title: Fanconi anemia links reactive oxygen species to insulin resistance and obesity.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  METHODS
  These findings establish a pathogenic and mechanistic link between ROS and insulin resistance in a unique human disease setting.
  
  
  CONCLUSIONS
  ROS accumulation contributes to the insulin resistance in FA deficiency by targeting both PTP-α and PKR.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Jared
authors.initials: J
authors.lastname: Sipple
authors.forename: Suzette
authors.initials: S
authors.lastname: Maynard
authors.forename: Parinda A
authors.initials: PA
authors.lastname: Mehta
authors.forename: Susan R
authors.initials: SR
authors.lastname: Rose
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
authors.forename: Qishen
authors.initials: Q
authors.lastname: Pang
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005199:Fanconi Anemia / Q000378:metabolism*; D052217:Fanconi Anemia Complementation Group A Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D052218:Fanconi Anemia Complementation Group C Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D011794:Quercetin / Q000008:administration & dosage / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C498471:FANCA protein, human; C497651:FANCC protein, human; C120277:Fanca protein, mouse; C497652:Fancc protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; D017382:Reactive Oxygen Species; D011794:Quercetin; D011972:Receptor, Insulin