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Fanconi anemia links reactive oxygen species to insulin resistance and obesity.

Antioxidants & redox signaling (2012-04-10)
Jie Li, Jared Sipple, Suzette Maynard, Parinda A Mehta, Susan R Rose, Stella M Davies, Qishen Pang
要旨

Insulin resistance is a hallmark of obesity and type 2 diabetes. Reactive oxygen species (ROS) have been proposed to play a causal role in insulin resistance. However, evidence linking ROS to insulin resistance in disease settings has been scant. Since both oxidative stress and diabetes have been observed in patients with the Fanconi anemia (FA), we sought to investigate the link between ROS and insulin resistance in this unique disease model. Mice deficient for the Fanconi anemia complementation group A (Fanca) or Fanconi anemia complementation group C (Fancc) gene seem to be diabetes-prone, as manifested by significant hyperglycemia and hyperinsulinemia, and rapid weight gain when fed with a high-fat diet. These phenotypic features of insulin resistance are characterized by two critical events in insulin signaling: a reduction in tyrosine phosphorylation of the insulin receptor (IR) and an increase in inhibitory serine phosphorylation of the IR substrate-1 in the liver, muscle, and fat tissues from the insulin-challenged FA mice. High levels of ROS, spontaneously accumulated or generated by tumor necrosis factor alpha in these insulin-sensitive tissues of FA mice, were shown to underlie the FA insulin resistance. Treatment of FA mice with the natural anti-oxidant Quercetin restores IR signaling and ameliorates the diabetes- and obesity-prone phenotypes. Finally, pairwise screen identifies protein-tyrosine phosphatase (PTP)-α and stress kinase double-stranded RNA-dependent protein kinase (PKR) that mediate the ROS effect on FA insulin resistance. These findings establish a pathogenic and mechanistic link between ROS and insulin resistance in a unique human disease setting. ROS accumulation contributes to the insulin resistance in FA deficiency by targeting both PTP-α and PKR.

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Sigma-Aldrich
モノクロナール抗β-アクチン マウス宿主抗体, clone AC-15, ascites fluid
Sigma-Aldrich
抗リン酸化チロシン抗体、クローン4G10®, clone 4G10®, Upstate®, from mouse
Sigma-Aldrich
Monoclonal Anti-PRKRA antibody produced in mouse, clone 1B9-1A7, purified immunoglobulin, buffered aqueous solution