyceride hydrolysis and esterfication through phosphorylation of hormone sensitive lipase (HSL) and glycerol-3-phosphate acyl-transferase, respectively. In skeletal muscle, exercise-induced activation of AMPK is associated with increases in fatty acid uptake, phosphorylation of HSL, and increased fatty acid oxidation, which is thought to occur via the acetyl-CoA carboxylase-malony-CoA-CPT-1 signalling axis. Despite the importance of AMPK in regulating fatty acid metabolism under resting conditions, recent evidence from transgenic models of AMPK deficiency suggest that alternative signalling pathways may also be important for the control of fatty acid metabolism during exercise.

Effect of phosphorylation by AMP-activated protein kinase on palmitoyl-CoA inhibition of skeletal muscle acetyl-CoA carboxylase

2005 ◽  
Vol 98 (4) ◽  
pp. 1221-1227 ◽  
Author(s):  
D. S. Rubink ◽  
W. W. Winder
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Oxidation Rates ◽  
Malonyl Coa ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) has previously been demonstrated to phosphorylate and inactivate skeletal muscle acetyl-CoA carboxylase (ACC), the enzyme responsible for synthesis of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 and fatty acid oxidation. Contraction-induced activation of AMPK with subsequent phosphorylation/inactivation of ACC has been postulated to be responsible in part for the increase in fatty acid oxidation that occurs in muscle during exercise. These studies were designed to answer the question: Does phosphorylation of ACC by AMPK make palmitoyl-CoA a more effective inhibitor of ACC? Purified rat muscle ACC was subjected to phosphorylation by AMPK. Activity was determined on nonphosphorylated and phosphorylated ACC preparations at acetyl-CoA concentrations ranging from 2 to 500 μM and at palmitoyl-CoA concentrations ranging from 0 to 100 μM. Phosphorylation resulted in a significant decline in the substrate saturation curve at all palmitoyl-CoA concentrations. The inhibitor constant for palmitoyl-CoA inhibition of ACC was reduced from 1.7 ± 0.25 to 0.85 ± 0.13 μM as a consequence of phosphorylation. At 0.5 mM citrate, ACC activity was reduced to 13% of control values in response to the combination of phosphorylation and 10 μM palmitoyl-CoA. Skeletal muscle ACC is more potently inhibited by palmitoyl-CoA after having been phosphorylated by AMPK. This may contribute to low-muscle malonyl-CoA values and increasing fatty acid oxidation rates during long-term exercise when plasma fatty acid concentrations are elevated.

AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle

1997 ◽  
Vol 273 (6) ◽  
pp. E1107-E1112 ◽  
Author(s):  
G. F. Merrill ◽  
E. J. Kurth ◽  
D. G. Hardie ◽  
W. W. Winder
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Fatty Acid Oxidation ◽  
Fold Increase ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Malonyl Coa ◽  
Amp Activated Protein Kinase

5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) has previously been reported to be taken up into cells and phosphorylated to form ZMP, an analog of 5′-AMP. This study was designed to determine whether AICAR can activate AMP-activated protein kinase (AMPK) in skeletal muscle with consequent phosphorylation of acetyl-CoA carboxylase (ACC), decrease in malonyl-CoA, and increase in fatty acid oxidation. Rat hindlimbs were perfused with Krebs-Henseleit bicarbonate containing 4% bovine serum albumin, washed bovine red blood cells, 200 μU/ml insulin, and 10 mM glucose with or without AICAR (0.5–2.0 mM). Perfusion with medium containing AICAR was found to activate AMPK in skeletal muscle, inactivate ACC, and decrease malonyl-CoA. Hindlimbs perfused with 2 mM AICAR for 45 min exhibited a 2.8-fold increase in fatty acid oxidation and a significant increase in glucose uptake. No difference was observed in oxygen uptake in AICAR vs. control hindlimb. These results provide evidence that decreases in muscle content of malonyl-CoA can increase the rate of fatty acid oxidation.

Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise

1996 ◽  
Vol 270 (2) ◽  
pp. E299-E304 ◽  
Author(s):  
W. W. Winder ◽  
D. G. Hardie
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Ammonium Sulfate ◽  
Quadriceps Muscle ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Rat Skeletal Muscle ◽  
Malonyl Coa ◽  
Amp Activated Protein Kinase

Malonyl-CoA, an inhibitor of fatty acid oxidation in skeletal muscle mitochondria, decreases in rat skeletal muscle during exercise or in response to electrical stimulation. Regulation of rat skeletal muscle acetyl-CoA carboxylase (ACC), the enzyme that synthesizes malonyl-CoA, was studied in vitro and in vivo. Avidin-Sepharose affinity-purified ACC from hindlimb skeletal muscle was phosphorylated by purified liver AMP-activated protein kinase with a concurrent decrease in ACC activity. AMP-activated protein kinase was quantitated in resuspended ammonium sulfate precipitates of the fast-twitch red (type IIa fibers) region of the quadriceps muscle. Rats running on a treadmill at 21 m/min up a 15% grade show a 2.4-fold activation of AMP-activated protein kinase concurrently with a marked decrease in ACC activity in the resuspended ammonium sulfate precipitates at all citrate concentrations ranging from 0 to 20 mM. Malonyl-CoA decreased from a resting value of 1.85 +/- 0.29 to 0.50 +/- 0.09 nmol/g in red quadriceps muscle after 30 min of treadmill running. The activation of the AMP-activated protein kinase with consequent phosphorylation and inactivation of ACC may be one of the primary events in the control of malonyl-CoA and hence fatty acid oxidation during exercise.

