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. 2016; 62(2): 12-23


Glucose tolerance in obese men is associated with dysregulation of some angiogenesis-related gene expressions in subcutaneous adipose tissue

O.H. Minchenko1, Y.M. Bashta1, D.O. Minchenko1,2, O.O. Ratushna1

  1. Palladin Institute of Biochemistry National Academy of Sciences of Ukraine, Kyiv, Ukraine
  2. Bogomolets National Medical University, Kyiv, Ukraine
DOI: https://doi.org/10.15407/fz62.02.012


Abstract

Obesity and its metabolic complications are one of the most profound public health problems and result from interactions between genes and environmental. The development of obesity is tightly connected with dysregulation of intrinsic gene expression mechanisms controlling majority of metabolic processes, which are essential for regulation many physiological functions, including insulin sensitivity, cellular proliferation and angiogenesis. Our objective was to evaluate if expression of angiogenesis related genes VEGF-A, CYR61, PDGFC, FGF1, FGF2, FGFR2, FGFRL1, E2F8, BAI2, HIF1A, and EPAS1 at mRNA level in adipose tissue could participate in the development of obesity and metabolic complications. We have shown that expression level of VEGF-A, PDGFC, FGF2, and FGFRL1 genes is decreased in adipose tissue of obese men with normal glucose tolerance (NGT) versus a group of control subjects. At the same time, in this group of obese individuals a significant up-regulation of CYR61, FGF1, FGFR2, E2F8, BAI2, and HIF1A gene expressions was observed. Impaired glucose tolerance (IGT) in obese patients associates with down-regulation of CYR61 and FGFR2 mRNA and up-regulations of E2F8, FGF1, FGF2, VEGF-A and its splice variant 189 mRNA expressions in adipose tissue versus obese (NGT) individuals. Thus, our data demonstrate that the expression of almost all studied genes is affected in subcutaneous adipose tissue of obese individuals with NGT and that glucose intolerance is associated with gene-specific changes in the expression of E2F8, FGF1, FGF2, VEGF-A, CYR61 and FGFR2 mRNAs. The data presented here provides evidence that VEGF-A, CYR61, PDGFC, FGF1, FGF2, FGFR2, FGFRL1, E2F8, BAI2, and HIF1A genes are possibly involved in the development of obesity and its complications.

Keywords: mRNA expression, VEGF-A, CYR61, FGF1, FGF2, FGFR2, E2F8, HIF1A, adipose tissue, obesity, men

