Ukr.Biochem.J. 2019; Volume 91, Issue 3, May-Jun, pp. 65-77


Insulin resistance in obese adolescents and adult men modifies the expression of proliferation related genes

O. H. Minchenko1, Y. M. Viletska1, D. O. Minchenko1,2, V. V. Davydov3

1Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
2Bohomolets National Medical University, Kyiv, Ukraine
3SI “Institute of Children and Adolescent Health Care,
National Academy of Medical Sciences of Ukraine”, Kharkiv

Received: 11 December 2018; Accepted: 14 March 2019

Numerous data demonstrate that key regulatory factors, enzymes and receptors including HSPA5, MEST, SLC1A3, PDGFC, and ADM represent poly-functional, endoplasmic reticulum stress-dependent proteins, which control variable metabolic pathways. The expression level of genes of these proteins in the blood and subcutaneous adipose tissue of obese adolescents and adult men with and without insulin resistance was studied. It was shown that in blood of obese adolescents without insulin resistance the expression level of SLC1A3, HSPA5, MEST, and PDGFC genes was significantly increased, but development of insulin resis­tance led to down-regulation of these genes expression except HSPA5 gene as compared to the control group as well as to the group of obese adolescents without insulin resistance. At the same time, the expression level of ADM gene did not change significantly in obese adolescents without insulin resistance, but the development of insulin resistance led to down-regulation of this gene expression. In subcutaneous adipose tissue of obese adult men without insulin resistance the level of SLC1A3 gene expression was decreased, although ADM, MEST, and HSPA5 genes – increased. It was also shown that the development of insulin resistance in obese men affected the expression level of ADM and SLC1A3 genes only. Results of this investigation provide evidence that insulin resistance in obese adolescents and adult men is associated with specific changes in the expression of genes, which related to proliferation and development of obesity and insulin resistance as well as to endoplasmic reticulum stress and contribute to the development of obesity complications.

