Advertisement

Molecular Medicine

, Volume 23, Issue 1, pp 225–234 | Cite as

Adipose Tissue and Serum CCDC80 in Obesity and Its Association with Related Metabolic Disease

  • Óscar Osorio-Conles
  • María Guitart
  • José María Moreno-Navarrete
  • Xavier Escoté
  • Xavier Duran
  • José Manuel Fernandez-Real
  • Anna María Gómez-Foix
  • Sonia Fernández-Veledo
  • Joan Vendrell
Research Article

Abstract

Coiled-coil domain-containing 80 (CCDC80) is an adipocyte-secreted protein that modulates glucose homeostasis in response to diet-induced obesity in mice. The objective of this study was to analyze the link between human CCDC80 and obesity. CCDC80 protein expression was assessed in paired visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from 10 patients (body mass index range 22.4–38.8 kg/m2). Circulating CCDC80 levels were quantified in serum samples from two independent cross-sectional cohorts comprising 33 lean and 15 obese (cohort 1) and 32 morbidly obese (cohort 2) male patients. Insulin sensitivity, insulin secretion and blood neutrophil count were quantified in serum samples from both cohorts. Additionally, circulating free insulin-like growth factor (IGF)-1 levels and oral glucose tolerance tests were assessed in cohort 1, whereas C-reactive protein levels and degree of atherosclerosis and hepatic steatosis were studied in cohort 2. In lean patients, total CCDC80 protein content assessed by immunoblotting was lower in VAT than in SAT. In obese patients, CCDC80 was increased in VAT (P < 0.05) but equivalent in SAT compared with lean counterparts. In cohort 1, serum CCDC80 correlated negatively with the acute insulin response to glucose and IGF-1 levels and positively with blood neutrophil count independent of BMI, but not with insulin sensitivity. In cohort 2, serum CCDC80 was positively linked to the inflammatory biomarker C-reactive protein (r = 0.46; P = 0.009), atherosclerosis (carotid intima-media thickness, r = 0.62; P < 0.001) and hepatic steatosis (analysis of variance P = 0.025). Overall, these results suggest for the first time that CCDC80 may be a component of the obesity-altered secretome in VAT and could act as an adipokine whose circulant levels are linked to glucose tolerance derangements and related to inflammation-associated chronic complications.

Notes

Acknowledgments

This study was supported by the following grants: SAF2012-37480 and SAF2015-65019R from the Spanish Ministerio de Ciencia e Innovación (MCI), FIS-PI14/00228, FIS-P15/01934 and FIS-PI14/00228 from the Fondo de Investigación Sanitaria (FIS), and FLORINASH (VII FP), CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CB07/08/0012) and CIBERobn Fisiopatologia de la Obesidad y Nutrición (CB06/03/010). SF-V acknowledges support from the “Miguel Servet” tenure track program (CPII16/00008) from FIS co-financed by the European Regional Development Fund (ERDF). Sadly, AMG-F passed away before the manuscript was completed.

Supplementary material

10020_2017_2301225_MOESM1_ESM.pdf (213 kb)
Supplementary material, approximately 213 KB.