References

  1. 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. Deficient of a clock gene, brain and muscle Arnt-like protein-1 (BMAL1), induces dyslipidemia and ectopic fat formation. PLoS One. 2011; 6 (9): e25231. CrossRef PubMed PubMedCentral
  2.  
  3. 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
  4.  
  5. Green CB, Takahashi JS, Bass J. The meter of metabolism. Cell. 2008; 134 (): 728-42.
  6.  
  7. Huo Y, Guo X, Li H, Xu H, Halim V, Zhang W, Wang H, Fan YY, Ong KT, Woo SL, Chapkin RS, Mashek DG, Chen Y, Dong H, Lu F, Wei L, Wu C. Targeted overexpression of inducible 6-phosphofructo-2-kinase in adipose tissue increases fat deposition but protects against diet-induced insulin resistance and inflammatory responses. J Biol Chem. 2012; 287 (25): 21492–500. CrossRef PubMed PubMedCentral
  8.  
  9. Tsushima Y, Matsuda K, Mori T, Inoue K, Nishizawa H, Tominaga M, Funahashi T, Shimomura I. Adipose hypothermia in obesity and its association with period homolog 1, insulin sensitivity, and inflammation in fat. PLoS One. 2014; 9 (11): e112813. CrossRef PubMed PubMedCentral
  10.  
  11. 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 (): 1347–54.
  12.  
  13. Huang W, Ramsey KM, Marcheva B, Bass J. Circadian rhythms, sleep, and metabolism. J Clin Invest. 2011; 121 (6): 2133–41. CrossRef PubMed PubMedCentral
  14.  
  15. Ando H, Takamura T, Matsuzawa-Nagata N, Shima KR, Eto T, Misu H, Shiramoto M, Tsuru T, Irie S, Fujimura A, Kaneko S. Clock gene expression in peripheral leucocytes of patients with type 2 diabetes. Diabetologia. 2009; 52 (): 329–35.
  16.  
  17. Duong HA, Robles MS, Knutti D, Weitz CJ. A molecular mechanism for circadian clock negative feedback. Science. 2011; 332 (): 1436–9.
  18.  
  19. Mueller MD, Vigne J-L, Minchenko AG, Lebovic DI, Leitman DC, Taylor RN. Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors "a" and "b". Proc Natl Acad Sci USA. 2000; 97 (20): 10972-7. CrossRef PubMed PubMedCentral
  20.  
  21. Rega G, Kaun C, Demyanets S, Pfaffenberger S, Rychli K, Hohensinner PJ, Kastl SP, Speidl WS, Weiss TW, Breuss JM, Furnkranz A, Uhrin P, Zaujec J, Zilberfarb V, Frey M, Roehle R, Maurer G, Huber K, Wojta J. Vascular endothelial growth factor is induced by the inflammatory cytokines interleukin-6 and oncostatin m in human adipose tissue in vitro and in murine adipose tissue in vivo. Arterioscler Thromb Vasc Biol. 2007; 27 (7): 1587-95. CrossRef PubMed
  22.  
  23. Red-Horse K, Ferrara N. Imaging tumor angiogenesis. J Clin Invest. 2006; 116 (10): 2585-7. CrossRef PubMed PubMedCentral
  24.  
  25. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005; 23 (5): 1011-27. CrossRef PubMed
  26.  
  27. Kowanetz M, Ferrara N. Vascular endothelial growth factor signaling pathways: therapeutic perspective. Clin Cancer Res. 2006; 12 (17): 5018–22. CrossRef PubMed
  28.  
  29. Minchenko OH, Kubaichuk KI, Minchenko DO, Kovalevska OV, Kulinich AO, Lypova NM. Molecular mechanisms of ERN1-mediated angiogenesis. Int J Physiol Pathophysiol. 2014; 5(1): 1-22. CrossRef  
  30. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004; 25 (4): 581-611. CrossRef PubMed
  31.  
  32. Dews M, Homayouni A, Yu D., Murphy D, Sevignani C, Wentzel E, Furth EE, Lee WM, Enders GH, Mendell JT, Thomas-Tikhonenko A. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet. 2006; 38 (9): 1060–5. CrossRef PubMed PubMedCentral
  33.  
  34. Barreto SC, Hopkins CA, Bhowmick M, Ray A. Extracellular matrix in obesity - cancer interactions. Horm Mol Biol Clin Investig. 2015; 22 (2): 63-77. CrossRef  
  35. Zencir S, Ovee M, Dobson MJ, Banerjee M, Topcu Z, Mohanty S. Identification of brain-specific angiogenesis inhibitor 2 as an interaction partner of glutaminase interacting protein. Biochem Biophys Res Commun. 2011; 411 (4): 792-7. CrossRef PubMed PubMedCentral
  36.  
  37. Wright JH, Johnson MM, Shimizu-Albergine M, Bauer RL, Hayes BJ, Surapisitchat J, Hudkins KL, Riehle KJ, Johnson SC, Yeh MM, Bammler TK, Beyer RP, Gilbertson DG, Alpers CE, Fausto N, Campbell JS. Paracrine activation of hepatic stellate cells in platelet-derived growth factor C transgenic mice: evidence for stromal induction of hepatocellular carcinoma. Int J Cancer. 2014; 134 (4): 778-88. CrossRef PubMed PubMedCentral