Keywords: , , , , , , ,


  1. Bass R, Eneli I. Severe childhood obesity: an under-recognised and growing health problem. Postgrad Med J. 2015 Nov;91(1081):639-45. PubMed, CrossRef
  2. Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013 Jul;123(7):2764-72. PubMed, PubMedCentral, CrossRef
  3. 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. 2017 Oct;6(10):1113-1125. PubMed, PubMedCentral, CrossRef
  4. Ghoshal S, Stevens JR, Billon C, Girardet C, Sitaula S, Leon AS, Rao DC, Skinner JS, Rankinen T, Bouchard C, Nuñez 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. 2018 Feb;8:51-64.PubMed, PubMed,CrossRef
  5. Mao Z, Zhang W. Role of mTOR in Glucose and Lipid Metabolism. Int J Mol Sci. 2018 Jul 13;19(7). pii: E2043. PubMed, PubMedCentral, CrossRef
  6. 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.  PubMed, PubMedCentral, CrossRef
  7. Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 2016 Jan 21;529(7586):326-35. PubMed, CrossRef
  8. Han J, Kaufman RJ. Measurement of the unfolded protein response to investigate its role in adipogenesis and obesity. Methods Enzymol. 2014;538:135-50. PubMed, CrossRef
  9. Lee J, Ozcan U. Unfolded protein response signaling and metabolic diseases. J Biol Chem. 2014 Jan 17;289(3):1203-11. PubMed, PubMedCentral, CrossRef
  10. 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 Apr;152(4):1347-54.  PubMed, CrossRef
  11. Yamaoka M, Maeda N, Nakamura S, Kashine S, Nakagawa Y, Hiuge-Shimizu A, Okita K, Imagawa A, Matsuzawa Y, Matsubara K, Funahashi T, Shimomura I. A pilot investigation of visceral fat adiposity and gene expression profile in peripheral blood cells. PLoS One. 2012;7(10):e47377.  PubMed, PubMedCentral, CrossRef
  12. 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 JR III, Itkin-Ansari P, Volkmann N, Kaufman RJ. The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells. PLoS Biol. 2015 Oct 15;13(10):e1002277.  PubMed, PubMedCentralCrossRef
  13. Minchenko DO, Davydov VV, Budreiko OA, Moliavko OS, Kulieshova DK, Tiazhka OV, Minchenko OH. The expression of CCN2, IQSEC, RSPO1, DNAJC15, RIPK2, IL13RA2, IRS1, and IRS2 genes in blood of obese boys with insulin resistance. Fiziol Zh. 2015;61(1):10-8.PubMed, CrossRef
  14. Aggarwal G, Ramachandran V, Javeed N, Arumugam T, Dutta S, Klee GG, Klee EW, Smyrk TC, Bamlet W, Han JJ, Rumie Vittar NB, de Andrade M, Mukhopadhyay D, Petersen GM, Fernandez-Zapico ME, Logsdon CD, Chari ST. Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice. Gastroenterology. 2012 Dec;143(6):1510-1517. PubMed, PubMedCentral, CrossRef
  15. Zhou C, Zheng Y, Li L, Zhai W, Li R, Liang Z, Zhao L. Adrenomedullin promotes intrahepatic cholangiocellular carcinoma metastasis and invasion by inducing epithelial-mesenchymal transition. Oncol Rep. 2015 Aug;34(2):610-6. PubMed, PubMedCentral, CrossRef
  16. Lee A, Anderson AR, Beasley SJ, Barnett NL, Poronnik P, Pow DV. A new splice variant of the glutamate-aspartate transporter: cloning and immunolocalization of GLAST1c in rat, pig and human brains. J Chem Neuroanat. 2012 Jan;43(1):52-63. PubMed, CrossRef
  17. Son D, Na YR, Hwang ES, Seok SH. Platelet-derived growth factor-C (PDGF-C) induces anti-apoptotic effects on macrophages through Akt and Bad phosphorylation. J Biol Chem. 2014 Feb 28;289(9):6225-35. PubMed, PubMedCentral, CrossRef
  18. Amin-Wetzel N, Saunders RA, Kamphuis MJ, Rato C, Preissler S, Harding HP, Ron D.  A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the Unfolded Protein Response. Cell. 2017 Dec 14;171(7):1625-1637. PubMed, PubMedCentral, CrossRef
  19. Bravo R, 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. PubMed, PubMedCentral, CrossRef
  20. Zhang SY, Lv Y, Zhang H, Gao S, Wang T, Feng J, Wang Y, Liu G, Xu MJ, Wang X, Jiang C. Adrenomedullin 2 Improves Early Obesity-Induced Adipose Insulin Resistance by Inhibiting the Class II MHC in Adipocytes. Diabetes. 2016 Aug;65(8):2342-55. PubMed, CrossRef
  21. Zhang H, Zhang SY, Jiang C, Li Y, Xu G, Xu MJ, Wang X. Intermedin/adrenomedullin 2 polypeptide promotes adipose tissue browning and reduces high-fat diet-induced obesity and insulin resistance in mice. Int J Obes (Lond). 2016 May;40(5):852-60.  PubMed, CrossRef
  22. Liao SB, Wong PF; WSO, Cheung BM, Tang F. Effects of adrenomedullin on tumour necrosis factor alpha, interleukins, endothelin-1, leptin, and adiponectin in the epididymal fat and soleus muscle of the rat. Horm Metab Res. 2013 Jan;45(1):31-7. PubMed, CrossRef
  23. Di Liddo R, Bridi D, Gottardi M, De Angeli S, Grandi C, Tasso A, Bertalot T, Martinelli G, Gherlinzoni F, Conconi MT. Adrenomedullin in the growth modulation and differentiation of acute myeloid leukemia cells. Int J Oncol. 2016 Apr;48(4):1659-69. PubMed, CrossRef
  24. Qu Z, Jiang Y, Xu M, Lu MZ, Zhou B, Ding Y. Correlation of adrenomedullin with the erythropoietin receptor and microvessel density in hepatocellular carcinoma. Arch Med Sci. 2015 Oct 12;11(5):978-81. PubMed, PubMedCentral
  25. 25. Tsai SF, Chen YW, Kuo YM. High-fat diet reduces the hippocampal content level of lactate which is correlated with the expression of glial glutamate transporters. Neurosci Lett. 2018 Jan 1;662:142-146. PubMed, CrossRef
