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  • Review Article
  • Published:

Obesity-driven disruption of haematopoiesis and the bone marrow niche

Nature Reviews Endocrinology volume 10, pages 737–748 (2014)Cite this article

Subjects

Key Points

  • Obesity represents a substantial public health challenge, including an increased burden of infectious diseases—suggesting the involvement of a compromised immune system

  • Haematopoietic stem cells reside in (and are regulated by) a complex, heterogeneous and tightly controlled microenvironment within the bone marrow

  • The bone marrow environment undergoes considerable changes during obesity, including adipocyte hyperplasia and a phenotypic shift of adipocytes towards a white adipose profile

  • Methods of limiting the progression of obesity and controlling its systemic and bone-marrow-based sequelae, such as exercise, might represent suitable approaches to maintain haematopoiesis and immune function

Abstract

Obesity markedly increases susceptibility to a range of diseases and simultaneously undermines the viability and fate selection of haematopoietic stem cells (HSCs), and thus the kinetics of leukocyte production that is critical to innate and adaptive immunity. Considering that blood cell production and the differentiation of HSCs and their progeny is orchestrated, in part, by complex interacting signals emanating from the bone marrow microenvironment, it is not surprising that conditions that disturb bone marrow structure inevitably disrupt both the numbers and lineage-fates of these key blood cell progenitors. In addition to the increased adipose burden in visceral and subcutaneous compartments, obesity causes a marked increase in the size and number of adipocytes encroaching into the bone marrow space, almost certainly disturbing HSC interactions with neighbouring cells, which include osteoblasts, osteoclasts, mesenchymal cells and endothelial cells. As the global obesity pandemic grows, the short-term and long-term consequences of increased bone marrow adiposity on HSC lineage selection and immune function remain uncertain. This Review discusses the differentiation and function of haematopoietic cell populations, the principal physicochemical components of the bone marrow niche, and how this environment influences HSCs and haematopoiesis in general. The effect of adipocytes and adiposity on HSC and progenitor cell populations is also discussed, with the goal of understanding how obesity might compromise the core haematopoietic system.

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Figure 1: The haematopoietic niche.
Figure 2: Haematopoietic stem cell differentiation.

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References

  1. Withrow, D. & Alter, D. A. The economic burden of obesity worldwide: a systematic review of the direct costs of obesity. Obes. Rev. 12, 131–141 (2010).

    Article  Google Scholar 

  2. Haslam, D. W. & James, W. P. Obesity. Lancet 366, 1197–1209 (2005).

    Article  PubMed  Google Scholar 

  3. Ogden, C. L., Carroll, M. D., Kit, B. K. & Flegal, K. M. Prevalence of obesity in the United States, 2009–2010 [online], (2012).

  4. Lazar, M. A. How obesity causes diabetes: not a tall tale. Science 307, 373–375 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Cara, J. F. & Chaiken, R. L. Type 2 diabetes and the metabolic syndrome in children and adolescents. Curr. Diab. Rep. 6, 241–250 (2006).

    Article  PubMed  Google Scholar 

  6. Baker, J. L., Olsen, L. W. & Sorensen, T. I. Childhood body-mass index and the risk of coronary heart disease in adulthood. N. Engl. J. Med. 357, 2329–2337 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Freedman, D. S., Mei, Z., Srinivasan, S. R., Berenson, G. S. & Dietz, W. H. Cardiovascular risk factors and excess adiposity among overweight children and adolescents: the Bogalusa Heart Study. J. Pediatr. 150, 12–17 (2007).

    Article  PubMed  Google Scholar 

  8. Adams, K. F. et al. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N. Engl. J. Med. 355, 763–778 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Carmona, R. H. The obesity crisis in America (US Surgeon General testimony before the Subcommittee on Education Reform Committee on Education and the Workforce, United States House of Representatives) [online], (2003).

    Google Scholar 

  10. Powell, K. Obesity: the two faces of fat. Nature 447, 525–527 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Svacina, S. Treatment of obese diabetics. Adv. Exp. Med. Biol. 771, 459–464 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Karlsson, E. A. & Beck, M. A. The burden of obesity on infectious disease. Exp. Biol. Med. 235, 1412–1424 (2010).

