1. bookVolume 53 (2019): Issue 2 (April 2019)
Journal Details
First Published
30 Mar 2016
Publication timeframe
4 times per year
access type Open Access

Insulin resistance in obese adolescents affects the expression of genes associated with immune response

Published Online: 13 May 2019
Volume & Issue: Volume 53 (2019) - Issue 2 (April 2019)
Page range: 71 - 82
Journal Details
First Published
30 Mar 2016
Publication timeframe
4 times per year

Objective. The development of obesity and its metabolic complications is associated with dysregulation of various intrinsic mechanisms, which control basic metabolic processes through changes in the expression of numerous regulatory genes.

Methods. The expression level of HLA-DRA, HLA-DRB1, HLA-G, HLA-F, and NFX1 genes as well as miR-190b was measured in the blood of obese adolescents without signs of resistance to insulin and with insulin resistance in comparison with the group of relative healthy control individuals without signs of obesity.

Results. It was shown that obesity without signs of insulin resistance is associated with upregulation of the expression level of HLA-DRA and HLA-DRB1 genes, but with down-regulation of HLA-G gene expression in the blood as compared to control group of relative healthy adolescents. At the same time, no significant changes were observed in the expression level of HLA-F and NFX1 genes in the blood of this group of obese adolescents. Development of insulin resistance in obese individuals leads to significant down-regulation of HLA-DRA, HLA-DRB1, HLA-G, and HLA-F gene expressions as well as to up-regulation of NFX1 gene as well as microRNA miR-190b in the blood as compared to obese patients without signs of insulin resistance.

Conclusions. Results of this study provide evidence that obesity affects the expression of the subset of genes related to immune response in the blood and that development of insulin resistance in obese adolescents is associated with strong down-regulation of the expressions of HLA-DRA, HLA-DRB1, HLA-F, and HLA-G genes, which may be contribute to the development of obesity complications. It is possible that transcription factor NFX1 and miR-190b participate in downregulation of HLA-DRA gene expression in the blood of obese adolescents with insulin resistance.


Amiot L, Vu N, Samson M. Biology of the immunomodulatory molecule HLA-G in human liver diseases. J Hepatol 62, 1430–1437, 2015.2577203810.1016/j.jhep.2015.03.00725772038Search in Google Scholar

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, 2011.10.1210/en.2010-106821285316Search in Google Scholar

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, 2013.10.1186/1471-2407-13-597387867024330607Search in Google Scholar

Bass R, Eneli I. Severe childhood obesity: an under-recognised and growing health problem. Postgrad Med J 91, 639–645, 2015.10.1136/postgradmedj-2014-13303326338983Search in Google Scholar

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 99, 900–908, 2006.10.1161/01.RES.0000245485.04489.ee16973904Search in Google Scholar

Boegel S, Lower M, Bukur T, Sorn P, Castle JC, Sahin U. HLA and proteasome expression body map. BMC Med Genomics 11, 36, 2018.10.1186/s12920-018-0354-x587258029587858Search in Google Scholar

Brown PJ, Wong KK, Felce SL, Lyne L, Spearman H, Soilleux EJ, Pedersen LM, Moller MB, Green TM, Gascoyne DM, Banham AH. FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas. Leukemia 30, 605–616, 2016.10.1038/leu.2015.299477777726500140Open DOISearch in Google Scholar

Cajander S, Backman A, Tina E, Stralin K, Soderquist B, Kallman J. Preliminary results in quantitation of HLA-DRA by real-time PCR: a promising approach to identify immunosuppression in sepsis. Crit Care 17, R223, 2013.10.1186/cc13046405720224093602Open DOISearch in Google Scholar

Cajander S, Tina E, Backman A, Magnuson A, Stralin K, Soderquist B, Kallman J. Quantitative real-time polymerase chain reaction measurement of HLA-DRA gene expression in whole blood is highly reproducible and shows changes that reflect dynamic shifts in monocyte surface HLA-DR expression during the course of sepsis. PLoS One 11, e0154690, 2016.2714464010.1371/journal.pone.0154690485638527144640Search in Google Scholar

