, Volume 36, Issue 2, pp 379–386 | Cite as

A High-Fat Diet Increases IL-1, IL-6, and TNF-α Production by Increasing NF-κB and Attenuating PPAR-γ Expression in Bone Marrow Mesenchymal Stem Cells

  • Mayara Cortez
  • Luciana Simão Carmo
  • Marcelo Macedo Rogero
  • Primavera Borelli
  • Ricardo Ambrósio FockEmail author


It is well established that a high-fat diet (HFD) can lead to overweight and ultimately to obesity, as well as promoting low-grade chronic inflammation associated with increased levels of such mediators as TNF-α, IL-1, and IL-6. Bone marrow mesenchymal stem cells (MSCs), which are involved in hematopoietic niches and microenvironments, can be affected by these cytokines, resulting in induction of NF-κB and inhibition of PPAR-γ. Because this phenomenon could ultimately lead to suppression of bone marrow adipogenesis, we set out to investigate the effect of an HFD on the expression of PPAR-γ and NF-κB, as well as the production of IL-1, IL-6, and TNF-α in MSCs. Two-month-old male Wistar rats were fed a HFD diet and evaluated by means of leukograms and myelograms along with blood total cholesterol, triglyceride, and C-reactive protein levels. MSCs were isolated, and PPAR-γ and NF-κB were quantified, as well as IL-1, IL-6, and TNF-α production. Animals that were fed a HFD showed higher levels of blood total cholesterol, triglycerides, and C-reactive protein with leukocytosis and bone marrow hyperplasia. MSCs from HFD animals showed increased production of IL-1, IL-6, and TNF-α and increased NF-κB and reduced PPAR-γ expression. Therefore, ingestion of an HFD induces alterations in MSCs that may influence modulation of hematopoiesis.


high-fat diet mesenchymal stem cells PPAR-γ NF-κB IL-1 IL-6 TNF-α 



This investigation was supported by grants from the Fundação de Amparo a Pesquisa do Estado de São Paulo.