    Article  CAS  Google Scholar 

  13. Wijga, A. et al. Comorbidities of obesity in school children: a cross-sectional study in the PIAMA birth cohort. BMC Public Health 10, 184 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Devlin, M. J. et al. Caloric restriction leads to high marrow adiposity and low bone mass in growing mice. J. Bone Miner. Res. 25, 2078–2088 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kawamoto, H., Ikawa, T., Masuda, K., Wada, H. & Katsura, Y. A map for lineage restriction of progenitors during hematopoiesis: the essence of the myeloid-based model. Immunol. Rev. 238, 23–36 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Parkin, J. & Cohen, B. An overview of the immune system. Lancet 357, 1777–1789 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Lang, R. A. et al. Transgenic mice expressing a hemopoietic growth factor gene (GM–CSF) develop accumulations of macrophages, blindness, and a fatal syndrome of tissue damage. Cell 51, 675–686 (1987).

    Article  CAS  PubMed  Google Scholar 

  18. Bonilla, F. A. & Oettgen, H. C. Adaptive immunity. J. Allergy Clin. Immunol. 125, S33–S40 (2010).

    Article  PubMed  Google Scholar 

  19. Singh, P. et al. Vaccinia virus infection modulates the hematopoietic cell compartments in the bone marrow. Stem Cells 26, 1009–1016 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cheshier, S. H., Prohaska, S. S. & Weissman, I. L. The effect of bleeding on hematopoietic stem cell cycling and self-renewal. Stem Cells Dev. 16, 707–718 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Danchakoff, V. Origin of the blood cells. Development of the haematopoietic organs and regeneration of the blood cells from the standpoint of the monophyletic school. Anat. Rec. 10, 397–413 (1916).

    Article  Google Scholar 

  22. Till, J. E. & McCulloch, E. A. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14, 213–222 (1961).

    Article  CAS  PubMed  Google Scholar 

  23. van Os, R., Kamminga, L. M. & de Haan, G. Stem cell assays: something old, something new, something borrowed. Stem Cells 22, 1181–1190 (2004).

    Article  PubMed  Google Scholar 

  24. de Bruijn, M. F., Speck, N. A., Peeters, M. C. E. & Dzierzak, E. Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo. EMBO J. 19, 2465–2474 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Morrison, S. J., Wandycz, A. M., Hemmati, H. D., Wright, D. E. & Weissman, I. L. Identification of a lineage of multipotent hematopoietic progenitors. Development 124, 1929–1939 (1997).

    CAS  PubMed  Google Scholar 

  26. Miller, P. H., Knapp, D. J. & Eaves, C. J. Heterogeneity in hematopoietic stem cell populations: implications for transplantation. Curr. Opin. Hematol. 20, 257–264 (2013).

    Article  PubMed  Google Scholar 

  27. Ema, H., Morita, Y. & Suda, T. Heterogeneity and hierarchy of hematopoietic stem cells. Exp. Hematol. 42, 74–82 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Akashi, K., Traver, D., Miyamoto, T. & Weissman, I. L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Zhu, J. & Emerson, S. G. Hematopoietic cytokines, transcription factors and lineage commitment. Oncogene 21, 3295–3313 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Oburoglu, L. et al. Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification. Cell Stem Cell 15, 169–184 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Teles, J. et al. Transcriptional regulation of lineage commitment—a stochastic model of cell fate decisions. PLoS Comput. Biol. 9, e1003197 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sanjuan-Pla, A. et al. Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy. Nature 502, 232–236 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Dzierzak, E. & Speck, N. A. Of lineage and legacy: the development of mammalian hematopoietic stem cells. Nat. Immunol. 9, 129–136 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Metcalf, D. Concise review: hematopoietic stem cells and tissue stem cells: current concepts and unanswered questions. Stem Cells 25, 2390–2395 (2007).

    Article  PubMed  Google Scholar 

  35. Carnot, P. & Deflandre, C. Sur l'activité hémopoiétique de sérum au cours de la régenération du sang [French]. C.R. Acad. Sci. 143, 384–386 (1906).

