Objective. The development of obesity and its metabolic complications is associated with dys-regulation of various intrinsic mechanisms, which control basic metabolic processes via changes in the expression of numerous regulatory genes. The main goal of this work was to study the association between the expression of insulin-like growth factors (IGF1 and IGF2) and IGF-binding proteins and insulin resistance in obese adolescents for evaluation of possible contribution of these genes in development of insulin resistance.
Methods. The expression of IGF1, IGF2, and IGFBPs mRNA was measured in blood of obese adolescents with normal insulin sensitivity and insulin resistance in comparison with the normal (control) individuals.
Results. In the blood of obese adolescents with normal insulin sensitivity the expression of IGFBP4, IGFBP5 and HTRA1 genes was down-regulated, but IGFBP2 and IGFBP7 genes up-regulated as compared to control (normal) group. At the same time, no significant changes in IGF1 and IGF2 gene expressions in this group of obese adolescents were found. Insulin resistance in obese adolescents led to up-regulation of IGF2, IGFBP2, and IGFBP7 gene expressions as well as to down-regulation of the expression of IGF1, IGFBP5 and HTRA1 genes in the blood in comparison with the obese patients, which have normal insulin sensitivity. Furthermore, the level of IGFBP4 gene expression was similar in both groups of obese adolescents.
Conclusions. Results of this investigation provide evidence that insulin resistance in obese adolescents is associated with gene specific changes in the expression of IGF1, IGF2, IGFBP2, IGFBP5, IGFBP7, and HTRA1 genes and these changes possibly contribute to the development of glucose intolerance and insulin resistance.
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Ahani N Karimi Arzenani M Shirkoohi R Rokouei M Alipour Eskandani M Nikravesh A. Expression of insulin-like growth factor binding protein-2 (IGFBP-2) gene in negative and positive human cytomegalovirus glioblastoma multiforme tissues. Med Oncol 31 812 2014.
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 152 1347–1354 2011.
Auf G Jabouille A Delugin M Guerit S Pineau R North S Platonova N Maitre M Favereaux A Vajkoczy P Seno M Bikfalvi A Minchenko D Minchenko O Moenner M. High epiregulin expression in human U87 glioma cells relies on IRE1 alpha and promotes autocrine growth through EGF receptor. BMC Cancer 13 597 2013.
Bass R Eneli I. Severe childhood obesity: an under-recognised and growing health problem. Postgrad Med J 91 639–645 2015.
Baxter RC. IGF binding proteins in cancer: mechanistic and clinical insights. Nat Rev Cancer 14 329–341 2014.
Cai X Wang L Wang X Hou F. Silence of IGFBP7 suppresses apoptosis and epithelial mesenchymal transformation of high glucose induced-podocytes. Exp Ther Med 16 1095–1102 2018.
Chen J Van Gulden S McGuire TL Fleming AC Oka C Kessler JA Peng CY. BMP-responsive protease HtrA1 is differentially expressed in astrocytes and regulates astrocytic development and injury response. J Neurosci 38 3840–3857 2018.
Chevet E Hetz C Samali A. Endoplasmic reticulum stress-activated cell reprogramming in oncogenesis. Cancer Discov 5 586–597 2015.
Contois LW Akalu A Caron JM Tweedie E Cretu A Henderson T Liaw L Friesel R Vary C Brooks PC. Inhibition of tumor-associated αvβ3 integrin regulates the angiogenic switch by enhancing expression of IGFBP-4 leading to reduced melanoma growth and angiogenesis in vivo. Angiogenesis 18 31–46 2015.
D’Angelo V Pecoraro G Indolf P Iannotta A Donofrio V Errico ME Indolf C Ramaglia M Lombardi A Di Martino M Gigantino V Baldi A Caraglia M De Luca A Casale F. Expression and localization of serine protease Htra1 in neuroblastoma: correlation with cellular differentiation grade. J Neurooncol 117 287–294 2014.
Ding M Bruick RK Yu Y. Secreted IGFBP5 mediates mTORC1-dependent feedback inhibition of IGF-1 signalling. Nat Cell Biol 18 319–327 2016.
