The Expression of TIMP1, TIMP2, VCAN, SPARC, CLEC3B and E2F1 in Subcutaneous Adipose Tissue of Obese Males and Glucose Intolerance


We investigated the expression of TIMP1, TIMP2, SPARC, VCAN, and CLEC3B genes, encoded matricellular proteins with pleiotropic functions, and glucose intolerance in obese male subjects with normal and impaired glucose tolerance. The purpose of this study was to examine the association between the gene expressions and glucose intolerance in obesity. The results indicate that obesity leads to significant increase of TIMP1, TIMP2, E2F1 and CLEC3B gene expressions in subcutaneous adipose tissue, especially TIMP2 gene. However, more significant increase of the expression of TIMP1 and TIMP2 was found in adipose tissue of obese patients with glucose intolerance. No significant changes were found in the expression of VCAN and SPARC genes in adipose tissue of obese subjects with normal glucose tolerance but increased in the group of obese subjects with glucose intolerance. At the same time, the E2F1 and CLEC3B gene expressions were decreased in adipose tissue of obese patients with glucose intolerance. Results of this study provide evidence that changes in the expression of genes encoded TIMP1, TIMP2, VCAN, SPARC, E2F1 and CLEC3B in subcutaneous adipose tissue of obese individuals associate with glucose intolerance.

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D. Minchenko, O. Ratushna, Y. Bashta, R. Herasymenko and O. Minchenko, "The Expression of TIMP1, TIMP2, VCAN, SPARC, CLEC3B and E2F1 in Subcutaneous Adipose Tissue of Obese Males and Glucose Intolerance," CellBio, Vol. 2 No. 2, 2013, pp. 45-53. doi: 10.4236/cellbio.2013.22006.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] M. S. Bray and M. E. Young, “Circadian Rhythms in the Development of Obesity: Potential Role for the Circadian Clock within the Adipocyte,” Obesity Reviews, Vol. 8, No. 2, 2007, pp. 169-181.
[2] M. S. Bray and M. E. Young, “The Role of Cell-Specific Circadian Clocks in Metabolism and Disease,” Obesity Reviews, Vol. 10, No. 2, 2009, pp. 6-13. doi:10.1111/j.1467-789X.2009.00684.x
[3] J. Kovac, J. Husse and H. Oster, “A Time to Fast, a Time to Feast: The Crosstalk between Metabolism and the Circadian Clock,” Molecules and Cells, Vol. 282, No. 2, 2009, pp. 75-80. doi:10.1007/s10059-009-0113-0
[4] E. M. Scott, A. M. Carter and P. J. Grant, “Association between Polymorphisms in the Clock Gene, Obesity and the Metabolic Syndrome in Man Clock Polymorphisms and Obesity,” International Journal of Obesity, Vol. 32, 2008, pp. 658-662. doi:10.1038/sj.ijo.0803778
[5] C. B. Green, J. S. Takahashi and J. Bass, “The Meter of Metabolism,” Cell, Vol. 134, No. 5, 2008, pp. 728-742. doi:10.1016/j.cell.2008.08.022
[6] K. M. Ramsey, B. Marcheva, A. Kohsaka and J. Bass, “The Clock Work of Metabolism,” Annual Review of Nutrition, Vol. 27, 2007, pp. 219-240. doi:10.1146/annurev.nutr.27.061406.093546
[7] M. S. Bray and M. E. Young, “Regulation of Fatty Acid Metabolism by Cell Autonomous Circadian Clocks: Time to Fatten Up on Information?” The Journal of Biological Chemistry, Vol. 286, 2011, pp. 11883-11889. doi:10.1074/jbc.R110.214643
