Українська English

ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)
DOI: https://doi.org/10.15407/fz

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2015; 61(1): 10-18


The expression of CСN2, IQSEC, RSPO1, DNAJC15, RIPK2, IL13RA2, IRS1, and IRS2 genes in blood of obese boys with insulin resistance

D. O. Minchenko1,2, V.V. Davydov3, O.A. Budreiko3, O.S. Moliavko1, D.K. Kulieshova3, O.V. Tiazhka2, O.H. Minchenko1

  1. Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, Kyiv, Ukraine
  2. Bohomolets National Medical University, Kyiv, Ukraine
  3. SI “Institute of children and adolescent health care National Academy of Medical Science of Ukraine”, Kharkiv, Ukraine
DOI: https://doi.org/10.15407/fz61.01.010


Abstract

The development of obesity and its metabolic complications is associated with dysregulation of various intrinsic mechanisms, which control basic metabolic processes via changes in the expression of numerous regulatory genes. We studied the expression of the subset of genes, which responsible for control of cell growth and glucose metabolism, in blood cells of obese boys with normal and impaired insulin sensitivity as well as in normal (control) individuals. It was shown that obesity with normal insulin sensitivity enhances the expression of IRS1, RIPK2, IL13RA2, RSPO1, IQSEC, and CCN2 genes, but decreases the expression level IRS2 and DNAJC15 genes in the blood cells as compared to control group. Insulin resistance in obese boys leads to up-regulation of IRS2, RSPO1, and DNAJC15 gene expressions as well as to down-regulation of IRS1 and RIPK2 genes in the blood cells versus obese patients with normal insulin sensitivity. Results of this study provide evidence that obesity affects the expression of the subset of genes related to cell growth and glucose metabolism in blood cells and that insulin resistance in obesity is associated with changes in the expression level of IRS1, IRS2, RIPK2, RSPO1, and DNAJC15 genes, which contribute to the development of insulin resistance and glucose intolerance and possibly re(ect some changes in fat tissue.

Keywords: mRNA expression; CСN2; IQSEC; RSPO1; DNAJC15; RIPK2; IL13RA2; IRS1; IRS2; blood; obesity; insulin resistance.