References

  1. 1.
    Leal VeO, Mafra D. (2013) Adipokines in obesity. Clin Chim Acta. 419:87–94.CrossRefGoogle Scholar
  2. 2.
    Gray SL, Vidal-Puig AJ. (2007) Adipose tissue expandability in the maintenance of metabolic homeostasis. Nutr. Rev. 65:S7–12.CrossRefGoogle Scholar
  3. 3.
    Rabe K, Lehrke M, Parhofer KG, Broedl UC. (2008) Adipokines and insulin resistance. Mol. Med. 14:741–751.CrossRefGoogle Scholar
  4. 4.
    Northcott JM, Yeganeh A, Taylor CG, Zahradka P, Wigle JT. (2012) Adipokines and the cardiovascular system: mechanisms mediating health and disease. Can. J. Physiol. Pharmacol. 90:1029–59.CrossRefGoogle Scholar
  5. 5.
    Buechler C, Wanninger J, Neumeier M. (2011) Adiponectin, a key adipokine in obesity related liver diseases. World J. Gastroenterol. 17:2801–11.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Aoki K, Sun YJ, Aoki S, Wada K, Wada E. (2002) Cloning, expression, and mapping of a gene that is upregulated in adipose tissue of mice deficient in bombesin receptor subtype-3. Biochem. Biophys. Res. Commun. 290:1282–88.CrossRefGoogle Scholar
  7. 7.
    Okada T, et al. (2008) URB is abundantly expressed in adipose tissue and dysregulated in obesity. Biochem. Biophys. Res. Commun. 367:370–76.CrossRefGoogle Scholar
  8. 8.
    Tremblay F, et al. (2009) Bidirectional modulation of adipogenesis by the secreted protein Ccdc80/DRO1/URB. J. Biol. Chem. 284:8136–47.CrossRefGoogle Scholar
  9. 9.
    Tremblay F, et al. (2012) Loss of coiled-coil domain containing 80 negatively modulates glucose homeostasis in diet-induced obese mice. Endocrinology. 153:4290–4303.CrossRefGoogle Scholar
  10. 10.
    Liu Y, et al. (2004) URB expression in human bone marrow stromal cells and during mouse development. Biochem. Biophys. Res. Commun. 322:497–507.CrossRefGoogle Scholar
  11. 11.
    Recasens M, et al. (2005) An inflammation score is better associated with basal than stimulated surrogate indexes of insulin resistance. J. Clin. Endocrinol. Metab 90:112–16.CrossRefGoogle Scholar
  12. 12.
    Moreno-Navarrete JM, et al. (2013) Decreased RB1 mRNA, protein, and activity reflect obesity-induced altered adipogenic capacity in human adipose tissue. Diabetes. 62:1923–31.CrossRefGoogle Scholar
  13. 13.
    Serrano M, et al. (2013) Serum lipopolysaccharide-binding protein as a marker of atherosclerosis. Atherosclerosis. 230:223–27.CrossRefGoogle Scholar
  14. 14.
    Kleiner DE, et al. (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 41:1313–21.CrossRefGoogle Scholar
  15. 15.
    World Health Organization. (2000) Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report Series 894. 1st ed. Geneva: World Health Organization.Google Scholar
  16. 16.
    Wabitsch M, et al. (2001) Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation. Int. J. Obes. Relat. Metab. Disord. 25:8–15.CrossRefGoogle Scholar
  17. 17.
    Chacón M, et al. (2008) Human serum levels of fetal antigen 1 (FA1/Dlk1) increase with obesity, are negatively associated with insulin sensitivity and modulate inflammation in vitro. Int. J. Obes. (Lond). 32:1122–29.CrossRefGoogle Scholar
  18. 18.
    Pérez-Pérez R, et al. (2012) Uncovering suitable reference proteins for expression studies in human adipose tissue with relevance to obesity. PLoS One. 7:e30326.CrossRefGoogle Scholar
  19. 19.
    Osorio-Conles O, et al. (2011) Plasma PTX3 protein levels inversely correlate with insulin secretion and obesity, whereas visceral adipose tissue PTX3 gene expression is increased in obesity. Am. J. Physiol. Endocrinol. Metab. 301:E1254–61.CrossRefGoogle Scholar
  20. 20.
    Taylor PR, et al. (2005) Macrophage receptors and immune recognition. Annu. Rev. Immunol. 23:901–44.CrossRefGoogle Scholar
  21. 21.
    Fernández-Real JM, et al. (2011) CD14 modulates inflammation-driven insulin resistance. Diabetes. 60:2179–86.CrossRefGoogle Scholar
  22. 22.