    CAS  Google Scholar 

  36. Jacobson, L. O., Goldwasser, E., Fried, W. & Plzak, L. Role of the kidney in erythropoiesis. Nature 179, 633–634 (1957).

    Article  CAS  PubMed  Google Scholar 

  37. Kaushansky, K. Lineage-specific hematopoietic growth factors. N. Engl. J. Med. 354, 2034–2045 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Lennartsson, J. & Rönnstrand, L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol. Rev. 92, 1619–1649 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Kirito, K., Fox, N. & Kaushansky, K. Thrombopoietin induces HOXA9 nuclear transport in immature hematopoietic cells: potential mechanism by which the hormone favorably affects hematopoietic stem cells. Mol. Cell. Biol. 24, 6751–6762 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Furitsu, T. et al. Identification of mutations in the coding sequence of the proto-oncogene c-Kit in a human mast cell leukemia cell line causing ligand-independent activation of c-Kit product. J. Clin. Invest. 92, 1736–1744 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pardanani, A. D. et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1,182 patients. Blood 108, 3472–3476 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Kiel, M. J. & Morrison, S. J. Uncertainty in the niches that maintain haematopoietic stem cells. Nat. Rev. Immunol. 8, 290–301 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Challen, G. A., Boles, N., Lin, K. K. & Goodell, M. A. Mouse hematopoietic stem cell identification and analysis. Cytometry A 75, 14–24 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Frisch, B. J., Porter, R. L. & Calvi, L. M. Hematopoietic niche and bone meet. Curr. Opin. Support. Palliat. Care 2, 211–217 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Arai, F. et al. Tie2/Angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Tzeng, Y.-S. et al. Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression. Blood 117, 429–439 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Weber, J. M. & Calvi, L. M. Notch signaling and the bone marrow hematopoietic stem cell niche. Bone 46, 281–285 (2010).

    Article  CAS  PubMed  Google Scholar 

  50. Varnum-Finney, B. et al. Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells. J. Clin. Invest. 121, 1207–1216 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chiba, H. et al. Diabetes impairs the interactions between long-term hematopoietic stem cells and osteopontin-positive cells in the endosteal niche of mouse bone marrow. Am. J. Physiol. Cell Physiol. 305, C693–C703 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fox, N., Priestley, G., Papayannopoulou, T. & Kaushansky, K. Thrombopoietin expands hematopoietic stem cells after transplantation. J. Clin. Invest. 110, 389–394 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang, L. D. & Wagers, A. J. Dynamic niches in the origination and differentiation of haematopoietic stem cells. Nat. Rev. Mol. Cell Biol. 12, 643–655 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Almeida, M. Aging mechanisms in bone. Bonekey Rep. 1, 102 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Bouxsein, M. L. & Rosen, C. J. Mechanisms of disease: is osteoporosis the obesity of bone? Nat. Clin. Pract. Rheumatol. 2, 35–43 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Manolagas, S. C. & Almeida, M. Gone with the Wnts: β-catenin, T-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism. Mol. Endocrinol. 21, 2605–2614 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Chambers, S. & Goodell, M. Hematopoietic stem cell aging: wrinkles in stem cell potential. Stem Cell Rev. Rep. 3, 201–211 (2007).