[8] H. Ando, T. Takamura, N. Matsuzawa-Nagata, K. R. Shima, T. Eto, H. Misu, M. Shiramoto, T. Tsuru, S. Irie, A. Fujimura and S. Kaneko, “Clock Gene Expression in Peripheral Leucocytes of Patients with Type 2 Diabetes,” Diabetologia, Vol. 52, No. 2, 2009, pp. 329-335. doi:10.1007/s00125-008-1194-6
[9] H. Ando, M. Kumazaki, Y. Motosugi, K. Ushijima, T. Maekawa, E. Ishikawa and A. Fujimura, “Impairment of Peripheral Circadian Clocks Precedes Metabolic Abnormalities in ob/ob mice,” Endocrinology, Vol. 152, No. 4, 2011, pp. 1347-1354. doi:10.1210/en.2010-1068
[10] W. Huang, K. M. Ramsey, B. Marcheva and J. Bass, “Circadian Rhythms, Sleep, and Metabolism,” Journal of Clinical Investigation, Vol. 121, No. 6, 2011, pp. 2133-2141. doi:10.1172/JCI46043
[11] S. Shimba, T. Ogawa, S. Hitosugi, Y. Ichihashi, Y. Nakadaira, M. Kobayashi, M. Tezuka, Y. Kosuge, K. Ishige, Y. Ito, K. Komiyama, Y. Okamatsu-Ogura, K. Kimura and M. Saito, “Deficient of a Clock Gene, Brain and Muscle Arnt-Like Protein-1 (BMAL1), Induces Dyslipidemia and Ectopic Fat Formation,” PLoS One, Vol. 6, 2011, e25231. doi:10.1371/journal.pone.0025231
[12] G. Hashimoto, I. Inoki, FujiiY, T. Aoki, E. Ikeda and Y. Okada, “Matrix Metalloproteinases Cleave Connective Tissue Growth Factor and Reactivate Angiogenic Activity of Vascular Endothelial Growth Factor 165,” The Journal of Biological Chemistry, Vol. 277, 2002, pp. 36288-36295. doi:10.1074/jbc.M201674200
[13] I. Inoki, T. Shiomi, G. Hashimoto, H. Enomoto, H. Nakamura, K. Makino, E. Ikeda, S. Takata, K. Kobayashi and Y. Okada, “Connective Tissue Growth Factor Binds Vascular Endothelial Growth Factor (VEGF) and Inhibits VEGF-Induced Angiogenesis,” FASEB Journal, Vol. 16, 2002, pp. 219-221. doi:10.1096/fj.01-0332fje
[14] W. G. Stetler-Stevenson, “Tissue Inhibitors of Metalloproteinases in Cell Signaling: Metalloproteinase-Independent Biological Activities,” Science Signal, Vol. 1, No. 27, 2008. doi:10.1126/scisignal.127re6
[15] B. Meissburger, L. Stachorski, E. Roder, G. Rudofsky and C. Wolfrum, “Tissue Inhibitor of Matrix Metalloproteinase 1 (TIMP1) Controls Adipogenesis in Obesity in Mice and in Humans,” Diabetologia, Vol. 54, No. 6, 2011, pp. 1468-1479. doi:10.1007/s00125-011-2093-9
[16] W. W. Du, B. B. Yang, B. L. Yang, Z. Deng, L. Fang, S. W. Shan, Z. Jeyapalan, Y. Zhang, A. Seth and A. J. Yee, “Versican G3 Domain Modulates Breast Cancer Cell Apoptosis: A Mechanism for Breast Cancer Cell Response to Chemotherapy and EGFR Therapy,” PLoS One, Vol. 6, 2011, Article ID:E26396. doi:10.1371/journal.pone.0026396
[17] K. Kos and J. P. Wilding, “SPARC: A Key Player in the Pathologies Associated with Obesity and Diabetes,” Nature Reviews Endocrinology, Vol. 6, 2010, pp. 225-235. doi:10.1038/nrendo.2010.18
[18] V. Tchaikovski, S. Olieslagers, F. D. Böhmer and J. Waltenberger, “Diabetes Mellitus Activates Signal Transduction Pathways Resulting in Vascular Endothelial Growth Factor Resistance of Human Monocytes,” Circulation, Vol. 120, 2009, pp. 150-159. doi:10.1161/CIRCULATIONAHA.108.817528
