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Weight reduction modulates expression of genes involved in extracellular matrix and cell death: the GENOBIN study

International Journal of Obesity volume 32, pages 292–303 (2008)Cite this article

Abstract

Objective:

Lifestyle and genetic factors interact in the development of obesity and the metabolic syndrome. The molecular mechanisms underlying the beneficial dietary modifications are, however, unclear. We aimed to examine the effect of the long-term moderate weight reduction on gene expression in adipose tissue (AT) and to identify genes and gene clusters responsive to treatment and thereby likely contributing to the development of the metabolic syndrome.

Design:

Randomized controlled and individualized weight reduction intervention.

Subjects:

Forty-six subjects with impaired fasting glycemia or impaired glucose tolerance and features of metabolic syndrome, aged 60±7 years were randomized either to a weight reduction (WR) (n=28) or a control (n=18) group lasting for 33 weeks.

Measurements:

Oral and intravenous glucose tolerance tests and subcutaneous AT biopsies were performed before and after the intervention. Gene expression of AT was studied using microarray technology in subgroups of WR (with weight reduction ⩾5%, n=9) and control group (n=10). The results were confirmed using quantitative PCR.

Results:

In the WR group, glucose metabolism improved. Moreover, an inverse correlation between the change in SI and the change in body weight was found (r=−0.44, P=0.026). Downregulation of gene expression (P<0.01) involving gene ontology groups of extracellular matrix and cell death was seen. Such changes did not occur in the control group. The tenomodulin-gene was one of the most downregulated genes (−39±16%, P<0.0001). Moreover, its expression correlated with insulin sensitivity (r=−0.34, P=0.005) before the intervention and with body adiposity both before (r=0.42, P=0.007) and after (r=0.30, P=0.056) the intervention.

Conclusion:

Genes regulating the extracellular matrix and cell death showed a strong downregulation after long-term weight reduction. This likely reflects a new stable state at the molecular level in AT. Further studies are warranted to elucidate the mechanisms of these genetic factors.

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References

  1. Uusitupa M . Gene-diet interaction in relation to the prevention of obesity and type 2 diabetes: evidence from the Finnish Diabetes Prevention Study. Nutr Metab Cardiovasc Dis 2005; 15: 225–233.

    Article  PubMed  Google Scholar 

  2. Eckel RH, Grundy SM, Zimmet PZ . The metabolic syndrome. Lancet 2005; 365: 1415–1428.

    Article  CAS  PubMed  Google Scholar 

  3. Moller DE, Kaufman KD . Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med 2005; 56: 45–62.

    Article  CAS  PubMed  Google Scholar 

  4. Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, Salonen JT, Lakka TA . Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemiol 2002; 156: 1070–1077.

    Article  PubMed  Google Scholar 

  5. Laaksonen DE, Niskanen L, Lakka HM, Lakka TA, Uusitupa M . Epidemiology and treatment of the metabolic syndrome. Ann Med 2004; 36: 332–346.

    Article  CAS  PubMed  Google Scholar 

  6. Uusitupa M, Lindi V, Louheranta A, Salopuro T, Lindström J, Tuomilehto J, Finnish Diabetes Prevention Study Group. Long-term improvement in insulin sensitivity by changing lifestyles of people with impaired glucose tolerance: 4-year results from the Finnish Diabetes Prevention Study. Diabetes 2003; 52: 2532–2538.

    Article  CAS  PubMed  Google Scholar 

  7. Kahn SE . The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. Diabetologia 2003; 46: 3–19.

    Article  CAS  PubMed  Google Scholar 

  8. Osei K, Rhinesmith S, Gaillard T, Schuster D . Impaired insulin sensitivity, insulin secretion, and glucose effectiveness predict future development of impaired glucose tolerance and type 2 diabetes in pre-diabetic African Americans: implications for primary diabetes prevention. Diabetes Care 2004; 27: 1439–1446.

    Article  CAS  PubMed  Google Scholar 

  9. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343–1350.

    Article  CAS  PubMed  Google Scholar 

  10. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393–403.

    Article  CAS  PubMed  Google Scholar 

  11. Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20: 537–544.

    Article  CAS  PubMed  Google Scholar 

  12. Kloting N, Berndt J, Kralisch S, Kovacs P, Fasshauer M, Schon MR et al. Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes. Biochem Biophys Res Commun 2006; 339: 430–436.

