Assessment of circulating Wnt1 inducible signalling pathway protein 1 (WISP-1)/CCN4 as a novel biomarker of obesity

Abstract

WNT1 inducible signaling pathway protein 1 (WISP-1/CCN4) is a novel adipokine, which is upregulated in obesity, and induces a pro-inflammatory response in macrophages in-vitro. Preclinical observations suggested WISP-1/CCN4 as a potential candidate for novel obesity therapy targeting adipose tissue inflammation. Whether circulating levels of WISP-1/CCN4 in humans are altered in obesity and/or type 2 diabetes (T2DM) and in the postprandial state, however, is unknown. This study assessed circulating WISP-1/CCN4 levels in a) paired liquid meal tests and hyperinsulinemic- euglycemic clamps (cohort I, n = 26), b) healthy individuals (cohort II, n = 207) and c) individuals with different stages of obesity and glucose tolerance (cohort III, n = 253). Circulating plasma and serum WISP-1/CCN4 concentrations were measured using a commercially available ELISA. WISP-1/CCN4 levels were not influenced by changes in insulin and/or glucose during the tests. In healthy individuals, WISP-1/CCN4 was detectable in 13% of plasma samples with the intraclass correlation coefficient of 0.93 (95% CI: 0.84–0.96) and in 58.1% of the serum samples in cohort III. Circulating WISP-1/CCN4 positively correlated with body mass index, body fat percentage, leptin and triglyceride levels, hip circumference and fatty liver index. No differences in WISP-1/CCN4 levels between individuals with normal glucose tolerance, impaired glucose tolerance and T2DM were found. The circulating concentrations of WISP-1/CCN4 showed no acute regulation in postprandial state and correlated with anthropometrical obesity markers and lipid profiles. In healthy individuals, WISP-1/CCN4 levels are more often below the detection limit. Thus, serum WISP-1/CCN4 levels may be used as a suitable biomarker of obesity.

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Abbreviations

ALT:

Alanine transaminase

CCN:

CTGF/Cyr61/Nov) family proteins

EPIC:

European Prospective Investigation into Cancer and Nutrition

FLI:

Fatty Liver Index

HOMA-IR:

Homeostatic model assessment insulin resistance

HEC:

Hyperinsulinemic euglycemic clamp

IFG:

Impaired fasting glucose

IGT:

Impaired glucose tolerance

IHL:

Intrahepatic liver fat

LMCT:

Liquid meal challenges tests

NGT:

Normal glucose tolerance

T2DM:

Type 2 diabetes mellitus

VAT:

Visceral adipose tissue

WHR:

Waist-to-hip ratio

WISP-1/CCN4:

WNT-inducible signaling pathway protein-1

References

  1. Abell SK, De Courten B, Boyle JA, Teede HJ (2015) Inflammatory and Other Biomarkers: Role in Pathophysiology and Prediction of Gestational Diabetes Mellitus. Int J Mol Sci 16:13442–13473

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Barchetta I, Cimini FA, Capoccia D, De Gioannis R, Porzia A, Mainiero F, Di Martino M, Bertoccini L, De Bernardinis M, Leonetti F et al (2017) WISP1 Is a Marker of Systemic and Adipose Tissue Inflammation in Dysmetabolic Subjects With or Without Type 2 Diabetes. J Endocrine Society 1:660–670

    Article  Google Scholar 

  3. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, Tiribelli C (2006) The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 6:33

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Berschneider B, Konigshoff M (2011) WNT1 inducible signaling pathway protein 1 (WISP1): a novel mediator linking development and disease. Int J Biochem Cell Biol 43:306–309

    Article  PubMed  CAS  Google Scholar 

  5. Blom AB, Brockbank SM, van Lent PL, van Beuningen HM, Geurts J, Takahashi N, van der Kraan PM, van de Loo FA, Schreurs BW, Clements K et al (2009) Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1. Arthritis Rheum 60:501–512