Carosella ED, Rouas-Freiss N, Tronik-Le Roux D, Moreau P, LeMaoult J. HLA-G: an immune checkpoint molecule. Adv Immunol 127, 33–144, 2015.10.1016/bs.ai.2015.04.00126073983Search in Google Scholar

Chevet E, Hetz C, Samali A. Endoplasmic reticulum stress-activated cell reprogramming in oncogenesis. Cancer Discov 5, 586–597, 2015.10.1158/2159-8290.CD-14-149025977222Search in Google Scholar

Cizeron-Clairac G, Lallemand F, Vacher S, Lidereau R, Bieche I, Callens C. MiR-190b, the highest up-regulated miRNA in ERalpha-positive compared to ERalpha-negative breast tumors, a new biomarker in breast cancers? BMC Cancer 15, 499, 2015.10.1186/s12885-015-1505-5449122226141719Search in Google Scholar

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, 2017.2845337610.1177/247255521770168528453376Search in Google Scholar

Farjadian S, Tabebordbar M, Mokhtari M, Safaei A, Malekzadeh M, Ghaderi A. HLA-G expression in tumor tissues and soluble HLA-G plasma levels in patients with gastrointestinal cancer. Asian Pac J Cancer Prev 19, 2731–2735, 2018.Search in Google Scholar

Han J, Kaufman RJ. Measurement of the unfolded protein response to investigate its role in adipogenesis and obesity. Methods Enzymol 538, 135–150, 2014.10.1016/B978-0-12-800280-3.00008-624529437Search in Google Scholar

Harada A, Ishigami S, Kijima Y, Nakajo A, Arigami T, Kurahara H, Kita Y, Yoshinaka H, Natsugoe S. Clinical implication of human leukocyte antigen (HLA)-F expression in breast cancer. Pathol Int 65, 569–574, 2015.2633265110.1111/pin.1234326332651Search in Google Scholar

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, 2015.10.1371/journal.pbio.1002277460742726469762Search in Google Scholar

Ishigami S, Arigami T, Okumura H, Uchikado Y, Kita Y, Kurahara H, Maemura K, Kijima Y, Ishihara Y, Sasaki K, Uenosono Y, Natsugoe S. Human leukocyte antigen (HLA)-E and HLA-F expression in gastric cancer. Anticancer Res 35, 2279–2285, 2015.Search in Google Scholar

Ishitani A, Geraghty DE. Alternative splicing of HLA-G transcripts yields proteins with primary structures resembling both class I and class II antigens. Proc Natl Acad Sci USA 89, 3947–3951, 1992.10.1073/pnas.89.9.39475256081570318Search in Google Scholar

Kochan G, Escors D, Breckpot K, Guerrero-Setas D. Role of non-classical MHC class I molecules in cancer immunosuppression. Oncoimmunology 2, e26491, 2013.10.4161/onci.26491389424024482746Search in Google Scholar

Lee J, Ozcan U. Unfolded protein response signaling and metabolic diseases. J Biol Chem 289, 1203–1211, 2014.10.1074/jbc.R113.534743389430624324257Search in Google Scholar

Leite FA, Lira RC, Fedatto PF, Antonini SR, Martinelli CE Jr, de Castro M, Neder L, Ramalho LN, Tucci S Jr, Mastelaro MJ, Seidinger AL, Cardinalli IA, Yunes JA, Brandalise SR, Tone LG, Scrideli CA. Low expression of HLA-DRA, HLA-DPA1, and HLA-DPB1 is associated with poor prognosis in pediatric adrenocortical tumors (ACT). Pediatr Blood Cancer 61, 1940–1948, 2014.10.1002/pbc.2511825156210Search in Google Scholar

Li P, Noegel AA. Inner nuclear envelope protein SUN1 plays a prominent role in mammalian mRNA export. Nucleic Acids Res 43, 9874–9888, 2015.10.1093/nar/gkv1058478776426476453Search in Google Scholar

