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Evaluation of chitotriosidase as a biomarker for adipose tissue inflammation in overweight individuals and type 2 diabetic patients

International Journal of Obesity volume 43, pages 1712–1723 (2019)Cite this article

Subjects

Abstract

Background

Overweight and obesity can lead to adipose tissue inflammation, which causes insulin resistance and on the long-term type 2 diabetes mellitus (T2D). The inflammatory changes of obese-adipose tissue are characterized by macrophage infiltration and activation, but validated circulating biomarkers for adipose tissue inflammation for clinical use are still lacking. One of the most secreted enzymes by activated macrophages is chitotriosidase (CHIT1).

Objective

To test whether circulating CHIT1 enzymatic activity levels reflect adipose tissue inflammation.

Methods

Plasma and adipose tissue samples of 105 subjects (35 lean, 37 overweight, and 33 T2D patients) were investigated. CHIT1 mRNA levels were determined in adipose tissue-resident innate immune cells. CHIT1 mRNA levels, protein abundance, and plasma enzymatic activity were subsequently measured in adipose tissue biopsies and plasma of control subjects with varying levels of obesity and adipose tissue inflammation as well as in T2D patients.

Results

In adipose tissue, CHIT1 mRNA levels were higher in stromal vascular cells compared to adipocytes, and higher in adipose tissue-residing macrophages compared to circulating monocytes (p < 0.001). CHIT1 mRNA levels in adipose tissue were enhanced in overweightcompared to lean subjects and even more in T2D patients (p < 0.05). In contrast, plasma CHIT1 enzymatic activity did not differ between lean, overweight subjects and T2D patients. A mutation of the CHIT1 gene decreases plasma CHIT1 activity.

Conclusions

CHIT1 is expressed by adipose tissue macrophages and expression is higher in overweight subjects and T2D patients, indicating its potential as tissue biomarker for adipose tissue inflammation. However, these differences do not translate into different plasma CHIT1 activity levels. Moreover, a common CHIT1 gene mutation causing loss of plasma CHIT1 activity interferes with its use as a biomarker of adipose tissue inflammation. These results indicate that plasma CHIT1 activity is of limited value as a circulating biomarker for adipose tissue inflammation in human subjects.

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References

  1. Goossens GH. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav. 2008;94:206–18.

    Article  CAS  Google Scholar 

  2. WHO. Global status report on noncommunicable diseases 2014. Geneva: World Health Organization; 2014.

    Google Scholar 

  3. Bluher M. Adipose tissue dysfunction contributes to obesity related metabolic diseases. Best Pract Res Clin Endocrinol Metab. 2013;27:163–77.

    Article  Google Scholar 

  4. Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev. 2013;93:1–21.

    Article  CAS  Google Scholar 

  5. Tack CJ, Stienstra R, Joosten LA, Netea MG. Inflammation links excess fat to insulin resistance: the role of the interleukin-1 family. Immunol Rev. 2012;249:239–52.

    Article  CAS  Google Scholar 

  6. Kusminski CM, Bickel PE, Scherer PE. Targeting adipose tissue in the treatment of obesity-associated diabetes. Nat Rev Drug Discov. 2016;15:639–60.

    Article  CAS  Google Scholar 

  7. Odegaard JI, Chawla A. Type 2 responses at the interface between immunity and fat metabolism. Curr Opin Immunol. 2015;36:67–72.

    Article  CAS  Google Scholar 

  8. Kohlgruber A, Lynch L. Adipose tissue inflammation in the pathogenesis of type 2 diabetes. Curr Diabetes Rep. 2015;15:92.

    Article  Google Scholar 

  9. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808.

    Article  CAS  Google Scholar 

  10. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.

    Article  CAS  Google Scholar 

  11. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18:363–74.

    Article  CAS  Google Scholar 

  12. Malaguarnera L. Chitotriosidase: the yin and yang. Cell Mol Life Sci. 2006;63:3018–29.

    Article  CAS  Google Scholar 

  13. Sonmez A, Haymana C, Tapan S, Safer U, Celebi G, Ozturk O, et al. Chitotriosidase activity predicts endothelial dysfunction in type-2 diabetes mellitus. Endocrine. 2010;37:455–9.