  38.  
  39. Jonker JW, Suh JM, Atkins AR, Ahmadian M, Li P, Whyte J, He M, Juguilon H, Yin YQ, Phillips CT, Yu RT, Olefsky JM, Henry RR, Downes M, Evans RM. A PPARγ-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature. 2012; 485 (7398): 391-4. CrossRef PubMed PubMedCentral
  40.  
  41. Kingwell K. Obesity and diabetes: FGF1 goes long to tackle diabetes. Nat Rev Drug Discov. 2014; 13 (9): 652-3. CrossRef PubMed
  42.  
  43. Li B, Pi Z, Liu L, Zhang B, Huang X, Hu P, Chevet E, Yi P, Liu J. FGF-2 prevents cancer cells from ER stressmediated apoptosis via enhancing proteasome-mediated Nck degradation. Biochem J. 2013; 452 (1): 139-45. CrossRef PubMed
  44.  
  45. Ranieri D, Belleudi F, Magenta A, Torrisi MR. HPV16 E5 expression induces switching from FGFR2b to FGFR2c and epithelial-mesenchymal transition. Int J Cancer. 2015; 137 (1): 61-72. CrossRef PubMed
  46.  
  47. di Martino E, Taylor CF, Roulson JA, Knowles MA. An integrated genomic, transcriptional and protein investigation of FGFRL1 as a putative 4p16.3 deletion target in bladder cancer. Genes Chromosomes Cancer. 2013; 52 (9): 860-71. CrossRef PubMed
  48.  
  49. Yoon H, Shin SH, Shin DH, Chun YS and Park JW. Differential roles of Sirt1 in HIF-1alpha and HIF-2alpha mediated hypoxic responses. Biochem Biophys Res Commun. 2014; 444 (1): 36-43. CrossRef PubMed
  50.  
  51. Deng Q, Wang Q, Zong WY, Zheng DL, Wen YX, Wang KS, Teng XM, Zhang X, Huang J, Han ZG. E2F8 contributes to human hepatocellular carcinoma via regulating cell proliferation. Cancer Res. 2010; 70(2): 782-91. CrossRef PubMed
  52.  
  53. Weijts BG, Bakker WJ, Cornelissen PW, Liang KH, Schaftenaar FH, Westendorp B, de Wolf CA, Paciejewska M, Scheele CL, Kent L, Leone G, Schulte-Merker S, de Bruin A. E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1. EMBO J. 2012; 31(19): 3871-84. CrossRef PubMed PubMedCentral
  54.  
  55. Faubert B, Vincent EE, Griss T, Samborska B, Izreig S, Svensson RU, Mamer OA, Avizonis D, Shackelford DB, Shaw RJ, Jones RG. Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF- 1alpha. Proc Natl Acad Sci USA. 2014; 111 (7): 2554-9. CrossRef PubMed PubMedCentral
  56.  
  57. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004; 306 (5695): 457–61. CrossRef PubMed
  58.  
  59. Bravo R1, Parra V, Gatica D, Rodriguez AE, Torrealba N, Paredes F, Wang ZV, Zorzano A, Hill JA, Jaimovich E, Quest AF, Lavandero S. Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration. Int Rev Cell Mol Biol. 2013; 301: 215-90. CrossRef PubMed PubMedCentral
  60.  
  61. Manié SN, Lebeau J, Chevet E. Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 3. Orchestrating the unfolded protein response in oncogenesis: an update. Am J Physiol Cell Physiol. 2014; 307 (10): C901-7. CrossRef PubMed
  62.  
  63. Pluquet O, Dejeans N, Chevet E. Watching the clock: endoplasmic reticulum-mediated control of circadian rhythms in cancer. Ann Med. 2014; 46 (4): 233-43. CrossRef PubMed
  64.  
  65. Bochkov VN, Philippova M, Oskolkova O, Kadl A, Furnkranz A, Karabeg E, Breuss J, Minchenko OH, Mechtcheriakova D, Hohensinner P, Rychli K, Wojta J, Resink T, Binder BR, Leitinger N. Oxidized phospholipids stimulate angiogenesis via induction of VEGF, IL-8, COX- 2 and ADAMTS-1 metalloprotease, implicating a novel role for lipid oxidation in progression and destabilization of atherosclerotic lesions. Circ Res. 2006; 99 (8): 900-8. CrossRef PubMed
  66.  
  67. Hose D, Moreaux J, Meissner T, Seckinger A, Goldschmidt H, Benner A, Mahtouk K, Hillengass J, Rème T, De Vos J, Hundemer M, Condomines M, Bertsch U, Rossi JF, Jauch A, Klein B, Möhler T. Induction of angiogenesis by normal and malignant plasma cells. Blood. 2009; 114(1): 128–43. CrossRef PubMed
  68.  
  69. Waltenberger J. VEGF resistance as a molecular basis to explain the angiogenesis paradox in diabetes mellitus. Biochemical Society Transactions. 2009; 37(Pt. 6): 1167-70. CrossRef PubMed

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