Mao Z, Zhang W. Role of mTOR in glucose and lipid metabolism. Int J Mol Sci 19, pii: E2043, 2018. 10.3390/ijms19072043607376630011848Open DOISearch in Google Scholar

Martinez-Canales S, Cifuentes F, Lopez De Rodas Gregorio M, Serrano-Oviedo L, Galan-Moya EM, Amir E, Pandiella A, Gyorffy B, Ocana A. Transcriptomic immunologic signature associated with favorable clinical outcome in basal-like breast tumors. PLoS One 12, e0175128, 2017.10.1371/journal.pone.0175128541748828472085Search in Google Scholar

Marzuillo P, Bellini G, Punzo F, Di Sessa A, Guarino S, Umano GR, Toraldo R, Miraglia Del Giudice E, Rossi F. Association between 14 bp insertion/deletion HLA-G functional polymorphism and insulin resistance in a cohort of Italian children with obesity. Pediatr Diabetes 19, 1357–1361, 2018.10.1111/pedi.1276830203576Open DOISearch in Google Scholar

Minchenko DO, Kharkova AP, Hubenia OV, Minchenko OH. Insulin receptor, IRS1, IRS2, INSIG1, INSIG2, RRAD, and BAIAP2 gene expressions in glioma U87 cells with ERN1 loss of function: effect of hypoxia and glutamine or glucose deprivation. Endocr Regul 47, 15–26, 2013.10.4149/endo_2013_01_1523363253Search in Google Scholar

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.10.4149/endo_2015_02_7325960008Search in Google Scholar

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 Regul 50, 43–54, 2016a.10.1515/enr-2016-000827560636Search in Google Scholar

Minchenko DO, Riabovol OO, Tsymbal DO, Ratushna OO, Minchenko OH. Inhibition of IRE1 affects the expression of genes encoded glucocorticoid receptor and some related factors and their hypoxic regulation in U87 glioma cells. Endocr Regul 50, 127–136, 2016b.10.1515/enr-2016-001427560795Search in Google Scholar

Mincenko DO, Riabovol OO, Ratushna OO, Minchenko OH. Hypoxic regulation of the expression of genes encoded estrogen related proteins in U87 glioma cells: effect of IRE1 inhibition. Endocr Regul 51, 8–19, 2017.10.1515/enr-2017-000228222026Search in Google Scholar

Minchenko OH, Opentanova IL, Minchenko DO, Ogura T, Esumi H. Hypoxia induces transcription of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 gene via hypoxia-inducible factor-1alpha activation. FEBS Lett 576, 14–20, 2004.10.1016/j.febslet.2004.08.05315474002Search in Google Scholar

Minchenko OH, Ochiai A, Opentanova IL, Ogura T, Minchenko DO, Caro J, Komisarenko SV, Esumi H. Overexpression of 6-phosphofructo-2-kinase/fructose-2,6bisphosphatase-4 in the human breast and colon malignant tumors. Biochimie 87, 1005–1010, 2005.10.1016/j.biochi.2005.04.00715925437Search in Google Scholar

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.10.1515/ersc-2015-0002Search in Google Scholar

Minchenko OH, Tsymbal DO Minchenko DO, Hnatiuk OS, Prylutskyy YI, Prylutska SV, Ritter U. Suppression of the expression of genes associated with immune response in normal human astrocytes upon treatment by single-walled carbon nanotubes. Toxicol In Vitro 52, 122–130, 2018.10.1016/j.tiv.2018.06.01129906516Open DOISearch in Google Scholar

Morandi F, Cangemi G, Barco S, Amoroso L, Giuliano M, Gigliotti AR, Pistoia V, Corrias MV. Plasma levels of soluble HLA-E and HLA-F at diagnosis may predict overall survival of neuroblastoma patients. Biomed Res Int 2013, 956878, 2013.10.1155/2013/956878385621824350297Search in Google Scholar