Possible involvement of the α1 isoform of 5′AMP-activated protein kinase in oxidative stress-stimulated glucose transport in skeletal muscle

2004 ◽  
Vol 287 (1) ◽  
pp. E166-E173 ◽  
Author(s):  
Taro Toyoda ◽  
Tatsuya Hayashi ◽  
Licht Miyamoto ◽  
Shin Yonemitsu ◽  
Masako Nakano ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Transport ◽  
Activation Process ◽  
Dependent Manner ◽  
Upstream Kinase ◽  
Metabolic Stresses ◽  
Amp Activated Protein Kinase

Recent studies have suggested that 5′AMP-activated protein kinase (AMPK) is activated in response to metabolic stresses, such as contraction, hypoxia, and the inhibition of oxidative phosphorylation, which leads to insulin-independent glucose transport in skeletal muscle. In the present study, we hypothesized that acute oxidative stress increases the rate of glucose transport via an AMPK-mediated mechanism. When rat epitrochlearis muscles were isolated and incubated in vitro in Krebs buffer containing the oxidative agent H2O2, AMPKα1 activity increased in a time- and dose-dependent manner, whereas AMPKα2 activity remained unchanged. The activation of AMPKα1 was associated with phosphorylation of AMPK Thr172, suggesting that an upstream kinase is involved in the activation process. H2O2-induced AMPKα1 activation was blocked in the presence of the antioxidant N-acetyl-l-cysteine (NAC), and H2O2 significantly increased the ratio of oxidized glutathione to glutathione (GSSG/GSH) concentrations, a sensitive marker of oxidative stress. H2O2 did not cause an increase in the conventional parameters of AMPK activation, such as AMP and AMP/ATP. H2O2 increased 3- O-methyl-d-glucose transport, and this increase was partially, but significantly, blocked in the presence of NAC. Results were similar when the muscles were incubated in a superoxide-generating system using hypoxanthine and xanthine oxidase. Taken together, our data suggest that acute oxidative stress activates AMPKα1 in skeletal muscle via an AMP-independent mechanism and leads to an increase in the rate of glucose transport, at least in part, via an AMPKα1-mediated mechanism.

Characterization of the role of the AMP-activated protein kinase in the stimulation of glucose transport in skeletal muscle cells

2002 ◽  
Vol 363 (1) ◽  
pp. 167-174 ◽  
Author(s):  
Lee G.D. FRYER ◽  
Fabienne FOUFELLE ◽  
Kay BARNES ◽  
Stephen A. BALDWIN ◽  
Angela WOODS ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Uptake ◽  
Glucose Transport ◽  
Phorbol Ester ◽  
Hyperosmotic Stress ◽  
Amp Activated Protein Kinase ◽  
Stimulation Of ◽  
Constitutively Active

Stimulation of AMP-activated protein kinase (AMPK) in skeletal muscle has been correlated with an increase in glucose transport. Here, we demonstrate that adenoviral-mediated expression of a constitutively active mutant of AMPKα leads to activation of glucose transport in a skeletal-muscle cell line, similar to that seen following treatment with 5-amino-imidazolecarboxamide (AICA) riboside, hyperosmotic stress or insulin. In contrast, expression of a dominant-negative form of AMPK blocked the stimulation of glucose transport by both AICA riboside and hyperosmotic stress, but was without effect on either insulin or phorbol-ester-stimulated transport. These results demonstrate that activation of AMPK is sufficient for stimulation of glucose uptake into muscle cells, and is a necessary component of the AICA riboside- and hyperosmotic-stress-induced pathway leading to increased glucose uptake. On the other hand, AMPK is not required in the insulin- or phorbol-ester-mediated pathways. Long-term (5 days) expression of the constitutively active AMPK mutant increased protein expression of GLUT1, GLUT4 and hexokinase II, consistent with previous reports on the chronic treatment of rats with AICA riboside. Expression of constitutively active AMPK had no detectable effect on p38 mitogen-activated protein kinase levels, although interestingly the level of protein kinase B was decreased. These results demonstrate that long-term activation of AMPK is sufficient to cause increased expression of specific proteins in muscle. Our results add further support to the hypothesis that long-term activation of AMPK is involved in the adaptive response of muscle to exercise training.

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