CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK

Watt, Matthew J.; Dzamko, Nicolas; Thomas, Walter G.; Rose-John, Stefan; Ernst, Matthias; Carling, David; Kemp, Bruce E.; Febbraio, Mark A.; Steinberg, Gregory R.

doi:10.1038/nm1383

Cited by 249 publications

(295 citation statements)

References 47 publications

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“…glucose injection (1 g/kg) using an ELISA kit (Millipore, Linco Research, Billerica, MA, USA) according to the manufacturer's recommendations. Leptin was measured in serum from fed mice using a mouse adipokine kit (Linco Research) and a workstation (Bio-plex 200; Bio-Rad Laboratories,) as described [38].…”

Section: Methodsmentioning

confidence: 99%

Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity

et al. 2009

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Aims/hypothesis Obesity-related insulin resistance is associated with accumulation of bioactive lipids in skeletal muscle. The AMP-activated protein kinase (AMPK) regulates lipid oxidation in muscle by inhibiting acetyl-CoA carboxylase-2 (ACC2) and increasing mitochondrial biogenesis. We investigated whether reduced levels of muscle AMPK promote lipid accumulation and insulin resistance during high-fat feeding. Methods Male C57/BL6 wild-type mice and transgenic littermates overexpressing an α2AMPK kinase-dead (KD) in muscle were fed control or high-fat diet. Whole-body glucose homeostasis was assessed by glucose and insulin tolerance tests, and by measuring fasting and fed serum insulin and glucose. Insulin action in muscle was determined by measuring 2-deoxy-[ 3 H]glucose uptake and Akt phosphorylation in incubated soleus and extensor digitorum longus muscles. Muscle triacylglycerol, diacylglycerol and ceramide content was measured by thin-layer chromatography. Mitochondrial proteins were measured by immunoblotting. Results KD mice had reduced skeletal muscle α2AMPK activity (50% in gastrocnemius and >80% in soleus and extensor digitorum longus) and ACC2 Ser228 phosphorylation (90% in gastrocnemius). High-fat feeding increased body mass and adiposity, and impaired insulin and glucose tolerance; however, there were no differences between wild-type and KD littermates. High-fat feeding impaired insulin-stimulated muscle glucose uptake and Akt-phosphorylation, while increasing muscle triacylglycerol, diacylglycerol (p=0.07) and ceramide, but these effects were not exacerbated in KD mice. In response to high-fat feeding, mitochondrial proteins were increased to similar levels in wild-type and KD muscles. Conclusions/interpretation Obesity-induced lipid accumulation and insulin resistance were not exacerbated in AMPK KD mice, suggesting that reduced levels of muscle α2AMPK do not promote insulin resistance in the early phase of obesity-related diabetes.

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Section: Methodsmentioning

confidence: 99%

Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity

et al. 2009

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“…Lipid analysis Plasma and faecal NEFA were analysed according to methods previously described [20]; liver and muscle lipids were analysed as outlined in ESM Methods.…”

Section: Methodsmentioning

confidence: 99%

“…Gene Set Enrichment Analyses (GSEA) was performed using GSEA software (www.broad.mit.edu/gsea/, accessed 1 July 2009) described in detail elsewhere [21,22]. Real-time RT-PCR was determined as previously described [20]. Proteins were analysed by SDS-PAGE and immunoblotting [20,23], using primary antibodies from Cell Signaling Technology (Danvers, MA USA), except for the western blotting antibody cocktail for total oxidative phosphorylation, which was obtained from MitoSciences (Eugene, OR, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Real-time RT-PCR was determined as previously described [20]. Proteins were analysed by SDS-PAGE and immunoblotting [20,23], using primary antibodies from Cell Signaling Technology (Danvers, MA USA), except for the western blotting antibody cocktail for total oxidative phosphorylation, which was obtained from MitoSciences (Eugene, OR, USA). For insulin signalling experiments, mice were anaesthetised with sodium pentobarbital (0.05 mg/g) before a portion of liver and skeletal muscle were excised and snap-frozen in liquid nitrogen.…”

Section: Methodsmentioning

confidence: 99%

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Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

et al. 2010

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Aims/hypothesis The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 −/− ) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance. Methods Male, 8-week-old Il6 −/− and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly. Results Il6 −/− mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 −/− and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 −/− mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 −/− relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme β-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins. Conclusions/interpretation Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism.

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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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CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK

Cited by 249 publications

References 47 publications

Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity

Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

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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