[19] J. Waltenberger, “VEGF Resistance as a Molecular Basis to Explain the Angiogenesis Paradox in Diabetes Mellitus,” Biochemical Society Transactions, Vol. 37, 2009, pp. 1167-1170. doi:10.1042/BST0371167
[20] D. W. Seo, H. Li, L. Guedez, P. T. Wingfield, T. Diaz, R. Salloum, B. Y. Wei and W. G. Stetler-Stevenson, “TIMP-2 Mediated Inhibition of Angiogenesis: An MMP-Independent Mechanism,” Cell, Vol. 114, No. 2, 200, pp. 171-180. doi:10.1016/S0092-8674(03)00551-8
[21] M. Dews, A. Homayouni, D. Yu, D. Murphy, C. Sevignani, E. Wentzel, E. E. Furth, W. M. Lee, G. H. Enders, J. T. Mendell and A. Thomas-Tikhonenko, “Augmentation of Tumor Angiogenesis by a Myc-Activated MicroRNA Cluster,” Nature Genetics, Vol. 38, 2006, pp. 1060-1065. doi:10.1038/ng1855
[22] D. Wu, L. Li, M Yang, H. Liu and G. Yang, “Elevated Plasma Levels of SPARC in Patients with Newly Diagnosed Type 2 Diabetes Mellitus,” European Journal of Endocrinology, Vol. 165, 2011, pp. 597-601. doi:10.1530/EJE-11-0131
[23] K. Kos, S. Wong, B. Tan, A. Gummesson, M. Jernas, N. Franck, D. Kerrigan, F. H. Nystrom, L. M. Carlsson, H. S. Randeva, J. H. Pinkney and J. P. Wilding, “Regulation of the Fibrosis and Angiogenesis Promoter SPARC/Osteonectin in Human Adipose Tissue by Weight Change, Leptin, Insulin, and Glucose,” Diabetes, Vol. 58, No. 8, 2009, pp. 1780-1788. doi:10.2337/db09-0211
[24] P. S. Zheng, J. Wen, L. C. Ang, W. Sheng, A. Viloria-Petit, Y. Wang, Y. Wu, R. S. Kerbel and B. B. Yang, “Versican/PG-M G3 Domain Promotes Tumor Growth and Angiogenesis,” FASEB Journal, Vol. 18, 2004, pp. 754-756,. doi:10.1096/fj.03-0545fje
[25] M. Rahmani, B. W. Wong, L. Ang, C. C. Cheung, J. M. Carthy, H. Walinski and B. M. McManus, “Versican: Signaling to Transcriptional Control Pathways,” Canadian Journal of Physiology and Pharmacology, Vol. 84, 2006, pp. 77-92. doi:10.1139/y05-154
[26] C. G. Rivera, J. S. Bader and A. S. Popel, “Angiogenesis-Associated Crosstalk between Collagens, CXC Chemokines, and Thrombospondin Domain-Containing Proteins,” Annals of Biomedical Engineering, Vol. 39, No. 8, 2011, pp. 2213-2222. doi:10.1007/s10439-011-0325-2
[27] J. S. Annicotte, E. Blanchet, C. Chavey, I. Iankova, S. Costes, S. Assou, J. Teyssier, S. Dalle, C. Sardet and L. Fajas, “The CDK4-pRB-E2F1 Pathway Controls Insulin Secretion,” NatCellBiol, Vol. 11, 2009, pp. 1017-1023. doi:10.1038/ncb1915
[28] A. Lombardi, L. Ulianich, A. S. Treglia, C. Nigro, L. Parrillo, D. D. Lofrumento, G. Nicolardi, C. Garbi, F. Beguinot, C. Miele and B. Di Jeso, “Increased Hexosamine Biosynthetic Pathway Flux Dedifferentiates INS-1E Cells and Murine Islets by an Extracellular Signal-Regulated Kinase (ERK)1/2-Mediated Signal Transmission Pathway,” Diabetologia, Vol. 55, No. 1, 2012, pp. 141-153. doi:10.1007/s00125-011-2315-1
[29] U. Ozcan, Q. Cao, E. Yilmaz, A. H. Lee, N. N. Iwakoshi, E. Ozdelen, G. Tuncman, C. Gorgun, L. H. Glimcher and G. S. Hotamisligil, “Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes,” Science, Vol. 306, No. 5695, 2004, pp. 457-461. doi:10.1126/science.1103160
