Fanconi Anemia Links Reactive Oxygen Species to Insulin Resistance and Obesity

Overview

Journal Antioxid Redox Signal

Specialty Endocrinology

Date 2012 Apr 10

PMID 22482891

Citations 35

Authors

Jie Li

Jared Sipple

Suzette Maynard

Parinda A Mehta

Susan R Rose

Stella M Davies

Qishen Pang

Affiliations

Soon will be listed here.

Abstract

Aims: 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.

Innovation: These findings establish a pathogenic and mechanistic link between ROS and insulin resistance in a unique human disease setting.

Conclusion: ROS accumulation contributes to the insulin resistance in FA deficiency by targeting both PTP-α and PKR.

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References

Pagano G, Degan P, dIschia M, Kelly F, Nobili B, Pallardo F . Oxidative stress as a multiple effector in Fanconi anaemia clinical phenotype. Eur J Haematol. 2005; 75(2):93-100. DOI: 10.1111/j.1600-0609.2005.00507.x. View

Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N . Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell. 2010; 140(3):338-48. PMC: 2820414. DOI: 10.1016/j.cell.2010.01.001. View

Bagby Jr G . Genetic basis of Fanconi anemia. Curr Opin Hematol. 2002; 10(1):68-76. DOI: 10.1097/00062752-200301000-00011. View

Virkamaki A, Ueki K, Kahn C . Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest. 1999; 103(7):931-43. PMC: 408269. DOI: 10.1172/JCI6609. View

Yamamura H . Redox control of protein tyrosine phosphorylation. Antioxid Redox Signal. 2002; 4(3):479-80. DOI: 10.1089/15230860260196272. View

Youngren J . Regulation of insulin receptor function. Cell Mol Life Sci. 2007; 64(7-8):873-91. PMC: 11135994. DOI: 10.1007/s00018-007-6359-9. View

Guilherme A, Virbasius J, Puri V, Czech M . Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008; 9(5):367-77. PMC: 2886982. DOI: 10.1038/nrm2391. View

Aguirre V, Werner E, Giraud J, Lee Y, Shoelson S, White M . Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem. 2001; 277(2):1531-7. DOI: 10.1074/jbc.M101521200. View

Cumming R, Lightfoot J, Beard K, Youssoufian H, OBrien P, Buchwald M . Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1. Nat Med. 2001; 7(7):814-20. DOI: 10.1038/89937. View

10.

MacKay C, Declais A, Lundin C, Agostinho A, Deans A, Macartney T . Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2. Cell. 2010; 142(1):65-76. PMC: 3710700. DOI: 10.1016/j.cell.2010.06.021. View

11.

Kennedy R, DAndrea A . The Fanconi Anemia/BRCA pathway: new faces in the crowd. Genes Dev. 2005; 19(24):2925-40. DOI: 10.1101/gad.1370505. View

12.

Lammers R, Moller N, Ullrich A . The transmembrane protein tyrosine phosphatase alpha dephosphorylates the insulin receptor in intact cells. FEBS Lett. 1997; 404(1):37-40. DOI: 10.1016/s0014-5793(97)00080-x. View

13.

Kobori M, Masumoto S, Akimoto Y, Takahashi Y . Dietary quercetin alleviates diabetic symptoms and reduces streptozotocin-induced disturbance of hepatic gene expression in mice. Mol Nutr Food Res. 2009; 53(7):859-68. DOI: 10.1002/mnfr.200800310. View

14.

Stoker A . Protein tyrosine phosphatases and signalling. J Endocrinol. 2005; 185(1):19-33. DOI: 10.1677/joe.1.06069. View

15.

Nakashima I, Kato M, Akhand A, Suzuki H, Takeda K, Hossain K . Redox-linked signal transduction pathways for protein tyrosine kinase activation. Antioxid Redox Signal. 2002; 4(3):517-31. DOI: 10.1089/15230860260196326. View

16.

Chakraborty A, Koldobskiy M, Bello N, Maxwell M, Potter J, Juluri K . Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. Cell. 2010; 143(6):897-910. PMC: 3052691. DOI: 10.1016/j.cell.2010.11.032. View

17.

Li J, Sejas D, Zhang X, Qiu Y, Nattamai K, Rani R . TNF-alpha induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells. J Clin Invest. 2007; 117(11):3283-95. PMC: 2040318. DOI: 10.1172/JCI31772. View

18.

Ni Y, Wang N, Cao D, Sachan N, Morris D, Gerard R . FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases. Proc Natl Acad Sci U S A. 2007; 104(51):20517-22. PMC: 2154463. DOI: 10.1073/pnas.0610290104. View

19.

Li J, Du W, Maynard S, Andreassen P, Pang Q . Oxidative stress-specific interaction between FANCD2 and FOXO3a. Blood. 2009; 115(8):1545-8. PMC: 2830760. DOI: 10.1182/blood-2009-07-234385. View

20.

Zhang X, Li J, Sejas D, Rathbun K, Bagby G, Pang Q . The Fanconi anemia proteins functionally interact with the protein kinase regulated by RNA (PKR). J Biol Chem. 2004; 279(42):43910-9. DOI: 10.1074/jbc.M403884200. View