    Bommer GT, et al. (2005) DRO1, a gene down-regulated by oncogenes, mediates growth inhibition in colon and pancreatic cancer cells. J. Biol. Chem. 280:7962–75.CrossRefGoogle Scholar
  23. 23.
    Matthae S, May S, Hubersberger M, Hauner H, Skurk T. (2013) Protein normalization in different adipocyte models and dependence on cell size. Horm. Metab. Res. 45:572–80.CrossRefGoogle Scholar
  24. 24.
    Ibrahim MM. (2010) Subcutaneous and visceral adipose tissue: structural and functional differences. Obes. Rev. 11:11–18.CrossRefGoogle Scholar
  25. 25.
    Insenser M, et al. (2012) A nontargeted proteomic approach to the study of visceral and subcutaneous adipose tissue in human obesity. Mol. Cell. Endocrinol. 363:10–19.CrossRefGoogle Scholar
  26. 26.
    Crandall DL, Hausman GJ, Kral JG. (1997) A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation. 4:211–32.CrossRefGoogle Scholar
  27. 27.
    Catalán V, Gómez-Ambrosi J, Rodríguez A, Frühbeck G. (2012) Role of extracellular matrix remodelling in adipose tissue pathophysiology: relevance in the development of obesity. Histol. Histopathol. 27:1515–28.PubMedGoogle Scholar
  28. 28.
    Lanthier N, Leclercq IA. (2014) Adipose tissues as endocrine target organs. Best Pract. Res. Clin. Gastroenterol. 28:545–58.CrossRefGoogle Scholar
  29. 29.
    Grill JI, et al. (2017) Loss of DRO1/CCDC80 results in obesity and promotes adipocyte differentiation. Mol. Cell. Endocrinol. 439:286–96.CrossRefGoogle Scholar
  30. 30.
    Bunt JC, Krakoff J, Ortega E, Knowler WC, Bogardus C. (2007) Acute insulin response is an independent predictor of type 2 diabetes mellitus in individuals with both normal fasting and 2-h plasma glucose concentrations. Diabetes Metab. Res. Rev. 23:304–10.CrossRefGoogle Scholar
  31. 31.
    Colao A, et al. (2008) Relationships between serum IGF1 levels, blood pressure, and glucose tolerance: an observational, exploratory study in 404 subjects. Eur. J. Endocrinol. 159:389–97.CrossRefGoogle Scholar
  32. 32.
    Mócsai A. (2013) Diverse novel functions of neutrophils in immunity, inflammation, and beyond. J. Exp. Med. 210:1283–99.CrossRefGoogle Scholar
  33. 33.
    Li Y, Liu L, Wang B, Wang J, Chen D. (2014) Simple steatosis is a more relevant source of serum inflammatory markers than omental adipose tissue. Clin. Res. Hepatol. Gastroenterol. 38:46–54.CrossRefGoogle Scholar
  34. 34.
    Targher G, et al. (2008) NASH predicts plasma inflammatory biomarkers independently of visceral fat in men. Obesity (Silver Spring). 16:1394–99.CrossRefGoogle Scholar
  35. 35.
    Corrado E, et al. (2010) An update on the role of markers of inflammation in atherosclerosis. J. Atheroscler. Thromb. 17:1–11.CrossRefGoogle Scholar
  36. 36.
    Raymond F, et al. (2010) Comparative gene expression profiling between human cultured myotubes and skeletal muscle tissue. BMC Genomics. 11:125.CrossRefGoogle Scholar
  37. 37.
    Wang GR, et al. (2013) Steroid-sensitive gene 1 is a novel cyclic GMP-dependent protein kinase I substrate in vascular smooth muscle cells. J. Biol. Chem. 288:24972–83.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2017

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Óscar Osorio-Conles
    • 1
    • 2
  • María Guitart
    • 2
  • José María Moreno-Navarrete
    • 3
  • Xavier Escoté
    • 1
    • 4
  • Xavier Duran
    • 1
    • 4
  • José Manuel Fernandez-Real
    • 3
  • Anna María Gómez-Foix
    • 1
    • 2
  • Sonia Fernández-Veledo
    • 1
    • 4
  • Joan Vendrell
    • 1
    • 4
  1. 1.CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos IIIMadridSpain
  2. 2.Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona, Facultat de BiologiaUniversitat de BarcelonaBarcelonaSpain
  3. 3.Service of Diabetes, Endocrinology and NutritionInstitut d’Investigacio Biomedica de Girona and CIBERobnGironaSpain
  4. 4.Research UnitJoan XXIII University Hospital, Rovira i Virgili University IISPVTarragonaSpain

Personalised recommendations