AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise

Kelly, Meghan; Keller, Charlotte; Avilucea, Paco R; Keller, Pernille; Luo, Zhijun; Xiang, Xiaoquin; Giralt, Marina; Hidalgo, Juan; Saha, Asish K.; Pedersen, Bente Klarlund; Ruderman, Neil B.

doi:10.1016/j.bbrc.2004.05.188

Cited by 240 publications

(230 citation statements)

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“…AMPK phosphorylation Previous studies have reported that IL-6 increases the phosphorylation of AMPK in several different cells [16][17][18][19]. Indeed, phosphorylated AMPK was markedly increased in the IL-6 mice, while gp130 was not altered (Fig.…”

Section: Resultsmentioning

confidence: 81%

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Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

et al. 2008

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Aims/hypothesis IL-6 is released by the adipose tissue and increased circulating levels in obesity are associated with hyperinsulinaemia and insulin resistance. Short-term experiments suggest that increased IL-6 release by the skeletal muscle following exercise may improve insulin sensitivity. Methods In order to examine the effect of chronically elevated IL-6 levels, we overexpressed Il6 in skeletal muscle in mice using an electro-transfer procedure.Results Circulating IL-6 levels were increased and the animals rapidly lost both weight and body fat, but food intake was unchanged, which is consistent with the finding that IL-6 increased energy expenditure. Insulin levels were inappropriately elevated and combined with hypoglycaemia in spite of reduced 2-deoxy-D-glucose uptake by skeletal muscle. Insulin-stimulated glucose uptake by skeletal muscles ex vivo was reduced, probably due to the decreased amounts of glucose transporter (GLUT)-4. Beta cell insulin content was increased, while apparent beta cell mass was unchanged. Circulating serum amyloid A cluster levels were increased tenfold due to a pronounced proinflammatory state in the liver with infiltration of inflammatory cells. However, no liver steatosis was found, which may be accounted for by concomitant AMP kinase activation. Conclusions/interpretation Chronically elevated IL-6 levels lead to inappropriate hyperinsulinaemia, reduced body weight, impaired insulin-stimulated glucose uptake by the skeletal muscles and marked inflammation in the liver. Thus, the pleiotrophic effects of chronically elevated IL-6 levels preclude any obvious usefulness in treating obesity or its associated metabolic complications in man, despite the fact that weight reduction may be expected.

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Section: Resultsmentioning

confidence: 81%

“…However, insulin-like effects in skeletal muscle cells, associated with AMP kinase (AMPK) activation, have also been shown [16][17][18][19]. Taken together, many experimental studies have shown that chronic exposure to IL-6 induces insulin resistance with the possible exception of skeletal muscle.…”

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confidence: 99%

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

et al. 2008

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“…Previous studies conducted in our laboratory first showed that in rodents exercise increases AMPK activity in intra-abdominal adipose tissue (21,22). Acute exercise is known to increase the release of catecholamines, which participate in the lipolytic response of adipose tissue to exercise.…”