  1. 1.
    Gainsford, T., T.A. Willson, D. Metcalf, E. Handman, C. McFarlane, A. Ng, N.A. Nicola, W.S. Alexander, and D.J. Hilton. 1996. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proceedings of the National Academy of Sciences USA 93: 14564–14568.CrossRefGoogle Scholar
  2. 2.
    Choi, K.D., M. Vodyanik, and I.I. Slukvin. 2011. Hematopoietic differentiation and production of mature myeloid cells from human pluripotent stem cells. Nature Protocols 6: 296–313.PubMedCrossRefGoogle Scholar
  3. 3.
    Fantuzzi, G., and R. Faggioni. 2000. Leptin in the regulation of immunity, inflammation, and hematopoiesis. Journal of Leukocyte Biology 68: 437–446.PubMedGoogle Scholar
  4. 4.
    Schäffler, A., J. Schölmerich, and B. Salzberger. 2007. Adipose tissue as an immunological organ: Toll-like receptors, C1q/TNFs and CTRPs. Trends in Immunology 28: 393–399.PubMedCrossRefGoogle Scholar
  5. 5.
    Laharrague, P., J.M. Oppert, P. Brousset, J.P. Charlet, A. Campfield, A.M. Fontanilles, B. Guy-Grand, J.X. Corberand, L. Pénicaud, and L. Casteilla. 2000. High concentration of leptin stimulates myeloid differentiation from human bone marrow CD34+ progenitors: potential involvement in leukocytosis of obese subjects. International Journal of Obesity and Related Metabolic Disorders 24: 1212–1216.PubMedCrossRefGoogle Scholar
  6. 6.
    Ogawa, M. 1993. Differentiation and proliferation of hematopoietic stem cells. Blood 81: 2844–2853.PubMedGoogle Scholar
  7. 7.
    Fuchs, E., T. Tumbar, and G. Guasch. 2004. Socializing with the neighbors: stem cells and their niche. Cell 116: 769–778.PubMedCrossRefGoogle Scholar
  8. 8.
    Rosen, E.D., and O.A. MacDougald. 2006. Adipocyte differentiation from the inside out. Nature Reviews Molecular Cell Biology 7: 885–896.PubMedCrossRefGoogle Scholar
  9. 9.
    Ichida, F., R. Nishimura, K. Hata, T. Matsubara, F. Ikeda, K. Hisada, H. Yatani, X. Cao, T. Komori, A. Yamaguchi, and T. Yoneda. 2004. Reciprocal roles of MSX2 in regulation of osteoblast and adipocyte differentiation. The Journal of Biological Chemistry 279: 34015–34022.PubMedCrossRefGoogle Scholar
  10. 10.
    Jeon, M.J., J.A. Kim, S.H. Kwon, S.W. Kim, K.S. Park, S.W. Park, S.Y. Kim, and C.S. Shin. 2003. Activation of peroxisome proliferator-activated receptor-y inhibits the Runx2-mediated transcription of osteocalcin in osteoblasts. The Journal of Biological Chemistry 278: 23270–23277.PubMedCrossRefGoogle Scholar
  11. 11.
    Arai, F., A. Hirao, M. Ohmura, H. Sato, S. Matsuoka, K. Takubo, K. Ito, G.Y. Koh, and T. Suda. 2004. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118: 149–161.PubMedCrossRefGoogle Scholar
  12. 12.
    Calvi, L.M., G.B. Adams, K.W. Weibrecht, J.M. Weber, D.P. Olson, M.C. Knight, R.P. Martin, E. Schipani, P. Divieti, F.R. Bringhurst, L.A. Milner, H.M. Kronenberg, and D.T. Scadden. 2003. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425: 841–846.PubMedCrossRefGoogle Scholar
  13. 13.
    Zhang, J., C. Niu, L. Ye, H. Huang, X. He, W.G. Tong, J. Ross, J. Haug, T. Johnson, J.Q. Feng, S. Harris, L.M. Wiedemann, Y. Mishina, and L. Li. 2003. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425: 836–841.PubMedCrossRefGoogle Scholar
  14. 14.
    Naveiras, O., V. Nardi, P.L. Wenzel, P.V. Hauschka, F. Fahey, and G.Q. Daley. 2009. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460: 259–263.PubMedCrossRefGoogle Scholar
  15. 15.
    Takada, I., A.P. Kouzmenko, and S. Kato. 2010. PPAR-gamma Signaling Crosstalk in Mesenchymal Stem Cells. PPAR Research. doi: 10.1155/2010/341671.
  16. 16.
    Suzawa, M., I. Takada, J. Yanagisawa, F. Ohtake, S. Ogawa, T. Yamauchi, T. Kadowaki, Y. Takeuchi, H. Shibuya, Y. Gotoh, K. Matsumoto, and S. Kato. 2003. Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade. Nature Cell Biology 5: 224–230.PubMedCrossRefGoogle Scholar
  17. 17.
    Wan, Y. 2010. PPARγ in bone homeostasis. Trends in Endocrinology and Metabolism 21: 722–728.PubMedCrossRefGoogle Scholar
  18. 18.
    Takada, I., M. Suzawa, and S. Kato. 2005. Nuclear receptors as targets for drug development: crosstalk between peroxisome proliferator-activated receptor gamma and cytokines in bone marrow-derived mesenchymal stem cells. Journal of Pharmacological Sciences 97: 184–189.PubMedCrossRefGoogle Scholar
  19. 19.
    Kelly, D., J.I. Campbell, T.P. King, G. Grant, E.A. Jansson, A.G. Coutts, S. Pettersson, and S. Conway. 2004. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nature Immunology 5: 104–112.PubMedCrossRefGoogle Scholar
  20. 20.
    Reeves, P.G., F.H. Nielsen, and G.C. Fahey Jr. 1993. AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. Journal of Nutrition 123: 1939–1951.PubMedGoogle Scholar
  21. 21.
    Pang, J., Y. Choi, and T. Park. 2008. Ilex paraguariensis extract ameliorates obesity induced by high-fat diet: potential role of AMPK in the visceral adipose tissue. Archives of Biochemistry and Biophysics 476: 178–185.PubMedCrossRefGoogle Scholar
