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Adipocyte and Cell Biology

Anti-inflammatory properties of bone morphogenetic protein 4 in human adipocytes

International Journal of Obesity volume 40, pages 319–327 (2016)Cite this article

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Abstract

Background:

Obesity is characterized by increased adipocyte number and size as well as white adipose tissue (WAT) inflammation, which is fundamental for the development of insulin resistance and type-2 diabetes. These processes, regulated by various endocrine, paracrine and autocrine factors, are extensively studied with the hope to interfere and to inhibit weight gain and related complications in obese patients. Recent data suggest an important role of bone morphogenic protein 4 (BMP4) in the regulation of adipogenesis and development of obesity. BMP4 is a growth factor of the transforming growth factor-β superfamily. Initially, BMPs were identified as inducers of ectopic bone formation. It is now apparent, however, that these proteins have different pleiotropic developmental actions and including playing a role in white adipogenesis.

Methods and Results:

Here, we demonstrate that the expression of BMP4 in human WAT is negatively correlated to body mass index and to the expression of pro-inflammatory cytokines. In vitro, BMP4 expression in cultured human adipocytes is upregulated after induction of differentiation. Cells treated with exogenous BMP4 increased peroxisome proliferator-activated receptor γ (PPARγ) expression and significantly reduced the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNF-α) and monocyte chemoattractant protein 1. TNF-α treatment of fully differentiated adipocytes resulted in downregulation of the expression of adipogenic genes and elevated expression of pro-inflammatory cytokines. Exogenous BMP4 addition significantly reduced the negative effect of TNF-α on the expression profile of adipocytes. Finally, treatment of human adipocytes with exogenous BMP4 reduced the adipocytes’ chemoattractant potential and the migration of monocytes toward adipocyte-conditioned medium.

Conclusions:

These results indicate that BMP4 is an important anti-inflammatory molecule, which may act through PPARγ and reduces TNF-α-mediated pro-inflammatory cytokine production in human adipocytes. Through its anti-inflammatory potential, BMP4 may serve as a protective factor for inflammation-related diseases such as insulin-tolerance or type-2 diabetes.

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References

  1. Hotamisligil GS . Inflammation and metabolic disorders. Nature 2006; 444: 860–867.

    CAS  PubMed  Google Scholar 

  2. Lumeng CN, Saltiel AR . Inflammatory links between obesity and metabolic disease. J Clin Invest 2011; 121: 2111–2117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hirsch J, Batchelor B . Adipose tissue cellularity in human obesity. Clinic Endocrinol Metab 1976; 5: 299–311.

    Article  CAS  Google Scholar 

  4. Chawla A, Nguyen KD, Goh YP . Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 2011; 11: 738–749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Skurk T, Alberti-Huber C, Herder C, Hauner H . Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 2007; 92: 1023–1033.

    Article  CAS  PubMed  Google Scholar 

  6. Ouchi N, Parker JL, Lugus JJ, Walsh K . Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011; 11: 85–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kitade H, Sawamoto K, Nagashimada M, Inoue H, Yamamoto Y, Sai Y et al. CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes 2012; 61: 1680–1690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dworacka M, Krzyzagorska E, Iskakova S, Bekmukhambetov Y, Urazayev O, Dworacki G . Increased circulating RANTES in type 2 diabetes. Eur Cytokine Netw 2014; 25: 46–51.

    PubMed  Google Scholar 

  9. Shah R, Hinkle CC, Ferguson JF, Mehta NN, Li M, Qu L et al. Fractalkine is a novel human adipochemokine associated with type 2 diabetes. Diabetes 2011; 60: 1512–1518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xueyao Y, Saifei Z, Dan Y, Qianqian P, Xuehong D, Jiaqiang Z et al. Circulating fractalkine levels predict the development of the metabolic syndrome. Int J Endocrinol 2014; 2014: 715148.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hotamisligil GS, Shargill NS, Spiegelman BM . Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87–91.

    Article  CAS  PubMed  Google Scholar 

  12. Kanety H, Feinstein R, Papa MZ, Hemi R, Karasik A . Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. J Biol Chem 1995; 270: 23780–23784.

    Article  CAS  PubMed  Google Scholar 

  13. Feve B, Bastard JP . The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 2009; 5: 305–311.

    Article  CAS  PubMed  Google Scholar 

  14. Xu H, Sethi JK, Hotamisligil GS . Transmembrane tumor necrosis factor (TNF)-alpha inhibits adipocyte differentiation by selectively activating TNF receptor 1. J Biol Chem 1999; 274: 26287–26295.