    Article  PubMed  Google Scholar 

  13. Marrades MP, Milagro FI, Martinez JA, Moreno-Aliaga MJ . Differential expression of aquaporin 7 in adipose tissue of lean and obese high fat consumers. Biochem Biophys Res Commun 2006; 339: 785–789.

    Article  CAS  PubMed  Google Scholar 

  14. Nordström EA, Ryden M, Backlund EC, Dahlman I, Kaaman M, Blomqvist L et al. A human-specific role of cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector A (CIDEA) in adipocyte lipolysis and obesity. Diabetes 2005; 54: 1726–1734.

    Article  PubMed  Google Scholar 

  15. Large V, Arner P . Regulation of lipolysis in humans. Pathophysiological modulation in obesity, diabetes, and hyperlipidaemia. Diabetes Metab 1998; 24: 409–418.

    CAS  PubMed  Google Scholar 

  16. Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 2006; 17: 4–12.

    CAS  PubMed  Google Scholar 

  17. Trayhurn P, Bing C, Wood IS . Adipose tissue and adipokines—energy regulation from the human perspective. J Nutr 2006; 136: 1935S–1939S.

    Article  CAS  PubMed  Google Scholar 

  18. Matsuzawa Y . The metabolic syndrome and adipocytokines. FEBS Lett 2006; 580: 2917–2921.

    Article  CAS  PubMed  Google Scholar 

  19. Viguerie N, Vidal H, Arner P, Holst C, Verdich C, Avizou S et al. Adipose tissue gene expression in obese subjects during low-fat and high-fat hypocaloric diets. Diabetologia 2005; 48: 123–131.

    Article  CAS  PubMed  Google Scholar 

  20. Arvidsson E, Viguerie N, Andersson I, Verdich C, Langin D, Arner P . Effects of different hypocaloric diets on protein secretion from adipose tissue of obese women. Diabetes 2004; 53: 1966–1971.

    Article  CAS  PubMed  Google Scholar 

  21. Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C et al. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 2005; 54: 2277–2286.

    Article  CAS  PubMed  Google Scholar 

  22. Rasmussen M, Belza A, Almdal T, Toubro S, Bratholm P, Astrup A et al. Change in beta1-adrenergic receptor protein concentration in adipose tissue correlates with diet-induced weight loss. Clin Sci (London) 2005; 108: 323–329.

    Article  CAS  Google Scholar 

  23. Kolehmainen M, Vidal H, Alhava E, Uusitupa MI . Sterol regulatory element binding protein 1c (SREBP-1c) expression in human obesity. Obes Res 2001; 9: 706–712.

    Article  CAS  PubMed  Google Scholar 

  24. Gomez-Ambrosi J, Catalan V, Diez-Caballero A, Martinez-Cruz LA, Gil MJ, Garcia-Foncillas J et al. Gene expression profile of omental adipose tissue in human obesity. FASEB J 2004; 18: 215–217.

    Article  CAS  PubMed  Google Scholar 

  25. Lee YH, Nair S, Rousseau E, Allison DB, Page GP, Tataranni PA et al. Microarray profiling of isolated abdominal subcutaneous adipocytes from obese vs non-obese Pima Indians: increased expression of inflammation-related genes. Diabetologia 2005; 48: 1776–1783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dahlman I, Linder K, Arvidsson Nordstrom E, Andersson I, Liden J, Verdich C et al. Changes in adipose tissue gene expression with energy-restricted diets in obese women. Am J Clin Nutr 2005; 81: 1275–1285.

    Article  CAS  PubMed  Google Scholar 

  27. Clement K, Viguerie N, Poitou C, Carette C, Pelloux V, Curat CA et al. Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J 2004; 18: 1657–1669.

    Article  CAS  PubMed  Google Scholar 

  28. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult treatment panel III). JAMA 2001; 285: 2486–2497.

    Article  Google Scholar 

  29. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Curr Opin Cardiol 2006; 21: 1–6.

    Article  PubMed  Google Scholar 

  30. Sarkkinen E, Schwab U, Niskanen L, Hannuksela M, Savolainen M, Kervinen K et al. The effects of monounsaturated-fat enriched diet and polyunsaturated-fat enriched diet on lipid and glucose metabolism in subjects with impaired glucose tolerance. Eur J Clin Nutr 1996; 50: 592–598.