Doultsinos D Avril T Lhomond S Dejeans N Guedat P Chevet E. Control of the Unfolded Protein Response in Health and Disease. SLAS Discov 22 787–800 2017.
Ellis BC Graham LD Molloy PL. CRNDE a long non-coding RNA responsive to insulin/IGF signaling regulates genes involved in central metabolism. Biochim Biophys Acta 1843 372–386 2014.
Ferris SP Kodali VK Kaufman RJ. Glycoprotein folding and quality-control mechanisms in protein-folding diseases. Dis Model Mech 7 331–341 2014.
Foulstone EJ Zeng L Perks CM Holly JM. Insulin-like growth factor binding protein 2 (IGFBP-2) promotes growth and survival of breast epithelial cells: novel regulation of the estrogen receptor. Endocrinology 154 1780–1793 2013.
Gambaro K Quinn MC Caceres-Gorriti KY Shapiro RS Provencher D Rahimi K Mes-Masson AM Tonin PN. Low levels of IGFBP7 expression in high-grade serous ovarian carcinoma is associated with patient outcome. BMC Cancer 15 135 2015.
Ghoshal S Stevens JR Billon C Girardet C Sitaula S Leon AS Rao DC Skinner JS Rankinen T Bouchard C Nunez MV Stanhope KL Howatt DA Daugherty A Zhang J Schuelke M Weiss EP Coffey AR Bennett BJ Sethupathy P Burris TP Havel PJ Butler AA. Adropin: An endocrine link between the biological clock and cholesterol homeostasis. Mol Metab 8 51–64 2018.
Gokulakrishnan K Velmurugan K Ganesan S Mohan V. Circulating levels of insulin-like growth factor binding protein-1 in relation to insulin resistance type 2 diabetes mellitus and metabolic syndrome (Chennai Urban Rural Epidemiology Study 118). Metab Clin Exp 61 43–46 2012.
Han J Kaufman RJ. Measurement of the unfolded protein response to investigate its role in adipogenesis and obesity. Methods Enzymol 538 135–150 2014.
Han S Li Z Master LM Master ZW Wu A. Exogenous IGFBP-2 promotes proliferation invasion and chemoresistance to temozolomide in glioma cells via the integrin β1-ERK pathway. Br J Cancer 111 1400–1409 2014.
Han J Kaufman RJ. The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res 57 1329–1338 2016.
Hassler JR Scheuner DL Wang S Han J Kodali VK Li P Nguyen J George JS Davis C Wu SP Bai Y Sartor M Cavalcoli J Malhi H Baudouin G Zhang Y Yates III JR Itkin-Ansari P Volkmann N Kaufman RJ. The IRE1α/XBP1s pathway is essential for the glucose response and protection of β cells. PLoS Biol 13 e1002277 2015.
Hermani A Shukla A Medunjanin S Werner H Mayer D. Insulin-like growth factor binding protein-4 and -5 modulate ligand-dependent estrogen receptor-alpha activation in breast cancer cells in an IGF-independent manner. Cell Signal 25 1395–1402 2013.
Holmes KM Annala M Chua CY Dunlap SM Liu Y Hugen N Moore LM Cogdell D Hu L Nykter M Hess K Fuller GN Zhang W. Insulin-like growth factor-binding protein 2-driven glioma progression is prevented by blocking a clinically significant integrin integrin-linked kinase and NF-κB network. Proc Natl Acad Sci U S A 109 3475–3480 2012.
Huang LE Cohen AL Colman H Jensen RL Fults DW Couldwell WT. IGFBP2 expression predicts IDH-mutant glioma patient survival. Oncotarget 8 191–202 2017.
Hwang JR Cho YJ Lee Y Park Y Han HD Ahn HJ Lee JH Lee JW. The C-terminus of IGFBP-5 suppresses tumor growth by inhibiting angiogenesis. Sci Rep 23 39334 2016.