Murdaca G, Calamaro P, Lantieri F, Pigozzi S, Mastracci L, Grillo F, Magnani O, Ceppa P, Puppo F, Fiocca R. HLAG expression in gastric carcinoma: clinicopathological correlations and prognostic impact. Virchows Arch 473, 425–433, 2018.10.1007/s00428-018-2379-029845360Search in Google Scholar

Nair S, Lee YH, Rousseau E, Cam M, Tataranni PA, Baier LJ, Bogardus C, Permana PA. Increased expression of inflammation-related genes in cultured preadipocytes/stromal vascular cells from obese compared with nonobese Pima Indians. Diabetologia 48, 1784–1788, 2005.10.1007/s00125-005-1868-2140982116034612Open DOISearch in Google Scholar

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, 2004.10.1126/science.110316015486293Search in Google Scholar

Pisapia L, Cicatiello V, Barba P, Malanga D, Maffei A, Hamilton RS, Del Pozzo G. Co-regulated expression of alpha and beta mRNAs encoding HLA-DR surface heterodimers is mediated by the MHCII RNA operon. Nucleic Acids Res 41, 3772–3786, 2013.10.1093/nar/gkt059361670023393186Open DOISearch in Google Scholar

Richardson SJ, Rodriguez-Calvo T, Gerling IC, Mathews CE, Kaddis JS, Russell MA, Zeissler M, Leete P, Krogvold L, Dahl-Jorgensen K, von Herrath M, Pugliese A, Atkinson MA, Morgan NG. Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia 59, 2448–2458, 2016.10.1007/s00125-016-4067-4504287427506584Search in Google Scholar

Rouas-Freiss N, Moreau P, LeMaoult J, Carosella ED. The dual role of HLA-G in cancer. J Immunol Res 2014, 359748, 2014.10.1155/2014/359748399510024800261Search in Google Scholar

Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest 123, 2764–2772, 2013.10.1172/JCI67227369653923863634Search in Google Scholar

Schaiff WT, Hruska KA Jr, McCourt DW, Green M, Schwartz BD. HLA-DR associates with specific stress proteins and is retained in the endoplasmic reticulum in invariant chain negative cells. J Exp Med 176, 657–666, 1992.10.1084/jem.176.3.65721193451512535Search in Google Scholar

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, 2011.10.1371/journal.pone.0025231317862921966465Search in Google Scholar

Song Z, Krishna S, Thanos D, Strominger JL, Ono SJ. A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocompatibility complex class II genes via a repeated Cys-His domain and functions as a transcriptional repressor. J Exp Med 180, 1763–1774, 1994.10.1084/jem.180.5.176321917547964459Search in Google Scholar

Sun Z, Jha HC, Pei YG, Robertson ES. Major histocompatibility complex class II HLA-DRα is downregulated by Kaposi’s sarcoma-associated herpesvirus-encoded lytic transactivator RTA and MARCH8. J Virol 90, 8047–8058, 2016.10.1128/JVI.01079-16500810027356905Search in Google Scholar

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, 2017.10.1016/j.molmet.2017.06.010564162829031713Search in Google Scholar

Tsuchihara K, Ogura T, Fujioka R, Fujii S, Kuga W, Saito M, Ochiya T, Ochiai A, Esumi H. Susceptibility of Snarkdeficient mice to azoxymethaneinduced colorectal tumorigenesis and the formation of aberrant crypt foci. Cancer Sci 99, 677–682, 2008.10.1111/j.1349-7006.2008.00734.x18307533Search in Google Scholar

Walentowicz-Sadlecka M, Dziobek K, Grabiec M, Sadlecki P, Walentowicz P, Mak P, Szymankiewicz M, Kwinta P, Dutsch-Wicherek M. The analysis of human leukocyte antigen-G level in patients with endometrial cancer by Western blot technique. Am J Reprod Immunol 10, e13070, 2018.10.1111/aji.1307030414280Search in Google Scholar

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 43, 2405–2419, 2017.10.1159/0004843942907363029073630Open DOISearch in Google Scholar