    CAS  PubMed  Google Scholar 

  31. Boston RC, Stefanovski D, Moate PJ, Sumner AE, Watanabe RM, Bergman RN . MINMOD Millennium: a computer program to calculate glucose effectiveness and insulin sensitivity from the frequently sampled intravenous glucose tolerance test. Diabetes Technol Ther 2003; 5: 1003–1015.

    Article  CAS  PubMed  Google Scholar 

  32. Ohisalo JJ, Kaartinen JM, Ranta S, Mustajoki P, Hreniuk SP, LaNoue KF et al. Weight loss normalizes the inhibitory effect of N6-(phenylisopropyl)adenosine on lipolysis in fat cells of massively obese human subjects. Clin Sci (London) 1992; 83: 589–592.

    Article  CAS  Google Scholar 

  33. Rodbell M . Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J Biol Chem 1964; 239: 375–380.

    CAS  PubMed  Google Scholar 

  34. Li C, Hung Wong W . Model-based analysis of oligonucleotide arrays: model validation, design issues and standard error application. Genome Biol 2001; 2: research0032.1–research0032.11, Published online 3 August 2001.

    Google Scholar 

  35. Li C, Hung Wong W . Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci 2001; 98: 31–36.

    Article  CAS  PubMed  Google Scholar 

  36. Kaput J, Rodriguez RL . Nutritional genomics: the next frontier in the postgenomic era. Physiol Genomics 2004; 16: 166–177.

    Article  CAS  PubMed  Google Scholar 

  37. Higami Y, Barger JL, Page GP, Allison DB, Smith SR, Prolla TA et al. Energy restriction lowers the expression of genes linked to inflammation, the cytoskeleton, the extracellular matrix, and angiogenesis in mouse adipose tissue. J Nutr 2006; 136: 343–352.

    Article  CAS  PubMed  Google Scholar 

  38. Martin A, Komada MR, Sane DC . Abnormal angiogenesis in diabetes mellitus. Med Res Rev 2003; 23: 117–145.

    Article  CAS  PubMed  Google Scholar 

  39. Hayden MR, Sowers JR, Tyagi SC . The central role of vascular extracellular matrix and basement membrane remodeling in metabolic syndrome and type 2 diabetes: the matrix preloaded. Cardiovasc Diabetol 2005; 4: 9–29.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Vaziri ND, Xu ZG, Shahkarami A, Huang KT, Rodriguez-Iturbe B, Natarajan R . Role of AT-1 receptor in regulation of vascular MCP-1, IL-6, PAI-1, MAP kinase, and matrix expressions in obesity. Kidney Int 2005; 68: 2787–2793.

    Article  CAS  PubMed  Google Scholar 

  41. Chavey C, Mari B, Monthouel MN, Bonnafous S, Anglard P, Van Obberghen E et al. Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation. J Biol Chem 2003; 278: 11888–11896.

    Article  CAS  PubMed  Google Scholar 

  42. Guan H, Arany E, van Beek JP, Chamson-Reig A, Thyssen S, Hill DJ et al. Adipose tissue gene expression profiling reveals distinct molecular pathways that define visceral adiposity in offspring of maternal protein-restricted rats. Am J Physiol Endocrinol Metab 2005; 288: E663–E673.

    Article  CAS  PubMed  Google Scholar 

  43. Wang P, Keijer J, Bunschoten A, Bouwman F, Renes J, Mariman E . Insulin modulates the secretion of proteins from mature 3T3-L1 adipocytes: a role for transcriptional regulation of processing. Diabetologia 2006; 49: 2453–2462.

    Article  CAS  PubMed  Google Scholar 

  44. Prins JB, O'Rahilly S . Regulation of adipose cell number in man. Clin Sci 1997; 92: 3–11.

    Article  CAS  Google Scholar 

  45. Prins JB, Walker NI, Winterford CM, Cameron DP . Human adipocyte apoptosis occurs in malignancy. Biochem and Biophys Res Commun 1994; 205: 625–630.

    Article  CAS  Google Scholar 

  46. Ishiko O, Sumi T, Yoshida H, Hyun Y, Ogita S . Comparison of expression of apoptosis regulatory proteins in the adipose tissue of tumor-bearing and diet-restricted rabbits. Internatl JMol Med 2001; 8: 543–547.