Kim MS Lee DY. Insulin-like growth factor (IGF)-I and IGF binding proteins axis in diabetes mellitus. Ann Pediatr Endocrinol Metab 20 69–73 2015.
Kuffer S Gutting T Belharazem D Sauer C Michel MS Marx A Trojan L Strobel P. Insulin-like growth factor 2 expression in prostate cancer is regulated by promoter-specific methylation. Mol Oncol 12 256–266 2018.
Kuijjer ML Peterse EF van den Akker BE Briaire-de Bruijn IH Serra M Meza-Zepeda LA Myklebost O Hassan AB Hogendoorn PC Cleton-Jansen AM. IR/IGF1R signaling as potential target for treatment of high-grade osteosarcoma. BMC Cancer 13 245 2013.
Lee J Ozcan U. Unfolded protein response signaling and metabolic diseases. J Biol Chem 289 1203–1211 2014.
Li X Liu X Zhang L Li C Zhang E Ma W Fan Q Yu JJ. Insulin growth factor binding protein 2 mediates the progression of lymphangioleiomyomatosis. Oncotarget 8 36628–36638 2017.
Liu L Yang Z Zhang W Yan B Gu Q Jiao J Yue X. Decreased expression of IGFBP7 was a poor prognosis predictor for gastric cancer patients. Tumour Biol 35 8875–8881 2014.
Lopez MF Zheng L Miao J Gali R Gorski G Hirschhorn JN. Disruption of the Igf2 gene alters hepatic lipid homeostasis and gene expression in the newborn mouse. Am J Physiol Endocrinol Metab 2018.
Mao Z Zhang W. Role of mTOR in glucose and lipid metabolism. Int J Mol Sci 19 pii: E2043 2018.
Maridas DE DeMambro VE Le PT Mohan S Rosen CJ. IGFBP4 is required for adipogenesis and influences the distribution of adipose depots. Endocrinology 158 3488–3500 2017.
Manie 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 307 C901–C907 2014.
Martin KA Mani MV Mani A. New targets to treat obesity and the metabolic syndrome. Eur J Pharmacol 763 64–74 2015.
Minchenko OH Kubaichuk KI Minchenko DO Kovalevska OV Kulinich AO Lypova NM. Molecular mechanisms of ERN1-mediated angiogenesis. Int J Physiol Pathophysiol 5 1–22 2014.
Minchenko DO Kharkova AP Karbovskyi LL Minchenko OH. Expression of insulin-like growth factor binding protein genes and its hypoxic regulation in U87 glioma cells depends on ERN1 mediated signaling pathway of endoplasmic reticulum stress. Endocr Regul 49 73–83 2015a.
Minchenko OH Tsymbal DO Minchenko DO Moenner M Kovalevska OV Lypova NM: Inhibition of the endoribonuclease of ERN1 signaling enzyme affects the expression of proliferation-related genes in U87 glioma cells. Endoplasm Reticul Stress Dis 2 18–29 2015b.
Minchenko DO Kharkova AP Halkin OV Karbovskyi LL Minchenko OH. Effect of hypoxia on the expression of genes encoded insulin-like growth factors and some related proteins in U87 glioma cells without IRE1 function. Endocr Reg 50 43–54 2016.
Neuzillet Y Chapeaublanc E Krucker C De Koning L Lebret T Radvanyi F Bernard-Pierrot I. IGF1R activation and the in vitro antiproliferative efficacy of IGF1R inhibitor are inversely correlated with IGFBP5 expression in bladder cancer. BMC Cancer 17 636 2017.
Ord T Ord D Adler P Vilo J Ord T. TRIB3 enhances cell viability during glucose deprivation in HEK293-derived cells by upregulating IGFBP2 a novel nutrient deficiency survival factor. Biochim Biophys Acta 1853 2492–2505 2015.
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 306 457–461 2004.
Peng T Zhou L Qi H Wang G Luan Y Zuo L. MiR-592 functions as a tumor suppressor in glioma by targeting IGFBP2. Tumour Biol 39 1010428317719273 2017.