    Article  CAS  Google Scholar 

  58. Wilson, A., Laurenti, E. & Trumpp, A. Balancing dormant and self-renewing hematopoietic stem cells. Curr. Opin. Genet. Dev. 19, 461–468 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Greenbaum, A. et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495, 227–230 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mendez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nuttall, M. et al. Adipocytes and the regulation of bone remodeling: a balancing act. Calcif. Tissue Int. 94, 78–87 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Chen, J.-R. et al. Obesity reduces bone density associated with activation of PPARγ and suppression of Wnt/β-catenin in rapidly growing male rats. PLoS ONE 5, e13704 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Keats, E. C., Dominguez, J. M., Grant, M. B. & Khan, Z. A. Switch from canonical to noncanonical Wnt signaling mediates high glucose-induced adipogenesis. Stem Cells 32, 1649–1660 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. da Silva Meirelles, L., Chagastelles, P. C. & Nardi, N. B. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J. Cell Sci. 119, 2204–2213 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Karp, J. M. & Leng Teo, G. S. Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4, 206–216 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Kollet, O. et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat. Med. 12, 657–664 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Halade, G. V., El Jamali, A., Williams, P. J., Fajardo, R. J. & Fernandes, G. Obesity-mediated inflammatory microenvironment stimulates osteoclastogenesis and bone loss in mice. Exp. Gerontol. 46, 43–52 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Lymperi, S., Ersek, A., Ferraro, F., Dazzi, F. & Horwood, N. J. Inhibition of osteoclast function reduces hematopoietic stem cell numbers in vivo. Blood 117, 1540–1549 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Silver, I. A., Murrills, R. J. & Etherington, D. J. Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Exp. Cell Res. 175, 266–276 (1988).

    Article  CAS  PubMed  Google Scholar 

  71. Adams, G. B. et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439, 599–603 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Xie, Y. et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature 457, 97–101 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Kiel, M. J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Kiel, M. J., Radice, G. L. & Morrison, S. J. Lack of evidence that hematopoietic stem cells depend on N-cadherin-mediated adhesion to osteoblasts for their maintenance. Cell Stem Cell 1, 204–217 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Garrett, R. W. & Emerson, S. G. Bone and blood vessels: the hard and the soft of hematopoietic stem cell niches. Cell Stem Cell 4, 503–506 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Ding, L., Saunders, T. L., Enikolopov, G. & Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ding, L. & Morrison, S. J. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495, 231–235 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ellis, S. L. et al. The relationship between bone, hemopoietic stem cells, and vasculature. Blood 118, 1516–1524 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Kunisaki, Y. et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502, 637–643 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wu, J. Y. et al. Osteoblastic regulation of B lymphopoiesis is mediated by Gsα-dependent signaling pathways. Proc. Natl Acad. Sci. USA 105, 16976–16981 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Tokoyoda, K., Egawa, T., Sugiyama, T., Choi, B.-I. & Nagasawa, T. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 20, 707–718 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Aguila, H. L. et al. Osteoblast-specific overexpression of human interleukin-7 rescues the bone mass phenotype of interleukin-7-deficient female mice. J. Bone Miner. Res. 27, 1030–1042 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Wu, J. Y., Scadden, D. T. & Kronenberg, H. M. Role of the osteoblast lineage in the bone marrow hematopoietic niches. J. Bone Miner. Res. 24, 759–764 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Griffith, J. F. et al. Bone marrow fat content in the elderly: a reversal of sex difference seen in younger subjects. J. Magn. Reson. Imaging 36, 225–230 (2012).

    Article  PubMed  Google Scholar 

  85. Koppen, A. & Kalkhoven, E. Brown vs white adipocytes: the PPARγ coregulator story. FEBS Lett. 584, 3250–3259 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Tang, Q. Q. & Lane, M. D. Adipogenesis: from stem cell to adipocyte. Annu. Rev. Biochem. 81, 715–736 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. Ahmadian, M., Wang, Y. & Sul, H. S. Lipolysis in adipocytes. Int. J. Biochem. Cell Biol. 42, 555–559 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Rosen, E. D. & MacDougald, O. A. Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biol. 7, 885–896 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Jo, J. et al. Hypertrophy and/or hyperplasia: dynamics of adipose tissue growth. PLoS Comput. Biol. 5, e1000324 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Strissel, K. J. et al. Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 56, 2910–2918 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Zeyda, M. & Stulnig, T. M. Obesity, inflammation, and insulin resistance: a mini-review. Gerontology 55, 379–386 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Yang, H. et al. Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance. J. Immunol. 185, 1836–1845 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Ong, W. K. & Sugii, S. Adipose-derived stem cells: fatty potentials for therapy. Int. J. Biochem. Cell Biol. 45, 1083–1086 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Han, J. et al. Adipose tissue is an extramedullary reservoir for functional hematopoietic stem and progenitor cells. Blood 115, 957–964 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Grenier, G. et al. Resident endothelial precursors in muscle, adipose, and dermis contribute to postnatal vasculogenesis. Stem Cells 25, 3101–3110 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Lin, R.-Z. et al. Human white adipose tissue vasculature contains endothelial colony-forming cells with robust in vivo vasculogenic potential. Angiogenesis 16, 735–744 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Poglio, S. et al. Adipose tissue as a dedicated reservoir of functional mast cell progenitors. Stem Cells 28, 2065–2072 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Heneidi, S. et al. Awakened by cellular stress: isolation and characterization of a novel population of pluripotent stem cells derived from human adipose tissue. PLoS ONE 8, e64752 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Nishiwaki, S. et al. Efficacy and safety of human adipose tissue-derived mesenchymal stem cells for supporting hematopoiesis. Int. J. Hematol. 96, 295–300 (2012).