    CAS  Google Scholar 

  47. Yang MU, Presta E, Bjorntorp P . Refeeding after fasting in rats: effects of duration of starvation and refeeding on food efficiency in diet-induced obesity. Am J Clin Nutr 1990; 51: 970–978.

    Article  CAS  PubMed  Google Scholar 

  48. Prins JB, Niesler CU, Winterford CM, Bright NM, Siddle K, O'Rahilly S et al. Tumor necrosis factor-α induces apoptosis of human adipose cells. Diabetes 1997; 46: 1939–1944.

    Article  CAS  PubMed  Google Scholar 

  49. Ulloa L, Messmer D . High-mobility group box 1 (HMGB1) protein: friend and foe. Cytokine Growth Factor Rev 2006; 17: 189–201.

    Article  CAS  PubMed  Google Scholar 

  50. Shukunami C, Oshima Y, Hiraki Y . Molecular cloning of tenomodulin, a novel chondromodulin-I related gene. Biochem Biophys Res Commun 2001; 280: 1323–1327.

    Article  CAS  PubMed  Google Scholar 

  51. Oshima Y, Shukunami C, Honda J, Nishida K, Tashiro F, Miyazaki J et al. Expression and localization of tenomodulin, a transmembrane type chondromodulin-I-related angiogenesis inhibitor, in mouse eyes. Invest Ophthalmol Vis Sci 2003; 44: 1814–1823.

    Article  PubMed  Google Scholar 

  52. Oshima Y, Sato K, Tashiro F, Miyazaki J, Nishida K, Hiraki Y et al. Anti-angiogenic action of the C-terminal domain of tenomodulin that shares homology with chondromodulin-I. J Cell Sci 2004; 117: 2731–2744.

    Article  CAS  PubMed  Google Scholar 

  53. Docheva D, Hunziker EB, Fassler R, Brandau O . Tenomodulin is necessary for tenocyte proliferation and tendon maturation. Mol Cell Biol 2005; 25: 699–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tolppanen AM, Pulkkinen L, Kolehmainen M, Schwab U, Lindström J, Tuomilehto J, et al., for the Finnish Diabetes Prevention Study Group. Tenomodulin gene variations associate with adiposity and risk of diabetes—the DPS study. Obesity 2007; 15: 1082–1088.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work has been financially supported by grants from Sigrid Juselius Foundation, the Academy of Finland (no. 209445; no. 211497), EVO funding (no. 5179, 5198), the Ministry of Education in Finland (no. 125/722/2003) and the Finnish Foundation for Diabetes Research.

The Genobin-study group is grateful for the valuable discussion and comments concerning the data analysis with Professor Sander Kersten from Wageningen University and Research Centre. The study group appreciates the excellent technical assistance of Minna Kiuttu, Kaija Kettunen, Tuomas Onnukka, Erja Kinnunen, Ulla Tuovinen and Tuula Turunen.

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Authors and Affiliations

  1. School of Public Health and Clinical Nutrition, Clinical Nutrition and Food and Health Research Center, University of Kuopio, Kuopio, Finland

    M Kolehmainen, T Salopuro, U S Schwab, P Kallio, L Pulkkinen, V I Lindi, K Sivenius, U Mager, N Siitonen, H Gylling & M Uusitupa

  2. Institute of Clinical Medicine, Internal Medicine, Kuopio University Hospital, Kuopio, Finland

    U S Schwab, D E Laaksonen, L Niskanen & H Gylling

  3. Department of Computer Science, University of Kuopio, Kuopio, Finland

    J Kekäläinen

  4. Institute of Biomedicine, Physiology, University of Kuopio, Kuopio, Finland

    D E Laaksonen

  5. Kuopio Research Institute of Exercise Medicine, University of Kuopio, Kuopio, Finland

    R Rauramaa

  6. Institute of Clinical Medicine, Clinical Physiology, Kuopio University Hospital, Kuopio, Finland

    R Rauramaa

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  1. M Kolehmainen
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  2. T Salopuro
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Correspondence to M Kolehmainen.

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Supplementary Information accompanies the paper on International Journal of Obesity website (http://www.nature.com/ijo)

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Kolehmainen, M., Salopuro, T., Schwab, U. et al. Weight reduction modulates expression of genes involved in extracellular matrix and cell death: the GENOBIN study. Int J Obes 32, 292–303 (2008). https://doi.org/10.1038/sj.ijo.0803718

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