Tumor necrosis factor α-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling
ABSTRACT 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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- "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. "
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 · 3.86 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 "
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 · 16.75 Impact Factor
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- "). TNF-α has been demonstrated to be a causative factor of obesity-related IR by directly inhibiting tyrosine phosphorylation of insulin receptor substrate (IRS), leading to impaired insulin signaling (Plomgaard et al., 2005; Steinberg et al., 2006). Increased local cytokine production induced by activation of RAS can worsen systemic insulin sensitivity (Yvan-Charvet and Quignard-Boulangé, 2011). "
ABSTRACT: Northern elephant seal pups naturally endure a 2-3 month post-weaning fast that is associated with activation of systemic renin-angiotensin system (RAS), a decrease in plasma adiponectin (Acrp30), and insulin resistance (IR)-like conditions. Angiotensin II (Ang II) and tumor necrosis factor-α (TNF-α) are potential causal factors of IR, while Acrp30 may improve insulin signaling. However, the effects of fasting-induced activation of RAS on IR-like condition in seals are not well described. To assess the effects of prolonged food deprivation on systemic and local RAS, and their potential contribution to TNF-α as they relate to an IR condition, the mRNA expressions of adipose and muscle RAS components and immuno-relevant molecules were measured along with plasma RAS components. Mean plasma renin activity and Ang II concentrations increased 89% and 1658%, respectively, while plasma angiotensinogen (AGT) decreased 49% over the fast, indicative of systemic RAS activation. Prolonged fasting was associated with decreases in adipose and muscle AGT mRNA expressions of 69% and 68%, respectively, corresponding with decreases in tissue protein content, suggesting suppression of local AGT production. Muscle TNF-α mRNA and protein increased 239% and 314%, whereas those of adipose Acrp30 decreased 32% and 98%, respectively. Collectively, this study suggests that prolonged fasting actives systemic RAS, which contributes to an increase in muscle TNF-α and suppression of adipose Acrp30. This targeted and tissue-specific regulation of TNF-α and Acrp30 are likely coordinated to synergistically contribute to the development of an IR-like condition, independent of local RAS activity. These data enhance our understanding of the adaptive mechanisms evolved by elephant seals to tolerate potentially detrimental conditions.Journal of Experimental Biology 05/2013; 216(17). DOI:10.1242/jeb.085225 · 3.00 Impact Factor