Wang L, Wei B, Hu G, Wang L, Bi M, Sun Z, Jin Y. Screening of differentially expressed genes associated with human glioblastoma and functional analysis using a DNA microarray. Mol Med Rep 12, 1991–1996, 2015.2590175410.3892/mmr.2015.365925901754Search in Google Scholar

Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529, 326–335, 2016.10.1038/nature1704126791723Search in Google Scholar

Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol 197, 857–867, 2012.10.1083/jcb.201110131338441222733998Search in Google Scholar

Winkler MS, Rissiek A, Priefler M, Schwedhelm E, Robbe L, Bauer A, Zahrte C, Zoellner C, Kluge S, Nierhaus A. Human leucocyte antigen (HLA-DR) gene expression is reduced in sepsis and correlates with impaired TNFα response: A diagnostic tool for immunosuppression? PLoS One 12, e0182427, 2017.2877157310.1371/journal.pone.0182427554266028771573Search in Google Scholar

Wu B, Yang H, Ying S, Lu H, Wang W, Lv J, Xiong H, Hu W. High HLA-F expression is a poor prognosis factor in patients with nasopharyngeal carcinoma. Anal Cell Pathol (Amst) 2018, 7691704, 2018.10.1155/2018/7691704623280430510890Search in Google Scholar

Wu C, Xu G, Tsai SA, Freed WJ, Lee CT. Transcriptional profiles of type 2 diabetes in human skeletal muscle reveal insulin resistance, metabolic defects, apoptosis, and molecular signatures of immune activation in response to infections. Biochem Biophys Res Commun 482, 282–288, 2017.10.1016/j.bbrc.2016.11.05527847319Search in Google Scholar

Xu Y, Han H, Zhang F, Lv S, Li Z, Fang Z. Lesion human leukocyte antigen-F expression is associated with a poor prognosis in patients with hepatocellular carcinoma. Oncol Lett 9, 300–304, 2013.10.3892/ol.2014.2686424668925435979Search in Google Scholar

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 7, e47377, 2012.2309161910.1371/journal.pone.0047377347299623091619Search in Google Scholar

Yamashita S, Fujii K, Zhao C, Takagi H, Katakura Y. Involvement of the NFX1-repressor complex in PKC-deltainduced repression of hTERT transcription. J Biochem 160, 309–313, 2016.10.1093/jb/mvw038589212927311997Search in Google Scholar

Yang YC, Chang TY, Chen TC, Lin WS, Chang SC, Lee YJ. Human leucocyte antigen-G polymorphisms are associated with cervical squamous cell carcinoma risk in Taiwanese women. Eur J Cancer 50, 469–474, 2014.10.1016/j.ejca.2013.10.0182426258624262586Open DOISearch in Google Scholar

Yang Z, Li H, Wang Z, Yang Y, Niu J, Liu Y, Sun Z, Yin C. Microarray expression profile of long non-coding RNAs in human lung adenocarcinoma. Thorac Cancer 9, 1312–1322, 2018.10.1111/1759-7714.12845616606930151992Search in Google Scholar

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 dietinduced insulin resistance mice. PLoS One 8, e54059, 2013.10.1371/journal.pone.0054059354697323342074Search in Google Scholar

Zhang X, Lin A, Zhang JG, Bao WG, Xu DP, Ruan YY, Yan WH. Alteration of HLA-F and HLA I antigen expression in the tumor is associated with survival in patients with esophageal squamous cell carcinoma. Int J Cancer, 132, 82–89, 2013.10.1002/ijc.2762122544725Search in Google Scholar

Zeestraten EC, Reimers MS, Saadatmand S, Dekker JW, Liefers GJ, van den Elsen PJ, van de Velde CJ, Kuppen PJ. Combined analysis of HLA class I, HLA-E and HLA-G predicts prognosis in colon cancer patients. Br J Cancer 110, 459–468, 2014.10.1038/bjc.2013.696389975324196788Search in Google Scholar

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