    Article  PubMed  Google Scholar 

  102. Poglio, S. et al. In situ production of innate immune cells in murine white adipose tissue. Blood 120, 4952–4962 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Ibrahim, M. M. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes. Rev. 11, 11–18 (2010).

    Article  PubMed  Google Scholar 

  104. Sniderman, A. D., Bhopal, R., Prabhakaran, D., Sarrafzadegan, N. & Tchernof, A. Why might South Asians be so susceptible to central obesity and its atherogenic consequences? The adipose tissue overflow hypothesis. Int. J. Epidemiol. 36, 220–225 (2007).

    Article  PubMed  Google Scholar 

  105. Joe, A. W., Yi, L., Even, Y., Vogl, A. W. & Rossi, F. M. Depot-specific differences in adipogenic progenitor abundance and proliferative response to high-fat diet. Stem Cells 27, 2563–2570 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Krings, A. et al. Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes. Bone 50, 546–552 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Lecka-Czernik, B. Marrow fat metabolism is linked to the systemic energy metabolism. Bone 50, 534–539 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Saric, M. & Kronzon, I. Aortic atherosclerosis and embolic events. Curr. Cardiol. Rep. 14, 342–349 (2012).

    Article  PubMed  Google Scholar 

  109. Ibrahim, S. H., Kohli, R. & Gores, G. J. Mechanisms of lipotoxicity in NAFLD and clinical implications. J. Pediatr. Gastroenterol. Nutr. 53, 131–140 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bredella, M. A. et al. Vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 in obese women. Obesity 19, 49–53 (2011).

    Article  CAS  PubMed  Google Scholar 

  111. Newton, A., L, Hanks, L., J., Davis, M. & Casazza, K. The relationships among total body fat, bone mineral content and bone marrow adipose tissue in early-pubertal girls. Bonekey Rep. 2, 315 (2013).

    Article  Google Scholar 

  112. Cohen, A. et al. Abdominal fat is associated with lower bone formation and inferior bone quality in healthy premenopausal women: a transiliac bone biopsy study. J. Clin. Endocrinol. Metab. 98, 2562–2572 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Trudel, G. et al. Bone marrow fat accumulation after 60 days of bed rest persisted 1 year after activities were resumed along with hemopoietic stimulation: the Women International Space Simulation for Exploration study. J. Appl. Physiol. 107, 540–548 (2009).

    Article  PubMed  Google Scholar 

  114. Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259–263 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Biro, F. M. & Wien, M. Childhood obesity and adult morbidities. Am. J. Clin. Nutr. 91, 1499S–1505S, (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Dixit, V. D. Adipose–immune interactions during obesity and caloric restriction: reciprocal mechanisms regulating immunity and health span. J. Leukoc. Biol. 84, 882–89 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mertz, D. et al. Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis. BMJ 347, f5061 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Falagas, M. E. & Kompoti, M. Obesity and infection. Lancet Infect. Dis. 6, 438–446 (2006).

    Article  PubMed  Google Scholar 

  119. Mancuso, P. Obesity and respiratory infections: does excess adiposity weigh down host defense? Pulm. Pharmacol. Ther. 26, 412–419 (2013).