Poepsel S Sprengel A Sacca B Kaschani F Kaiser M Gatsogiannis C Raunser S Clausen T Ehrmann M. Determinants of amyloid fibril degradation by the PDZ protease HTRA1. Nat Chem Biol 11 862–869 2015.
Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer 12 159–169 2012.
Praveen Kumar VR Sehgal P Thota B Patil S Santosh V Kondaiah P. Insulin like growth factor binding protein 4 promotes GBM progression and regulates key factors involved in EMT and invasion. J Neurooncol 116 455–464 2014.
Ruderman NB Carling D Prentki M Cacicedo JM. AMPK insulin resistance and the metabolic syndrome. J Clin Invest 123 2764–2772 2013.
Sabin MA Russo VC Azar WJ Yau SW Kiess W Werther GA: IGFBP-2 at the interface of growth and metabolism implications for childhood obesity. Pediatr Endocrinol Rev 8 382–393 2011.
Schillinger J Severin K Kaschani F Kaiser M Ehrmann M. HTRA1-Dependent Cell Cycle Proteomics. J Proteome Res 17 2679–2694 2018.
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 6 e25231 2011.
Sun J Lu Z Deng Y Wang W He Q Yan W Wang A. Up-regulation of INSR/IGF1R by C-myc promotes TSCC tumorigenesis and metastasis through the NF-kappaB pathway. Biochim Biophys Acta 1864 1873–1882 2018.
Sunderic M Dukanovic B Malenkovic V Nedic O. Molecular forms of the insulin-like growth factor-binding protein-2 in patients with colorectal cancer. Exp Mol Pathol 96 48–53 2014.
Tam J Szanda G Drori A Liu Z Cinar R Kashiwaya Y Reitman ML Kunos G. Peripheral cannabinoid-1 receptor blockade restores hypothalamic leptin signaling. Mol Metab 6 1113–1125 2017.
Tang H Leung L Saturno G Viros A Smith D Di Leva G Morrison E Niculescu-Duvaz D Lopes F Johnson L Dhomen N Springer C Marais R. Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface. Nat Commun 8 14909 2017.
Tiaden AN Bahrenberg G Mirsaidi A Glanz S Bluher M Richards PJ. Novel function of serine protease HTRA1 in inhibiting adipogenic differentiation of human mesenchymal stem cells via MAP Kinase-mediated MMP upregulation. Stem Cells 34 1601–1614 2016.
Tsuchihara K Ogura T Fujioka R Fujii S Kuga W Saito M Ochiya T Ochiai A Esumi H. Susceptibility of Snark-deficient mice to azoxymethaneinduced colorectal tumorigenesis and the formation of aberrant crypt foci. Cancer Sci 99 677–682 2008.
Wang S Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol 197 857–867 2012.
Wang J Ding N Li Y Cheng H Wang D Yang Q Deng Y Yang Y Li Y Ruan X Xie F Zhao H Fang X. Insulin-like growth factor binding protein 5 (IGFBP5) functions as a tumor suppressor in human melanoma cells. Oncotarget 6 20636–20649 2015.
Wang M Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529 326–335 2016.
Yang B Zhang L Cao Y Chen S Cao J Wu D Chen J Xiong H Pan Z Qiu F Chen J Ling X Yan M Huang S Zhou S Li T Yang L Huang Y Lu J. Overexpression of lncRNA IGFBP4-1 reprograms energy metabolism to promote lung cancer progression. Mol Cancer 16 154 2017.
Yuan ZS Cao Y Li ZY. IGFBP2 induces SPRY1 expression via NF-kappaB signaling pathway in glioblastoma multi-forme (GBM). Eur Rev Med Pharmacol Sci 21 5072–5080 2017.
Yuzefovych LV Musiyenko SI Wilson GL Rachek LI. Mitochondrial 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 8 e54059 2013.
Zurawa-Janicka D Wenta T Jarzab M Skorko-Glonek J Glaza P Gieldon A Ciarkowski J Lipinska B. Structural insights into the activation mechanisms of human HtrA serine proteases. Arch Biochem Biophys 621 6–23 2017.