    Article  CAS  PubMed  Google Scholar 

  15. Whitehead JP, Richards AA, Hickman IJ, Macdonald GA, Prins JB . Adiponectin—a key adipokine in the metabolic syndrome. Diabetes Obes Metab 2006; 8: 264–280.

    Article  CAS  PubMed  Google Scholar 

  16. Chen G, Goeddel DV . TNF-R1 signaling: a beautiful pathway. Science 2002; 296: 1634–1635.

    Article  CAS  PubMed  Google Scholar 

  17. Shi Y, Massague J . Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003; 113: 685–700.

    Article  CAS  PubMed  Google Scholar 

  18. Gustafson B, Smith U . The WNT inhibitor Dickkopf 1 and bone morphogenetic protein 4 rescue adipogenesis in hypertrophic obesity in humans. Diabetes 2012; 61: 1217–1224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bowers RR, Kim JW, Otto TC, Lane MD . Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation: role of the BMP-4 gene. Proc Natl Acad Sci USA 2006; 103: 13022–13027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wabitsch M, Brenner RE, Melzner I, Braun M, Moller P, Heinze E et al. Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation. Int J Obes Relat Metab Disord 2001; 25: 8–15.

    Article  CAS  PubMed  Google Scholar 

  21. Schlottmann I, Ehrhart-Bornstein M, Wabitsch M, Bornstein SR, Lamounier-Zepter V . Calcium-dependent release of adipocyte fatty acid binding protein from human adipocytes. Int J Obes (Lond) 2014; 38: 1221–1227.

    Article  CAS  Google Scholar 

  22. Hotamisligil GS, Spiegelman BM . Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 1994; 43: 1271–1278.

    Article  CAS  PubMed  Google Scholar 

  23. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116: 1494–1505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 2006; 281: 26602–26614.

    Article  CAS  PubMed  Google Scholar 

  25. Qian SW, Tang Y, Li X, Liu Y, Zhang YY, Huang HY et al. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci USA 2013; 110: E798–E807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jansson PA, Pellme F, Hammarstedt A, Sandqvist M, Brekke H, Caidahl K et al. A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. FASEB J 2003; 17: 1434–1440.

    Article  CAS  PubMed  Google Scholar 

  28. Neeland IJ, Turer AT, Ayers CR, Powell-Wiley TM, Vega GL, Farzaneh-Far R et al. Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults. JAMA 2012; 308: 1150–1159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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: 1796–1808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. McQuaid SE, Hodson L, Neville MJ, Dennis AL, Cheeseman J, Humphreys SM et al. Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition? Diabetes 2011; 60: 47–55.

    Article  CAS  PubMed  Google Scholar 

  31. Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 2007; 117: 2621–2637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huang H, Song TJ, Li X, Hu L, He Q, Liu M et al. BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci USA 2009; 106: 12670–12675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gustafson B, Hammarstedt A, Hedjazifar S, Hoffmann JM, Svensson PA, Grimsby J et al. BMP4 and BMP antagonists regulate human white and beige adipogenesis. Diabetes 2015; 64: 1670–1681.

    Article  CAS  PubMed  Google Scholar 

  34. Cho N, Momose Y . Peroxisome proliferator-activated receptor gamma agonists as insulin sensitizers: from the discovery to recent progress. Cur Top Med Chem 2008; 8: 1483–1507.

    Article  CAS  Google Scholar 

  35. 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: 1821–1830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr med. Holger Pult, Dresden, for his help in obtaining human WAT.

Author information

Authors and Affiliations

  1. Division of Molecular Endocrinology, Medical Clinic III, Technische Universität Dresden, Dresden, Germany

    E Baraban, T Chavakis, S Sales, S R Bornstein & M Ehrhart-Bornstein

  2. Department of Clinical Pathobiochemistry, Institute of Clinical Chemistry and Laboratory Medicine, University Clinic, Technische Universität Dresden, Dresden, Germany

    T Chavakis

  3. CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany

    B S Hamilton

  4. Max Planck Institute of Molecular Cell Biology and Genetics, Shevchenko Lab, Dresden, Germany

    S Sales

  5. Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany

    M Wabitsch

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  1. E Baraban
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Correspondence to M Ehrhart-Bornstein.

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Competing interests

Dr BS Hamilton is employed by Boehringer Ingelheim Pharma GmbH & Co. KG. This study was supported by a research grant from Boehringer Ingelheim GmbH & Co. (da steht and, muss geändert werden) KG. The remaining authors declare no conflict of interest.

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Baraban, E., Chavakis, T., Hamilton, B. et al. Anti-inflammatory properties of bone morphogenetic protein 4 in human adipocytes. Int J Obes 40, 319–327 (2016). https://doi.org/10.1038/ijo.2015.141

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