  22. 22.
    Dacie, J.V., and S.M. Lewis. 1995. Practical haematology, 57–58. Edinburgh: Churchill Livingstone.Google Scholar
  23. 23.
    Buettner, R., J. Scholmerich, and L.C. Bollheimer. 2007. High-fat diets: Modeling the metabolic disorders of human obesity in rodents. Obesity 15: 798–808.PubMedCrossRefGoogle Scholar
  24. 24.
    Buettner, R., K.G. Parhofer, M. Woenckhaus, C.E. Wrede, L.A. Kunz-Schughart, J. Schölmerich, and L.C. Bollheimer. 2006. Defining high-fat-diet rat models: metabolic and molecular effects of different fat types. Journal of Molecular Endocrinology 36: 485–501.PubMedCrossRefGoogle Scholar
  25. 25.
    Hariri, N., and L. Thibault. 2010. High-fat diet-induced obesity in animal models. Nutrition Research Reviews 23: 270–299.PubMedCrossRefGoogle Scholar
  26. 26.
    Cohen-Lahav, M., S. Shany, D. Tobvin, C. Chaimovitz, and A. Douvdevani. 2006. Vitamin D decreases NF kappa B activity by increasing I kappa B alpha levels. Nephrology, Dialysis, Transplantation 21: 889–897.PubMedCrossRefGoogle Scholar
  27. 27.
    Wintergerst, E.S., S. Maggini, and D.H. Hornig. 2007. Contribution of selected vitamins and trace elements to immune function. Annals of Nutrition and Metabolism 51: 301–323.PubMedCrossRefGoogle Scholar
  28. 28.
    Ghibaudi, L., J. Cook, C. Farley, M. van Heek, and J.J. Hwa. 2002. Fat intake affects adiposity, comorbidity factors, and energy metabolism of Sprague-Dawley rats. Obesity Research 10: 956–963.PubMedCrossRefGoogle Scholar
  29. 29.
    Pratley, R.E., C. Wilson, and C. Bogardus. 1995. Relation of the white blood cell count to obesity and insulin resistance: effect of race and gender. Obesity Research 3: 563–571.PubMedCrossRefGoogle Scholar
  30. 30.
    Dixon, J.B., and P.E. O’Brien. 2006. Obesity and the white blood cell count: Changes with sustained weight loss. Obesity Surgery 16: 251–257.PubMedCrossRefGoogle Scholar
  31. 31.
    Hotamisligil, G.S., P. Arner, J.F. Caro, R.L. Atkinson, and B.M. Spiegelman. 1995. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. The Journal of Clinical Investigation 95: 2409–2415.PubMedCrossRefGoogle Scholar
  32. 32.
    Saghizadeh, M., J.M. Ong, W.T. Garvey, R.R. Henry, and P.A. Kern. 1996. The expression of TNF alpha by human muscle. Relationship to insulin resistance. The Journal of Clinical Investigation 97: 1111–1116.PubMedCrossRefGoogle Scholar
  33. 33.
    Crisostomo, P.R., Y. Wang, T.A. Markel, M. Wang, T. Lahm, and D.R. Meldrum. 2008. Human mesenchymal stem cells stimulated by TNF-alpha, LPS, or hypoxia produce growth factors by an NF kappa B- but not JNK-dependent mechanism. American Journal of Physiology. Cell Physiology 294: C675–C682.PubMedCrossRefGoogle Scholar
  34. 34.
    Hideshima, T., C. Mitsiades, G. Tonon, P.G. Richardson, and K.C. Anderson. 2007. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nature Reviews. Cancer 7: 585–598.PubMedCrossRefGoogle Scholar
  35. 35.
    Ricote, M., and C.K. Glass. 2007. PPARs and molecular mechanisms of transrepression. Biochimica et Biophysica Acta 1771: 926–935.PubMedCrossRefGoogle Scholar
  36. 36.
    Kota, B.P., T.H. Huang, and B.D. Roufogalis. 2005. An overview on biological mechanisms of PPARs. Pharmacological Research 51: 85–94.PubMedCrossRefGoogle Scholar
  37. 37.
    Takada, I., M. Suzawa, K. Matsumoto, and S. Kato. 2007. Suppression of PPAR transactivation switches cell fate of bone marrow stem cells from adipocytes into osteoblasts. Annals of the New York Academy of Sciences 1116: 182–195.PubMedCrossRefGoogle Scholar
  38. 38.
    Gordeladze, J.O., C.A. Drevon, U. Syversen, and J.E. Reseland. 2002. Leptin stimulates human osteoblastic cell proliferation, de novo collagen synthesis, and mineralization: Impact on differentiation markers, apoptosis, and osteoclastic signaling. Journal of Cellular Biochemistry 85: 825–836.PubMedCrossRefGoogle Scholar
  39. 39.
    Thomas, T., F. Gori, S. Khosla, M.D. Jensen, B. Burguera, and B.L. Riggs. 1999. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology 140: 1630–1638.PubMedCrossRefGoogle Scholar
  40. 40.
    Yin, T., and L. Li. 2006. The stem cell niches in bone. The Journal of Clinical Investigation 116: 1195–1201.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Mayara Cortez
    • 1
  • Luciana Simão Carmo
    • 1
  • Marcelo Macedo Rogero
    • 2
  • Primavera Borelli
    • 1
  • Ricardo Ambrósio Fock
    • 1
    • 3
    Email author
  1. 1.Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical SciencesUniversity of São PauloSão PauloBrazil
  2. 2.Department of Nutrition, School of Public HealthSão Paulo UniversitySão PauloBrazil
  3. 3.Experimental Hematology Laboratory, Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical SciencesUniversity of São PauloSão PauloBrazil

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