  26. 26. Krycer JR, Fazakerley DJ, Cater RJ, C Thomas K, Naghiloo S, Burchfield JG, Humphrey SJ, Vandenberg RJ, Ryan RM, James DE. The amino acid transporter, SLC1A3, is plasma membrane-localised in adipocytes and its activity is insensitive to insulin. FEBS Lett. 2017 Jan;591(2):322-330. PubMed, CrossRef
  27. Bartoschek M, Pietras K. PDGF family function and prognostic value in tumor biology. Biochem Biophys Res Commun. 2018 Sep 5;503(2):984-990. PubMed, CrossRef
  28. Wang C, Cai L, Liu J, Wang G, Li H, Wang X, Xu W, Ren M, Feng L, Liu P, Zhang C. MicroRNA-30a-5p Inhibits the Growth of Renal Cell Carcinoma by Modulating GRP78 Expression. Cell Physiol Biochem. 2017;43(6):2405-2419. PubMed, CrossRef
  29. Kang JM, Park S, Kim SJ, Kim H, Lee B, Kim J, Park J, Kim ST, Yang HK, Kim WH, Kim SJ. KIAA1324 Suppresses Gastric Cancer Progression by Inhibiting the Oncoprotein GRP78. Cancer Res. 2015 Aug 1;75(15):3087-97. PubMed, CrossRef
  30. López I, Tournillon AS, Prado Martins R, Karakostis K, Malbert-Colas L, Nylander K, Fåhraeus R. p53-mediated suppression of BiP triggers BIK-induced apoptosis during prolonged endoplasmic reticulum stress. Cell Death Differ. 2017 Oct;24(10):1717-1729. PubMed, PubMedCentral, CrossRef
  31. Smaldone G, Pirone L, Capolupo A, Vitagliano L, Monti MC, Di Gaetano S, Pedone E. The essential player in adipogenesis GRP78 is a novel KCTD15 interactor. Int J Biol Macromol. 2018 Aug;115:469-475. PubMed, CrossRef
  32. Lin C, Wang J, Wang Y, Zhu P, Liu X, Li N, Liu J, Yu L, Wang W. GRP78 Participates in PCA3-regulated Prostate Cancer Progression. Anticancer Res. 2017 Aug;37(8):4303-4310. PubMed, CrossRef
  33. Ogawa H, Kaira K, Takahashi K, Shimizu A, Altan B, Yoshinari D, Asao T, Oyama T.  Prognostic role of BiP/GRP78 expression as ER stress in patients with gastric adenocarcinoma. Cancer Biomark. 2017 Sep 7;20(3):273-281. PubMed, CrossRef
  34. Luo J, Xia Y, Luo J, Li J, Zhang C, Zhang H, Ma T, Yang L, Kong L. GRP78 inhibition enhances ATF4-induced cell death by the deubiquitination and stabilization of CHOP in human osteosarcoma. Cancer Lett. 2017 Dec 1;410:112-123. PubMed, CrossRef
  35. Yin Y, Chen C, Chen J, Zhan R, Zhang Q, Xu X, Li D, Li M. Cell surface GRP78 facilitates hepatoma cells proliferation and migration by activating IGF-IR. Cell Signal. 2017; 35: 154-162.  CrossRef
  36. El Hajj N, Pliushch G, Schneider E, Dittrich M, Müller T, Korenkov M, Aretz M, Zechner U, Lehnen H, Haaf T. Metabolic programming of MEST DNA methylation by intrauterine exposure to gestational diabetes mellitus. Diabetes. 2013 Apr;62(4):1320-8. PubMed, PubMedCentral, CrossRef
  37. Garcia-Carrizo F, Priego T, Szostaczuk N, Palou A, Picó C. Sexual Dimorphism in the Age-Induced Insulin Resistance, Liver Steatosis, and Adipose Tissue Function in Rats. Front Physiol. 2017 Jul 11;8:445. PubMed, PubMedCentral, CrossRef
  38. Anunciado-Koza RP, Manuel J, Mynatt RL, Zhang J, Kozak LP, Koza RA. Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest). PLoS One. 2017 Jun 22;12(6):e0179879.  PubMed, PubMedCentral, CrossRef
  39. Minchenko OH, Tsymbal DO, Minchenko DO, Kubaychuk OO. Hypoxic regulation of MYBL1, MEST, TCF3, TCF8, GTF2B, GTF2F2 and SNAI2 genes expression in U87 glioma cells upon IRE1 inhibition. Ukr Biochem J. 2016 Nov-Dec;88(6):52-62. PubMed, CrossRef
  40. Mesman S, van Hooft JA, Smidt MP. Mest/Peg1 Is Essential for the Development and Maintenance of a SNc Neuronal Subset. Front Mol Neurosci. 2017 Jan 13;9:166. PubMed, PubMedCentral, CrossRef
  41. Tsuchihara K, Ogura T, Fujioka R, Fujii S, Kuga W, Saito M, Ochiya T, Ochiai A, Esumi H. Susceptibility of Snark-deficient mice to azoxymethane-induced colorectal tumorigenesis and the formation of aberrant crypt foci. Cancer Sci. 2008 Apr;99(4):677-82. PubMed, CrossRef
  42. 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 Nov 15;307(10):C901-7.  PubMed, CrossRef
  43. Chevet E, Hetz C, Samali A. Endoplasmic reticulum stress-activated cell reprogramming in oncogenesis. Cancer Discov. 2015 Jun;5(6):586-97.
    PubMed, CrossRef
  44. Doultsinos D, Avril T, Lhomond S, Dejeans N, Guédat P, Chevet E. Control of the Unfolded Protein Response in Health and Disease. SLAS Discov. 2017 Aug;22(7):787-800. PubMed, CrossRef
  45. 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): 45–53. CrossRef
  46. Kim JH, Lee E, Friedline RH, Suk S, Jung DY, Dagdeviren S, Hu X, Inashima K, Noh HL, Kwon JY, Nambu A, Huh JR, Han MS, Davis RJ, Lee AS, Lee KW, Kim JK. Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity. FASEB J. 2018 Apr;32(4):2292-2304. PubMed, PubMedCentral, CrossRef
  47. Liong S, Lappas M. Endoplasmic reticulum stress regulates inflammation and insulin resistance in skeletal muscle from pregnant women. Mol Cell Endocrinol. 2016 Apr 15;425:11-25. PubMed, CrossRef
  48. Luo J, Huang L, Wang A, Liu Y, Cai R, Li W, Zhou MS. Resistin-Induced Endoplasmic Reticulum Stress Contributes to the Impairment of Insulin Signaling in Endothelium. Front Pharmacol. 2018 Oct 26;9:1226. PubMed, PubMedCentral, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.