[30] B. Meissburger, J. Ukropec, E. Roeder, N. Beaton, M. Geiger, D. Teupser, B. Civan, W. Langhans, P. P. Nawroth, D. Gasperikova, G. Rudofsky and C. Wolfrum, “Adipogenesis and Insulin Sensitivity in Obesity Are Regulated by Retinoid-Related Orphan Receptor Gamma,” EMBO Molecular Medicine, Vol. 3, 2011, pp. 637-651. doi:10.1002/emmm.201100172
[31] S. W. Park, Y. Zhou, J. Lee, J. Lee and U. Ozcan, “Sarco(endo)plasmic Reticulum Ca2+-ATPase 2b Is a Major Regulator of Endoplasmic Reticulum Stress and Glucose Homeostasis in Obesity,” Proceedings of the National Academy of Sciences of USA, Vol. 107, 2010, pp. 19320-19325. doi:10.1073/pnas.1012044107
[32] Y. Zhou, J. Lee, C. M. Reno, C. Sun, S. W. Park, J. Chung, J. Lee, S. J. Fisher, M. F. White and S. B. Biddinger, U. Ozcan, “Regulation of Glucose Homeostasis through a XBP-1-FoxO1 Interaction,” Nature Medicine, Vol. 17, 2011, pp. 356-365. doi:10.1038/nm.2293
[33] G. P. Nagaraju and D. Sharma, “Anti-Cancer Role of SPARC, an Inhibitor of Adipogenesis,” Cancer Treatment Reviews, Vol. 37, No. 7, 2011, pp. 559-566. doi:10.1016/j.ctrv.2010.12.001
[34] A. D. Bradshaw, “Diverse Biological Functions of the SPARC Family of Proteins,” The International Journal of Biochemistry & Cell Biology, Vol. 44, No. 3, 2012, pp. 480-488. doi:10.1016/j.biocel.2011.12.021
[35] M. Rahmani, J. M. Carthy and B M. McManus, “Mapping of the Wnt/β-Catenin/TCF Response Elements in the Human Versican Promoter,” Methods in Molecular Biology, Vol. 836, 2012, pp. 35-52. doi:10.1007/978-1-61779-498-8_3
[36] E. Blanchet, J. S. Annicotte, S. Lagarrigue, V. Aguilar, C. Clapé, C. Chavey, V. Fritz, F. Casas, F. Apparailly, J. Auwerx and L. Fajas, “E2F Transcription Factor-1 Regulates Oxidative Metabolism,” Nature Cell Biology, Vol. 13, 2011, pp. 1146-1152. doi:10.1038/ncb2309
[37] R. J. Shaw, “LKB1 and AMP-Activated Protein Kinase Control of mTOR Signalling and Growth,” Acta Physiologica, Vol. 196, 2009, pp. 65-80. doi:10.1111/j.1748-1716.2009.01972.x
[38] K. Tsuchihara, T. Ogura, R. Fujioka, S. Fujii, W. Kuga, M. Saito, T. Ochiya, A. Ochiai and H. Esumi, “Susceptibility of Snark-Deficient Mice to Azoxymethane Induced Colorectal Tumorigenesis and the Formation of Aberrant Crypt Foci,” Cancer Science, Vol. 99, No. 4, 2008, pp. 677-682. doi:10.1111/j.1349-7006.2008.00734.x
[39] A. S. John, X. Hu, V. L. Rothman and G. P. Tuszynski, “Thrombospondin-1 (TSP-1) Up-Regulates Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Production in Human Tumor Cells: Exploring the Functional Significance in Tumor Cell Invasion,” Experimental and Molecular Pathology, Vol. 87, No. 3, 2009, pp. 184-188. doi:10.1016/j.yexmp.2009.09.002
[40] D. Hose, J. Moreaux, T. Meissner, A. Seckinger, H. Goldschmidt, A. Benner, K. Mahtouk, J. Hillengass, T. Rème, J. De Vos, M. Hundemer, M. Condomines, U. Bertsch, J. F. Rossi, A. Jauch, B. Klein and T. Möhler, “Induction of Angiogenesis by Normal and Malignant Plasma Cells,” Blood, Vol. 114, No. 1, 2009, pp. 128-143. doi:10.1182/blood-2008-10-184226

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