Tumor necrosis factor α-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling

St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Vic, 3065, Australia.
Cell Metabolism (Impact Factor: 17.57). 01/2007; 4(6):465-74. DOI: 10.1016/j.cmet.2006.11.005
Source: PubMed


Elevated levels of tumor necrosis factor (TNFalpha) are implicated in the development of insulin resistance, but the mechanisms mediating these chronic effects are not completely understood. We demonstrate that TNFalpha signaling through TNF receptor (TNFR) 1 suppresses AMPK activity via transcriptional upregulation of protein phosphatase 2C (PP2C). This in turn reduces ACC phosphorylation, suppressing fatty-acid oxidation, increasing intramuscular diacylglycerol accumulation, and causing insulin resistance in skeletal muscle, effects observed both in vitro and in vivo. Importantly even at pathologically elevated levels of TNFalpha observed in obesity, the suppressive effects of TNFalpha on AMPK signaling are reversed in mice null for both TNFR1 and 2 or following treatment with a TNFalpha neutralizing antibody. Our data demonstrate that AMPK is an important TNFalpha signaling target and is a contributing factor to the suppression of fatty-acid oxidation and the development of lipid-induced insulin resistance in obesity.

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    • "İnflamasyon sinyal yolu nüklear faktör-K B (NFKB) azalan miyogenesiz ve yağ hücre farklılaşmasının uyarılması ile (Ardite ve ark., 2004) ilişkilidir. Ayrıca, tümör nekroz faktörü-α (TNF)'ın iskelet kaslarında AMPaktive protein kinaz (AMPK) aktivitesini azalttığı rapor edilmiştir (Steinberg ve ark., 2006). Et sığırlarında yapılan çalışmalarda AMPK ativitesinin kaslılık ile pozitif intramuskular adipositlerin sayısı ile negatif ilişkili olduğu belirtilmiştir (Underwood ve ark., 2008). "
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    ABSTRACT: Kasaplık hayvanlarda gebeliğin başarısı embriyonal ve fetal dönemde ananın besin madde alım düzeyi ile fetüsün(lerin) büyümesi ve gelişmesi arasındaki ilişkiye bağlıdır. Bu durum yavrunun hayatı boyunca verimliliğini belirlemede (postnatal vücut kompozisyonu, büyüme oranı, verimlilik parametreleri, et kalitesi vb.) oldukça önem taşımaktadır. Beside günlük canlı ağırlık artışı ve ette mermerleşme oranının artması ve dolayısıyla üretici ve tüketici açısından daha fazla ve kaliteli et elde edilmesi, doğum öncesi fetal dönemde kas (miyogenesiz) ve yağ (adipogenesiz) oluşumunu etkileyen faktörlerin düzenlenmesine bağlıdır. Bu derlemede fetal dönemde miyogenesiz ve adipogenesiz sürecini yöneten, dolayısıyla fetüste kas (Wnt, β-catenin, Shh, Pax7, vb.) ve yağ (PPARγ, Nükleer faktör-KB, Tümör nekroz faktörü-α, vb.) dokusu oluşumunu etkileyerek et verimi ve kalitesini (mermerleşme) artıran çeşitli sinyal yolları ve reseptörleri üzerinde durulmuştur. Ayrıca bu sinyal yollarının gebelik dönemindeki besleme düzeyi ve bazı yem katkı maddeleri ile engellenmesi veya aktivasyonu da değerlendirilmiştir. Sonuç olarak fetal dönemde miyogenesiz ve adipogenesiz sürecini yöneten sinyal yollarını ve reseptörlerini aktive eden mekanizmaların ve bu mekanizma üzerinde beslemenin etkilerinin daha iyi anlaşılabilmesi için daha fazla araştırmaya ihtiyaç vardır. ABSTRACT The success of pregnancy in slaughter animals depends on the relationship between growth and development of fetus (es) and the level of nutrient intake of the maternal and fetus in the embryonic and fetal period. This situation is very important in determining the efficiency throughout the life of offspring (postnatal body composition, growth rate, efficiency parameters, meat quality, etc.). Increasing of the daily live weight gains and marble rate in meat in the fattening and consequently to obtain higher and quality meat in terms of producers and consumers depend on manipulation of factors affecting foetal muscle (myogenesis) and fat (adipogenesis) formation during prenatal period. In this review, it was focused on various signal pathways and their receptors managed the myogenesis and adipogenesis process prenatal and thus influenced the meat yield and quality (marble) by affecting formation of muscle (Wnt, β-catenin, Shh, Pax7, etc.) and fat (PPARγ, nuclear factor-KB, tumor necrosis factor-α, etc.) in fetus .The inhibition or activation of these signal paths with the feeding level and some feed additives during pregnancy were also evaluated. As a result, there are need further investigations for better understanding of mechanisms which are activated signal pathways and receptors managed the fetal muscle (myogenesis) and fat (adipogenesis) formation during prenatal period and the effects of feeding on this mechanism.