    Article  PubMed  CAS  Google Scholar 

  6. Brigstock DR (2003) The CCN family: a new stimulus package. J Endocrinol 178:169–175

    Article  PubMed  CAS  Google Scholar 

  7. Catalano PM, Kirwan JP, Haugel-de Mouzon S, King J (2003) Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus. J Nutr 133:1674S–1683S

    Article  PubMed  CAS  Google Scholar 

  8. Gurbuz I, Chiquet-Ehrismann R (2015) CCN4/WISP1 (WNT1 inducible signaling pathway protein 1): a focus on its role in cancer. Int J Biochem Cell Biol 62:142–146

    Article  PubMed  CAS  Google Scholar 

  9. Gustafson B, Hammarstedt A, Hedjazifar S, Smith U (2013) Restricted adipogenesis in hypertrophic obesity: the role of WISP2, WNT, and BMP4. Diabetes 62:2997–3004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Holbourn KP, Acharya KR, Perbal B (2008) The CCN family of proteins: structure-function relationships. Trends Biochem Sci 33:461–473

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Jun JI, Lau LF (2011) Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discov 10:945–963

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Leask A, Abraham DJ (2006) All in the CCN family: essential matricellular signaling modulators emerge from the bunker. J Cell Sci 119:4803–4810

    Article  PubMed  CAS  Google Scholar 

  13. Liu J, Ren Y, Kang L, Zhang L (2014) Overexpression of CCN3 inhibits inflammation and progression of atherosclerosis in apolipoprotein E-deficient mice. PLoS One 9:e94912

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Murahovschi V, Pivovarova O, Ilkavets I, Dmitrieva RM, Docke S, Keyhani-Nejad F, Gogebakan O, Osterhoff M, Kemper M, Hornemann S et al (2015a) WISP1 Is a Novel Adipokine Linked to Inflammation in Obesity. Diabetes 64:856–866

    Article  PubMed  CAS  Google Scholar 

  15. Murahovschi VTC, Pivovarova O, Kruse M, Seltmann AC, Kemper M, Hornemann S, Pfeiffer AFH, Rudovich N (2015b) Regulation of WNT signaling receptors and co-receptors by high fat diet in humans. Exp Clin Endocrinol Diabetes 123:P08_02

    Google Scholar 

  16. Pakradouni J, Le Goff W, Calmel C, Antoine B, Villard E, Frisdal E, Abifadel M, Tordjman J, Poitou C, Bonnefont-Rousselot D et al (2013) Plasma NOV/CCN3 levels are closely associated with obesity in patients with metabolic disorders. PLoS One 8:e66788

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Perbal B (2009) Alternative splicing of CCN mRNAs .... it has been upon us. J Cell Commun Signal 3:153–157

    Article  PubMed  PubMed Central  Google Scholar 

  18. Riboli E, Hunt KJ, Slimani N, Ferrari P, Norat T, Fahey M, Charrondiere UR, Hemon B, Casagrande C, Vignat J et al (2002) European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr 5:1113–1124

    Article  PubMed  CAS  Google Scholar 

  19. Rudovich NN, Weickert MO, Pivovarova O, Bernigau W, Pfeiffer AF (2011) Effects of acarbose treatment on markers of insulin sensitivity and systemic inflammation. Diabetes Technol Ther 13:615–623

    Article  PubMed  CAS  Google Scholar 

  20. Sahin Ersoy G, Altun Ensari T, Subas S, Giray B, Simsek EE, Cevik O (2016) WISP1 is a novel adipokine linked to metabolic parameters in gestational diabetes mellitus. J Matern Fetal Neonatal Med 30:1–5

    Google Scholar 

  21. Stephens S, Palmer J, Konstantinova I, Pearce A, Jarai G, Day E (2015) A functional analysis of Wnt inducible signalling pathway protein −1 (WISP-1/CCN4). J Cell Commun Signal 9:63–72