    Article  CAS  Google Scholar 

  14. Hollak CE, van Weely S, van Oers MH, Aerts JM. Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest. 1994;93:1288–92.

    Article  CAS  Google Scholar 

  15. Kanneganti M, Kamba A, Mizoguchi E. Role of chitotriosidase (chitinase 1) under normal and disease conditions. J Epithel Biol Pharmacol. 2012;5:1–9.

    Article  CAS  Google Scholar 

  16. Kabaroglu C, Onur E, Barutcuoglu B, Ozhan B, Erdinc S, Var A, et al. Inflammatory marker levels in obese adolescents with glucose intolerance: increased chitotriosidase activity. Clin Biochem. 2012;45:281–4.

    Article  CAS  Google Scholar 

  17. Zurawska-Plaksej E, Knapik-Kordecka M, Rorbach-Dolata A, Piwowar A. Increased chitotriosidase activity in plasma of patients with type 2 diabetes. Arch Med Sci. 2016;12:977–84.

    Article  CAS  Google Scholar 

  18. Zurawska-Plaksej E, Kratz EM, Ferens-Sieczkowska M, Knapik-Kordecka M, Piwowar A. Changes in glycosylation of human blood plasma chitotriosidase in patients with type 2 diabetes. Glycoconj J. 2016;33:29–39.

    Article  CAS  Google Scholar 

  19. Zurawska-Plaksej E, Lugowska A, Hetmanczyk K, Knapik-Kordecka M, Adamiec R, Piwowar A. Proteins from the 18 glycosyl hydrolase family are associated with kidney dysfunction in patients with diabetes type 2. Biomarkers. 2015;20:52–7.

    Article  CAS  Google Scholar 

  20. Ballak DB, van Diepen JA, Moschen AR, Jansen HJ, Hijmans A, Groenhof GJ, et al. IL-37 protects against obesity-induced inflammation and insulin resistance. Nat Commun. 2014;5:4711.

    Article  CAS  Google Scholar 

  21. Ballak DB, van Asseldonk EJ, van Diepen JA, Jansen H, Hijmans A, Joosten LA, et al. TLR-3 is present in human adipocytes, but its signalling is not required for obesity-induced inflammation in adipose tissue in vivo. PLoS ONE. 2015;10:e0123152.

    Article  Google Scholar 

  22. Jansen HJ, Stienstra R, van Diepen JA, Hijmans A, van der Laak JA, Vervoort GM, et al. Start of insulin therapy in patients with type 2 diabetes mellitus promotes the influx of macrophages into subcutaneous adipose tissue. Diabetologia. 2013;56:2573–81.

    Article  CAS  Google Scholar 

  23. van Diepen JA, Robben JH, Hooiveld GJ, Carmone C, Alsady M, Boutens L, et al. SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes. Diabetologia. 2017;60:1304–13.

    Article  Google Scholar 

  24. Jackson AS, Pollock ML, Ward A. Generalized equations for predicting body density of women. Med Sci Sports Exerc. 1980;12:175–81.

    CAS  PubMed  Google Scholar 

  25. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005;46:2347–55.

    Article  CAS  Google Scholar 

  26. Lin K, Kools H, de Groot PJ, Gavai AK, Basnet RK, Cheng F, et al. MADMAX - management and analysis database for multiple ~omics experiments. J Integr Bioinforma. 2011;8:160.

    Article  Google Scholar 

  27. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003;4:249–64.

    Article  Google Scholar 

  28. Dai M, Wang P, Boyd AD, Kostov G, Athey B, Jones EG, et al. Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic Acids Res. 2005;33:e175.

    Article  Google Scholar 

  29. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.

    Article  Google Scholar 

  30. Sartor MA, Tomlinson CR, Wesselkamper SC, Sivaganesan S, Leikauf GD, Medvedovic M. Intensity-based hierarchical Bayes method improves testing for differentially expressed genes in microarray experiments. BMC Bioinforma. 2006;7:538.

    Article  Google Scholar 

  31. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B (Methodol). 1995;57:289–300.

    Google Scholar 

  32. Moore DS, Notz, WI, Flinger, MA The basic practice of statistics. 6th ed. New York, NY: W. H. Freeman and Company; 2013.