    Article  CAS  PubMed  Google Scholar 

  120. Huttunen, R. & Syrjanen, J. Obesity and the risk and outcome of infection. Int. J. Obes. 37, 333–340 (2013).

    Article  CAS  Google Scholar 

  121. Choban, P. S., Heckler, R., Burge, J. C. & Flancbaum, L. Increased incidence of nosocomial infections in obese surgical patients. Am. Surg. 61, 1001–1005 (1995).

    CAS  PubMed  Google Scholar 

  122. Dossett, L. A. et al. Obesity and site-specific nosocomial infection risk in the intensive care unit. Surg. Infect. 10, 137–142 (2009).

    Article  Google Scholar 

  123. Yang, H. et al. Obesity accelerates thymic aging. Blood 114, 3803–3812 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Chan, M. E., Adler, B. J., Green, D. E. & Rubin, C. T. Bone structure and B-cell populations, crippled by obesity, are partially rescued by brief daily exposure to low-magnitude mechanical signals. FASEB J. 26, 4855–4863 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Karlsson, E. A., Sheridan, P. A. & Beck, M. A. Diet-induced obesity in mice reduces the maintenance of influenza-specific CD8+ memory T cells. J. Nutr. 140, 1691–1697 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Karlsson, E. A., Sheridan, P. A. & Beck, M. A. Diet-induced obesity impairs the T cell memory response to influenza virus infection. J. Immunol. 184, 3127–3133 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Smith, A. G., Sheridan, P. A., Harp, J. B. & Beck, M. A. Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. J. Nutr. 137, 1236–1243 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Yokota, T. et al. Adiponectin, a fat cell product, influences the earliest lymphocyte precursors in bone marrow cultures by activation of the cyclooxygenase–prostaglandin pathway in stromal cells. J. Immunol. 171, 5091–5099 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Bilwani, F. A. & Knight, K. L. Adipocyte-derived soluble factor(s) inhibits early stages of B lymphopoiesis. J. Immunol. 189, 4379–4386 (2012).

    Article  CAS  PubMed  Google Scholar 

  130. Pini, M., Rhodes, D. H. & Fantuzzi, G. Hematological and acute-phase responses to diet-induced obesity in IL-6 KO mice. Cytokine 56, 708–716 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zaldivar, F. et al. Body fat and circulating leukocytes in children. Int. J. Obes. 30, 906–911 (2006).

    Article  CAS  Google Scholar 

  132. Inzaugarat, M. E. et al. Alterations in innate and adaptive immune leukocytes are involved in paediatric obesity. Pediatr. Obes. http://dx.doi.org/10.1111/j.2047-6310.2013.00179.x.

  133. Viardot, A. et al. Obesity is associated with activated and insulin resistant immune cells. Diabetes Metab. Res. Rev. 28, 447–454 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Wagner, N.-M. et al. Circulating regulatory T cells are reduced in obesity and may identify subjects at increased metabolic and cardiovascular risk. Obesity 21, 461–468 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Lynch, L. A. et al. Are natural killer cells protecting the metabolically healthy obese patient? Obesity 17, 601–605 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Zhu, R. J., Wu, M. Q., Li, Z. J., Zhang, Y. & Liu, K. Y. Hematopoietic recovery following chemotherapy is improved by BADGE-induced inhibition of adipogenesis. Int. J. Hematol. 97, 58–72 (2013).

    Article  CAS  PubMed  Google Scholar 

  137. Green, D. E., Adler, B. J., Chan, M. E. & Rubin, C. T. Devastation of adult stem cell pools by irradiation precedes collapse of trabecular bone quality and quantity. J. Bone Miner. Res. 27, 749–759 (2011).