Section: Amp-activated Protein Kinase (Ampk)mentioning

confidence: 98%

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

Gauthier

Miyoshi

Souza

et al. 2008

Journal of Biological Chemistry

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AMP-activated protein kinase (AMPK) is activated in adipocytes during exercise and other states in which lipolysis is stimulated. However, the mechanism(s) responsible for this effect and its physiological relevance are unclear. To examine these questions, 3T3-L1 adipocytes were treated with cAMP-inducing agents (isoproterenol, forskolin, and isobutylmethylxanthine), which stimulate lipolysis and activate AMPK. When lipolysis was partially inhibited with the general lipase inhibitor orlistat, AMPK activation by these agents was also partially reduced, but the increases in cAMP levels and cAMP-dependent protein kinase (PKA) activity were unaffected. Likewise, small hairpin RNA-mediated silencing of adipose tissue triglyceride lipase inhibited both forskolin-stimulated lipolysis and AMPK activation but not that of PKA. Forskolin treatment increased the AMP:ATP ratio, and this too was reduced by orlistat. When acyl-CoA synthetase, which catalyzes the conversion of fatty acids to fatty acyl-CoA, was inhibited with triacsin C, the increases in both AMPK activity and AMP:ATP ratio were blunted. Isoproterenol-stimulated lipolysis was accompanied by an increase in oxidative stress, an effect that was quintupled in cells incubated with the AMPK inhibitor compound C. The isoproterenol-induced increase in the AMP:ATP ratio was also much greater in these cells. In conclusion, the results indicate that activation of AMPK in adipocytes by cAMP-inducing agents is a consequence of lipolysis and not of PKA activation. They suggest that AMPK activation in this setting is caused by an increase in the AMP:ATP ratio that appears to be due, at least in part, to the acylation of fatty acids. Finally, this AMPK activation appears to restrain the energy depletion and oxidative stress caused by lipolysis. AMP-activated protein kinase (AMPK)2 is a sensor of cellular energy state that responds to metabolic stresses and other regulatory signals. The mechanism of activation of AMPK is a complex phenomenon and is still not fully understood, although it is recognized that it involves phosphorylation of the critical Thr-172 residue of its ␣ catalytic subunit by upstream kinases such as LKB1, Ca 2ϩ -calmodulin-dependent protein kinase kinase, and possibly Tak1, a member of the mitogenactivated protein kinase kinase kinase family (1-5). AMPK is also regulated by AMP allosterically and the current view is that this both increases AMPK activity directly and makes it a poorer substrate for phosphatases (6).The role and regulation of AMPK in muscle, liver, and various cultured cells have been extensively studied. It is now well established that energy depletion because of starvation, hypoxia, and exercise increases the intracellular AMP:ATP ratio and secondarily AMPK activity (7). Upon its activation, a major role of AMPK is to replete cellular energy stores by stimulating processes that generate ATP, such as fatty acid oxidation, and inhibiting ATP-consuming pathways (e.g. lipogenesis, triglyceride synthesis, and gluconeogenesis) that are not acutel...

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“…However, by using transfection of macrophages with a constitutively active and dominant negative form of AMPKα1, it was recently shown that activation of AMPK suppresses proinflammatory responses and promotes macrophage polarisation towards an anti-inflammatory functional phenotype [16]. In different cell types, stimulation by inflammatory mediators such as macrophage migration inhibitory factor, ciliary neurotrophic factor and IL-6 correlates with AMPK activation [17][18][19][20], further supporting a possible cross-talk between these pathways.…”

Section: Introductionmentioning

confidence: 99%

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

et al. 2010

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Aim/hypothesis The aim of the study was to examine the possible role of AMP-activated protein kinase (AMPK) in the regulation of the inflammatory response induced by cytokine action in human liver cells. Methods IL-6-stimulated expression of the genes for acutephase response markers serum amyloid A (SAA1, SAA2) and haptoglobin (HP) in the human hepatocarcinoma cell line HepG2 were quantified after modulation of AMPK activity by pharmacological agonists (5-amino-4-imidazolecarboxamideriboside [AICAR], metformin) or by using small interfering (si) RNA transfection. The intracellular signalling pathway mediating the effect of AMPK on IL-6-stimulated acute-phase marker expression was characterised by assessing the phosphorylation levels of the candidate protein signal transducer and activator of transcription 3 (STAT3) in response to AMPK agonists. Results AICAR and metformin markedly blunt the IL-6-stimulated expression of SAA cluster genes as well as of haptoglobin in a dose-dependent manner. Moreover, the repression of AMPK activity by siRNA significantly reversed the inhibition of SAA expression by both AICAR and metformin, indicating that the effect of the agonists is dependent on AMPK. For the first time we show that AMPK appears to regulate IL-6 signalling by directly inhibiting the activation of the main downstream target of IL-6, STAT3. Conclusions/interpretation We provide evidence for a key function of AMPK in suppression of the acute-phase response caused by the action of IL-6 in liver, suggesting that AMPK may act as an intracellular link between chronic low-grade inflammation and metabolic regulation in peripheral metabolic tissues.

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AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise

Cited by 240 publications

References 32 publications

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

AMP-activated protein kinase inhibits IL-6-stimulated inflammatory response in human liver cells by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3)

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