    Article  PubMed  PubMed Central  Google Scholar 

  22. Tanaka S, Sugimachi K, Saeki H, Kinoshita J, Ohga T, Shimada M, Maehara Y, Sugimachi K (2001) A novel variant of WISP1 lacking a Von Willebrand type C module overexpressed in scirrhous gastric carcinoma. Oncogene 20:5525–5532

    Article  PubMed  CAS  Google Scholar 

  23. WHO (2006) Definition and Diagnosis of Diabetes Mellitus and Intermediate Hyperglycemia. World Health Organization, Geneva, pp 1–46

    Google Scholar 

  24. Yanagita T, Kubota S, Kawaki H, Kawata K, Kondo S, Takano-Yamamoto T, Tanaka S, Takigawa M (2007) Expression and physiological role of CCN4/Wnt-induced secreted protein 1 mRNA splicing variants in chondrocytes. FEBS J 274:1655–1665

    Article  PubMed  CAS  Google Scholar 

  25. Zhong X, Tu YJ, Li Y, Zhang P, Wang W, Chen SS, Li L, Chung AC, Lan HY, Chen HY et al (2017) Serum levels of WNT1-inducible signaling pathway protein-1 (WISP-1): a noninvasive biomarker of renal fibrosis in subjects with chronic kidney disease. Am J Transl Res 9:2920–2932

    PubMed  PubMed Central  Google Scholar 

  26. Zhou Y, Yu X, Chen H, Sjoberg S, Roux J, Zhang L, Ivoulsou AH, Bensaid F, Liu CL, Liu J et al (2015) Leptin Deficiency Shifts Mast Cells toward Anti-Inflammatory Actions and Protects Mice from Obesity and Diabetes by Polarizing M2 Macrophages. Cell Metab 22:1045–1058

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We thank all study participants for their cooperation. We thank the Human Study Centre at the DIfE for data collection and biological sample logistics. We express thanks to Dr. Manuela Bergmann for her contribution by leading the underlying processes of data generation, as well as to Silke Navia Fruth and Herbert Piechot for their valuable assistance with biosamples management. Particular thanks are given to the EPIC Potsdam data manager - Ellen Kohlsdorf. We gratefully acknowledge the excellent technical assistance of Katrin Sprengel, and Tanja Ahrens. We thank Stephanie Sucher for her extensive advice regarding nutritional counselling and June Inderthal for reading and correcting the manuscript.

Funding

This work was financially supported by grant from German Diabetes Center (DZD) (NR, DMO) and grant of European Foundation for Study of Diabetes (EFSD) (NR, DMO). The funding source had no role in study design, data collection, analysis or interpretation, report writing, or the decision to submit this paper for publication.

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Authors

Contributions

Study concept and design: AFHP, OP, and NR. Acquisition of data: CT, KA, TH, MK, SH, CG and SK. Analysis and interpretation of data: CT, KA, DMO, VM, MM, CG, MR, DMO, TH, MOW, HB, AFHP, OP, and NR. Drafting of the manuscript: CT, AFHP, OP, and NR. Critical revision of the manuscript: CT, KA, MR, VM, MM, MK, SH, UK, CH, SK, TH, DMO, MOW, HB, AFHP, OP and NR. Obtained funding: DMO and NR. All authors contributed to and approved the final version of the manuscript. AFHP, OP, and NR are the guarantors of this work and as such had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to Natalia Rudovich.

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The authors declare that there is no duality of interest associated with this manuscript.

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The authors declare no conflict of interest.

Additional information

Some of the data were presented as abstracts at the D·A·CH meeting 2015 and at the European Association for the Study of Diabetes annual meeting in 2016.

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Tacke, C., Aleksandrova, K., Rehfeldt, M. et al. Assessment of circulating Wnt1 inducible signalling pathway protein 1 (WISP-1)/CCN4 as a novel biomarker of obesity. J. Cell Commun. Signal. 12, 539–548 (2018). https://doi.org/10.1007/s12079-017-0427-1

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Keywords

  • CCN proteins
  • Insulin resistance
  • Obesity
  • WISP-1/CCN4