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    • "To our surprise, however, this does not result in a worsening of HFDinduced insulin resistance. Although current dogma demonstrates that an acceleration of muscle fatty acid oxidation alleviates insulin resistance via reducing lipid metabolite accumulation (Steinberg et al., 2006; Watt et al., 2006; Choi et al., 2007; Bruce et al., 2009), this is an extremely controversial area of active debate with numerous studies reporting conflicting findings. As a matter of fact, the original work of Randle et al. (1963) demonstrated that an increase in fatty acid oxidation reduces glucose oxidation and subsequent glucose uptake in the isolated perfused heart and diaphragm, although these conclusions were simply extrapolated to skeletal muscle. "
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    ABSTRACT: There is a growing need to understand the underlying mechanisms involved in the progression of cardiovascular disease during obesity and diabetes. While inhibition of fatty acid oxidation has been proposed as a novel approach to treat ischemic heart disease and heart failure, reduced muscle fatty acid oxidation rates may contribute to the development of obesity-associated insulin resistance. Our aim was to determine whether treatment with the antianginal agent, trimetazidine, which inhibits fatty acid oxidation in the heart secondary to inhibition of 3-ketoacyl CoA thiolase (3-KAT), may have off-target effects on glycemic control in obesity. We fed C57BL/6 mice a high fat diet (HFD) for 10 weeks prior to a 22-day treatment with the 3-KAT inhibitor, trimetazidine (15 mg/kg/day). Insulin resistance was assessed via glucose/insulin tolerance testing, while lipid metabolite content was assessed in gastrocnemius muscle. Trimetazidine-treatment led to a mild shift in substrate preference towards carbohydrates as an oxidative fuel source in obese mice, evidenced by an increase in the respiratory exchange ratio. This shift in metabolism was accompanied by an accumulation of long-chain acyl CoA and a trend to an increase in triacylglycerol content in gastrocnemius muscle, but did not exacerbate HFD-induced insulin resistance compared to control treated mice. Interestingly, trimetazidine treatment reduced palmitate oxidation rates in the isolated working mouse heart and neonatal cardiomyocytes, but not C2C12 skeletal myotubes. Our findings demonstrate that trimetazidine therapy does not adversely affect HFD-induced insulin resistance, suggesting that treatment with trimetazidine would not worsen glycemic control in obese patients with angina.
    Journal of Pharmacology and Experimental Therapeutics 04/2014; 349(3). DOI:10.1124/jpet.114.214197 · 3.97 Impact Factor
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    • "In metabolic disorders, ER stress has been linked to insulin resistance and proinflammatory TNF-a signaling (Ozcan et al., 2006; Steinberg et al., 2006). To determine whether TNF-a activation was involved in AbO-induced phospho-PKR and eIF2a-P in hippocampal neurons, we first treated cultures with infliximab, a "
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    ABSTRACT: Alzheimer's disease (AD) and type 2 diabetes appear to share similar pathogenic mechanisms. dsRNA-dependent protein kinase (PKR) underlies peripheral insulin resistance in metabolic disorders. PKR phosphorylates eukaryotic translation initiation factor 2α (eIF2α-P), and AD brains exhibit elevated phospho-PKR and eIF2α-P levels. Whether and how PKR and eIF2α-P participate in defective brain insulin signaling and cognitive impairment in AD are unknown. We report that β-amyloid oligomers, AD-associated toxins, activate PKR in a tumor necrosis factor α (TNF-α)-dependent manner, resulting in eIF2α-P, neuronal insulin receptor substrate (IRS-1) inhibition, synapse loss, and memory impairment. Brain phospho-PKR and eIF2α-P were elevated in AD animal models, including monkeys given intracerebroventricular oligomer infusions. Oligomers failed to trigger eIF2α-P and cognitive impairment in PKR(-/-) and TNFR1(-/-) mice. Bolstering insulin signaling rescued phospho-PKR and eIF2α-P. Results reveal pathogenic mechanisms shared by AD and diabetes and establish that proinflammatory signaling mediates oligomer-induced IRS-1 inhibition and PKR-dependent synapse and memory loss.
    Cell metabolism 12/2013; 18(6):831-43. DOI:10.1016/j.cmet.2013.11.002 · 17.57 Impact Factor
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