  33. Westerhuis JA, Hoefsloot HCJ, Smit S, Vis DJ, Smilde AK, van Velzen EJJ, et al. Assessment of PLSDA cross validation. Metabolomics. 2008;4:81–9.

    Article  CAS  Google Scholar 

  34. Wold S, Sjöström M, Eriksson L. PLS-regression: a basic tool of chemometrics. Chemom Intell Lab Syst. 2001;58:109–30.

    Article  CAS  Google Scholar 

  35. 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;54:2277–86.

    Article  CAS  Google Scholar 

  36. Sprenger R, Doneanu C, Langridge J, Vissers H, Aerts H. MRM quantification of chitotriosidase in human plasma. Application Note Waters Corporation.

  37. Boot RG, Renkema GH, Verhoek M, Strijland A, Bliek J, de Meulemeester TM, et al. The human chitotriosidase gene. Nature of inherited enzyme deficiency. J Biol Chem. 1998;273:25680–5.

    Article  CAS  Google Scholar 

  38. Di Rosa M, Malaguarnera G, De Gregorio C, D’Amico F, Mazzarino MC, Malaguarnera L. Modulation of chitotriosidase during macrophage differentiation. Cell Biochem Biophys. 2013;66:239–47.

    Article  CAS  Google Scholar 

  39. Di Rosa M, De Gregorio C, Malaguarnera G, Tuttobene M, Biazzo F, Malaguarnera L. Evaluation of AMCase and CHIT-1 expression in monocyte macrophages lineage. Mol Cell Biochem. 2013;374:73–80.

    Article  CAS  Google Scholar 

  40. Di Rosa M, Malaguarnera G, De Gregorio C, Drago F, Malaguarnera L. Evaluation of CHI3L-1 and CHIT-1 expression in differentiated and polarized macrophages. Inflammation. 2013;36:482–92.

    Article  CAS  Google Scholar 

  41. Renkema GH, Boot RG, Strijland A, Donker-Koopman WE, van den Berg M, Muijsers AO, et al. Synthesis, sorting, and processing into distinct isoforms of human macrophage chitotriosidase. Eur J Biochem. 1997;244:279–85.

    Article  CAS  Google Scholar 

  42. Malaguarnera L, Di Rosa M, Zambito AM, dell’Ombra N, Di Marco R, Malaguarnera M. Potential role of chitotriosidase gene in nonalcoholic fatty liver disease evolution. Am J Gastroenterol. 2006;101:2060–9.

    Article  CAS  Google Scholar 

  43. Pecht T, Gutman-Tirosh A, Bashan N, Rudich A. Peripheral blood leucocyte subclasses as potential biomarkers of adipose tissue inflammation and obesity subphenotypes in humans. Obes Rev. 2014;15:322–37.

    Article  CAS  Google Scholar 

  44. Eckel N, Li Y, Kuxhaus O, Stefan N, Hu FB, Schulze MB. Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90 257 women (the Nurses’ Health Study): 30 year follow-up from a prospective cohort study. Lancet Diabetes Endocrinol. 2018;6:714–24.

    Article  Google Scholar 

  45. Greenhill C. Redefining metabolically healthy obesity. Nat Rev Endocrinol. 2018. [Epub ahead of print].

  46. McDonnell ME, Ganley-Leal LM, Mehta A, Bigornia SJ, Mott M, Rehman Q, et al. B lymphocytes in human subcutaneous adipose crown-like structures. Obesity . 2012;20:1372–8.

    Article  CAS  Google Scholar 

  47. Curat CA, Wegner V, Sengenès C, Miranville A, Tonus C, Busse R, et al. Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin. Diabetologia. 2006;49:744.

    Article  CAS  Google Scholar 

  48. Lee BC, Lee J. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta. 2014;1842:446–62.

    Article  CAS  Google Scholar 

  49. Dahlman I, Kaaman M, Olsson T, Tan GD, Bickerton AS, Wahlen K, et al. A unique role of monocyte chemoattractant protein 1 among chemokines in adipose tissue of obese subjects. J Clin Endocrinol Metab. 2005;90:5834–40.