    Article  Google Scholar 

  138. Green, D. E. et al. Altered composition of bone as triggered by irradiation facilitates the rapid erosion of the matrix by both cellular and physicochemical processes. PLoS ONE 8, e64952 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Adler, B. J., Green, D. E., Pagnotti, G. M., Chan, M. E. & Rubin, C. T. High fat diet rapidly suppresses B lymphopoiesis by disrupting the supportive capacity of the bone marrow niche. PLoS ONE 9, e90639 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Claycombe, K., King, L. E. & Fraker, P. J. A role for leptin in sustaining lymphopoiesis and myelopoiesis. Proc. Natl Acad. Sci. USA 105, 2017–2021 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Trottier, M. D., Naaz, A., Li, Y. & Fraker, P. J. Enhancement of hematopoiesis and lymphopoiesis in diet-induced obese mice. Proc. Natl Acad. Sci. USA 109, 7622–7629 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Spindler, T. J., Tseng, A. W., Zhou, X. & Adams, G. B. Adipocytic cells augment the support of primitive hematopoietic cells in vitro but have no effect in the bone marrow niche under homeostatic conditions. Stem Cells Dev. 23, 434–441 (2014).

    Article  CAS  PubMed  Google Scholar 

  143. Chitteti, B. R. et al. Impact of interactions of cellular components of the bone marrow microenvironment on hematopoietic stem and progenitor cell function. Blood 115, 3239–3248 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Pratley, R. E., Wilson, C. & Bogardus, C. Relation of the white blood cell count to obesity and insulin resistance: effect of race and gender. Obes. Res. 3, 563–571 (1995).

    Article  CAS  PubMed  Google Scholar 

  145. Herishanu, Y., Rogowski, O., Polliack, A. & Marilus, R. Leukocytosis in obese individuals: possible link in patients with unexplained persistent neutrophilia. Eur. J. Haematol. 76, 516–520 (2006).

    Article  PubMed  Google Scholar 

  146. Procaccini, C., Jirillo, E. & Matarese, G. Leptin as an immunomodulator. Mol. Aspects Med. 33, 35–45, (2012).

    Article  CAS  PubMed  Google Scholar 

  147. Carbone, F., La Rocca, C. & Matarese, G. Immunological functions of leptin and adiponectin. Biochimie 94, 2082–2088 (2012).

    Article  CAS  PubMed  Google Scholar 

  148. do Carmo, L. S. et al. A high-fat diet increases interleukin-3 and granulocyte colony-stimulating factor production by bone marrow cells and triggers bone marrow hyperplasia and neutrophilia in Wistar rats. Exp. Biol. Med. 238, 375–384 (2013).

    Article  CAS  Google Scholar 

  149. Rosen, C. J., Ackert-Bicknell, C., Rodriguez, J. P. & Pino, A. M. Marrow fat and the bone microenvironment: developmental, functional, and pathological implications. Crit. Rev. Eukaryot. Gene Expr. 19, 109–124 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Moerman, E. J., Teng, K., Lipschitz, D. A. & Lecka-Czernik, B. Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-γ2 transcription factor and TGF-β/BMP signaling pathways. Aging Cell 3, 379–389 (2004).

    Article  CAS  PubMed  Google Scholar 

  151. Villareal, D. T. et al. Weight loss, exercise, or both and physical function in obese older adults. N. Engl. J. Med. 364, 1218–1229 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Foster-Schubert, K. E. et al. Effect of diet and exercise, alone or combined, on weight and body composition in overweight-to-obese postmenopausal women. Obesity (Silver Spring) 20, 1628–1638 (2012).

    Article  CAS  Google Scholar 

  153. Church, T., Earnest, C. P., Skinner, J. S. & Blair, S. N. Effects of different doses of physical activity on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women with elevated blood pressure: a randomized controlled trial. JAMA 297, 2081–2091 (2007).

    Article  CAS  PubMed  Google Scholar 

  154. Pescatello, L. S. et al. Exercise and hypertension. Med. Sci. Sports Exerc. 36, 533–553 (2004).

    Article  PubMed  Google Scholar 

  155. Fealy, C. E. et al. Short-term exercise reduces markers of hepatocyte apoptosis in nonalcoholic fatty liver disease. J. Appl. Physiol. 113, 1–6 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Rantalainen, T. et al. Differential effects of exercise on tibial shaft marrow density in young female athletes. J. Clin. Endocrinol. Metab. 98, 2037–2044 (2013).

    Article  CAS  PubMed  Google Scholar 

  157. Sikiö, M. et al. Influence of exercise loading on magnetic resonance image texture of thigh soft tissues. Clin. Physiol. Funct. Imaging 34, 370–376 (2013).