References

  1. Bray MS, Young ME. The role of cell-specific circadian clocks in metabolism and disease. Obes Rev 2009; 10(Suppl 2): 6–13.
  2.  
  3. Bray MS, Young ME. Regulation of fatty acid metabolism by cell autonomous circadian clocks: time to fatten up on information? J Biol Chem 2011; 286 (14): 11883–9.
  4.  
  5. Kovac J, Husse J, Oster H. A time to fast, a time to feast: the crosstalk between metabolism and the circadian clock. Mol Cells 2009; 282: 75–80. CrossRef PubMed
  6.  
  7. Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest 2013; 123 (7): 2764–72. CrossRef PubMed PubMedCentral
  8.  
  9. Huang W, Ramsey KM, Marcheva B, Bass J. Circadian rhythms, sleep, and metabolism. J Clin Invest 2011; 121 (6): 2133–41. CrossRef PubMed PubMedCentral
  10.  
  11. Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol 2012; 197 (7): 857–67. CrossRef PubMed PubMedCentral
  12.  
  13. Ando H, Kumazaki M, Motosugi Y, Ushijima K, Maekawa T, Ishikawa E, Fujimura A. Impairment of peripheral circadian clocks precedes metabolic abnormalities in ob/ob mice. Endocrinology 2011; 152 (4): 1347–54. CrossRef PubMed
  14.  
  15. Shimba S, Ogawa T, Hitosugi S, Ichihashi Y, Nakadaira Y, Kobayashi M, Tezuka M, Kosuge Y, Ishige K, Ito Y, Komiyama K, Okamatsu-Ogura Y, Kimura K, Saito M. DeŸcient of a clock gene, brain and muscle Arnt-like protein-1 (BMAL1), induces dyslipidemia and ectopic fat formation. PLoS One 2011; 6 (9): e25231.
  16.  
  17. Duong HA, Robles MS, Knutti D, Weitz CJ. A molecular mechanism for circadian clock negative feedback. Science 2011; 332 (6036): 1436–9. CrossRef PubMed PubMedCentral
  18.  
  19. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306: 457–61. CrossRef PubMed
  20.  
  21. Ridderstrale M, Degerman E, Tornqvist H. Growth hormone stimulates the tyrosine phosphorylation of the insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase in primary adipocytes. J Biol Chem 1995; 270 (8): 3471–4 .
  22.  
  23. Copps KD, White MF. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 2012; 55(10): 2565-82. CrossRef PubMed PubMedCentral
  24.  
  25. Zhao Y, Biswas SK, McNulty PH, Kozak M, Jun JY, Segar L. PDGF-induced vascular smooth muscle cell proliferation is associated with dysregulation of insulin receptor substrates. Am J Physiol, Cell Physiol 2011; 300 (6): C1375–85.
  26.  
  27. Kilpelainen TO, Zillikens MC, Stancakova A, Finucane FM, Ried JS, Langenberg C, Zhang W, Beckmann JS, Luan J, Vandenput L. et al. Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic proŸle. Nat Genet 2011; 43 (8): 753–60. CrossRef PubMed PubMedCentral
  28.  
  29. Yang X, Nath A, Opperman MJ, Chan C. The double-stranded RNA-dependent protein kinase differentially regulates insulin receptor substrates 1 and 2 in HepG2 cells. Mol Biol Cell 2010; 21: 3449–58.16. Fujisawa T, Joshi B, Nakajima A, Puri RK. A novel role of interleukin-13 receptor alpha2 in pancreatic cancer invasion and metastasis. Cancer Res 2009; 69 (22): 8678–85. CrossRef PubMed
  30.  
  31. Lai EW, Joshi BH, Martiniova L, Dogra R, Fujisawa T, Leland P, de Krijger RR, Lubensky IA, Elkahloun AG, Morris JC, Puri RK, Pacak K. Overexpression of interleukin-13 receptor-alpha2 in neuroendocrine malignant pheochromocytoma: a novel target for receptor directed anti-cancer therapy. J Clin Endocrinol Metab 2009; 94 (8): 2952–7. CrossRef PubMed PubMedCentral
  32.  
  33. Wu S, Kanda T, Nakamoto S, Imazeki F, Yokosuka O. Knockdown of receptor-interacting serine/threonine protein kinase-2 (RIPK2) affects EMT-associated gene expression in human hepatoma cells. Anticancer Res 2012; 32: 3775–83.
  34.  
  35. Tigno-Aranjuez JT, Asara JM, Abbott DW. Inhibition of RIP2's tyrosine kinase activity limits NOD2-driven cyto-kine responses. Genes Dev 2010; 24: 2666–77. CrossRef PubMed PubMedCentral
  36.  
  37. Chang CC, Hsu WH, Wang CC, Chou CH, Kuo MY, Lin BR, Chen ST, Tai SK, Kuo ML, Yang MH. Connective tissue growth factor activates pluripotency genes and mesenchymal-epithelial transition in head and neck cancer cells. Cancer Res 2013; 73 (13): 4147–57. CrossRef PubMed
  38.  
  39. Battula VL, Chen Y, Cabreira Mda G, Ruvolo V, Wang Z, Ma W, Konoplev S, Shpall E, Lyons K, Strunk D, Bueso-Ramos C, Davis RE, Konopleva M, Andreeff M. Connective tissue growth factor regulates adipocyte differentiation of mesenchymal stromal cells and facilitates leukemia bone marrow engraftment. Blood 2013; 122 (3): 357–-66.
  40.  
  41. Wong VS, Yeung A, Schultz W, Brubaker PL. R-spondin-1 is a novel beta-cell growth factor and insulin secretagogue. J Biol Chem 2010; 285 (28): 21292–302. CrossRef PubMed PubMedCentral
  42.  
  43. Lau YF, Li Y. The human and mouse sex-determining SRY genes repress the Rspol/beta-catenin signaling. J Genet Genomics 2009; 36 (4): 193–202. CrossRef  
  44. Schusdziarra C, Blamowska M, Azem A, Hell K. Methylation-controlled J-protein MCJ acts in the import of proteins into human mitochondria. Hum Mol Genet 2013; 22 (7): 1348-1357. CrossRef PubMed
  45.  
  46. Hatle KM, Neveu W, Dienz O, Rymarchyk S, Barrantes R, Hale S, Farley N, Lounsbury KM, Bond JP, Taatjes D, Rincon M. Methylation-controlled J protein promotes c-Jun degradation to prevent ABCB1 transporter expression. Mol Cell Biol 2007; 27 (8): 2952-2966. CrossRef PubMed PubMedCentral
  47.  
  48. Lee J, Ozcan U. Unfolded Protein Response Signaling and Metabolic Diseases. J Biol Chem 2014; 289 (3): 1203–11. CrossRef PubMed PubMedCentral
  49.  
  50. Minchenko OH, Kubaichuk KI, Minchenko DO, Kova-levska OV, Kulinich AO, Lypova NM. Molecular mecha-nisms of ERN1-mediated angiogenesis. Int J Physiol Pathophysiol 2014; 5 (1): 1–22. CrossRef  
  51. Yuzefovych LV, Musiyenko SI, Wilson GL, Rachek LI. Mi-tochondrial DNA damage and dysfunction, and oxidative stress are associated with endoplasmic reticulum stress, protein degradation and apoptosis in high fat diet-induced insulin resistance mice. PLoS One 2013; 8 (1): e54059.
  52.  
  53. Minchenko D, Ratushna O, Bashta Y, Herasymenko R, Minchenko O. The expression of TIMP1, TIMP2, VCAN, SPARC, CLEC3B and E2F1 in subcutaneous adipose tissue of obese males and glucose intolerance. CellBio 2013; 2 (2): 25–33. CrossRef  
  54. Long YC, Cheng Z, Copps KD, White MF. Insulin receptor substrates Irs1 and Irs2 coordinate skeletal muscle growth and metabolism via the Akt and AMPK pathways. Mol Cell Biol 2011; 31 (3): 430-41. CrossRef PubMed PubMedCentral
  55.  
  56. Guo S, Copps KD, Dong X, Park S, Cheng Z, Pocai A, Rossetti L, Sajan M, Farese RV, White MF. The Irs1 branch of the insulin signaling cascade plays a dominant role in hepatic nutrient homeostasis. Mol Cell Biol 2009; 29 (18): 5070-83. CrossRef PubMed PubMedCentral
  57.  

© National Academy of Sciences of Ukraine, Bogomoletz Institute of Physiology, 2014-2024.