    Article  CAS  Google Scholar 

  50. Murdolo G, Hammarstedt A, Sandqvist M, Schmelz M, Herder C, Smith U, et al. Monocyte chemoattractant protein-1 in subcutaneous abdominal adipose tissue: characterization of interstitial concentration and regulation of gene expression by insulin. J Clin Endocrinol Metab. 2007;92:2688–95.

    Article  CAS  Google Scholar 

  51. Di Gregorio GB, Yao-Borengasser A, Rasouli N, Varma V, Lu T, Miles LM, et al. Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes. 2005;54:2305–13.

    Article  Google Scholar 

  52. Bruun JM, Lihn AS, Pedersen SB, Richelsen B. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT. J Clin Endocrinol Metab. 2005;90:2282–9.

    Article  CAS  Google Scholar 

  53. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K-i, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Investig. 2006;116:1494–505.

    Article  CAS  Google Scholar 

  54. Martin BC, Warram JH, Krolewski AS, Soeldner JS, Kahn CR, Martin BC, et al. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet. 1992;340:925–9.

    Article  CAS  Google Scholar 

  55. Elmonem MA, Amin HS, El-Essawy RA, Mehaney DA, Nabil M, Kamel LN, et al. Association of chitotriosidase enzyme activity and genotype with the risk of nephropathy in type 2 diabetes. Clin Biochem. 2016;49:444–8.

    Article  CAS  Google Scholar 

  56. Kundak Ahmet A, Tascılar Mehmet E, Abaci A, Devrim I, Ozgen Ilker T, Demirpek U, et al. Serum chitotriosidase activity: is it a new inflammatory marker in obese children? J Pediatr Endocrinol Metab. 2012;25:63.

    PubMed  Google Scholar 

  57. Turan E, Sozmen B, Eltutan M, Sozmen EY. Serum chitotriosidase enzyme activity is closely related to HbA1c levels and the complications in patients with diabetes mellitus type 2. Diabetes Metab Syndr. 2017;11:S503–S6.

    Article  Google Scholar 

  58. Fusetti F, von Moeller H, Houston D, Rozeboom HJ, Dijkstra BW, Boot RG, et al. Structure of human chitotriosidase. Implications for specific inhibitor design and function of mammalian chitinase-like lectins. J Biol Chem. 2002;277:25537–44.

    Article  CAS  Google Scholar 

  59. Di Rosa M, Malaguarnera L. Chitotriosidase: a new inflammatory marker in diabetic complications. Mol Cell Biol. 2016;83:211–9.

    Google Scholar 

  60. Malaguarnera L, Simpore J, Prodi DA, Angius A, Sassu A, Persico I, et al. A 24-bp duplication in exon 10 of human chitotriosidase gene from the sub-Saharan to the Mediterranean area: role of parasitic diseases and environmental conditions. Genes Immun. 2003;4:570–4.

    Article  CAS  Google Scholar 

  61. Di Rosa M, Mangano K, De Gregorio C, Nicoletti F, Malaguarnera L. Association of chitotriosidase genotype with the development of non-alcoholic fatty liver disease. Hepatol Res. 2013;43:267–75.

    Article  Google Scholar 

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Acknowledgements

This work is part of the Perspectief Biomarker Development Center Research Programme with project number 13543, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO). We thank Jacqueline Ratter for collecting and isolating CD14+ cells from adipose tissues and blood samples. We thank Astrid van Rens for measuring the plasma CHIT1 enzyme activity in blood plasma samples.

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Authors and Affiliations

  1. Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands

    Roel Tans, Anouk Suppers, Ron A. Wevers, Jolein Gloerich & Alain J. van Gool

  2. Department of Internal Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands

    Janna A. van Diepen, Rinke Stienstra & Cees J. Tack

  3. Department of Risk Analysis for Products In Development, TNO, Zeist, The Netherlands

    Sabina Bijlsma

  4. Department of Microbiology and Systems Biology, TNO, Zeist, The Netherlands

    Lars Verschuren

  5. Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands

    Rinke Stienstra

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  1. Roel Tans
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Tans, R., van Diepen, J.A., Bijlsma, S. et al. Evaluation of chitotriosidase as a biomarker for adipose tissue inflammation in overweight individuals and type 2 diabetic patients. Int J Obes 43, 1712–1723 (2019). https://doi.org/10.1038/s41366-018-0225-8

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