    Article  PubMed  Google Scholar 

  158. Styner, M. et al. Bone marrow fat accumulation accelerated by high fat diet is suppressed by exercise. Bone 64, 39–46 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Menagh, P. J. et al. Growth hormone regulates the balance between bone formation and bone marrow adiposity. J. Bone and Miner. Res. 25, 757–768 (2010).

    CAS  Google Scholar 

  160. Smilios, I., Tsoukos, P., Zafeiridis, A., Spassis, A. & Tokmakidis, S. P. Hormonal responses after resistance exercise performed with maximum and submaximum movement velocities. Appl. Physiol. Nutr. Metab. 39, 351–357 (2013).

    Article  CAS  PubMed  Google Scholar 

  161. Kim, E. et al. Hormone responses to an acute bout of low intensity blood flow restricted resistance exercise in college-aged females. J. Sports Sci. Med. 13, 91–96 (2014).

    PubMed  PubMed Central  Google Scholar 

  162. Akune, T. et al. PPARγ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J. Clin. Invest. 113, 846–855 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Chen, Y. et al. Treadmill training prevents bone loss by inhibition of PPARγ expression but not promoting of Runx2 expression in ovariectomized rats. Eur. J. Appl. Physiol. 111, 1759–1767 (2011).

    Article  CAS  PubMed  Google Scholar 

  164. Rubin, C. T. et al. Adipogenesis is inhibited by brief, daily exposure to high-frequency, extremely low-magnitude mechanical signals. Proc. Natl Acad. Sci. USA 104, 17879–17884 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Luu, Y. K. et al. Mechanical stimulation of mesenchymal stem cell proliferation and differentiation promotes osteogenesis while preventing dietary-induced obesity. J. Bone Miner. Res. 24, 50–61 (2009).

    Article  CAS  PubMed  Google Scholar 

  166. Case, N. et al. Mechanical input restrains PPARγ2 expression and action to preserve mesenchymal stem cell multipotentiality. Bone 52, 454–464 (2013).

    Article  CAS  PubMed  Google Scholar 

  167. Sen, B. et al. Mechanical strain inhibits adipogenesis in mesenchymal stem cells by stimulating a durable β-catenin signal. Endocrinology 149, 6065–6075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Case, N. et al. Mechanical activation of β-catenin regulates phenotype in adult murine marrow-derived mesenchymal stem cells. J. Orthop. Res. 28, 1531–1538 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Wang, J. et al. E3-ligase Skp2 regulates β-catenin expression and maintains hematopoietic stem cell homing. Biochem. Biophys. Res. Commun. 445, 566–571 (2014).

    Article  CAS  PubMed  Google Scholar 

  170. Dolnikov, A. et al. GSK-3β inhibition promotes early engraftment of ex vivo-expanded haematopoietic stem cells. Cell Prolif. 47, 113–123 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Lento, W. et al. Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration. Genes Dev. 28, 995–1004 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge support from the NIH (grants EB014351 and AR43498).

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Authors and Affiliations

  1. Department of Biomedical Engineering, Bioengineering Building, Stony Brook University, Stony Brook, 11794–5281, NY, USA

    Benjamin J. Adler & Clinton T. Rubin

  2. Department of Medicine, Health Sciences Centre, Stony Brook University, Stony Brook, 11794–8430, NY, USA

    Kenneth Kaushansky

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Contributions

B.J.A., K.K. and C.T.R. made substantial contributions to discussions of the content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Clinton T. Rubin.

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Competing interests

C.T.R. declares that he is the Scientific Director of Marodyne Medical and is named as an inventor on several patent applications related to the use of mechanical signals to influence stem cell fate selection, including: “A unique biomechanical treatment for the suppression of diabetes and obesity (PCT/US2007/069,154)”; “Compositions and methods for enhancing the response to pharmaceutical agents and mechanical signals (PCT/US2011/056,289)”; and “Methods of applying physical stimuli to cells (PCT/US2009/035,777)”. The other authors declare no competing interests.

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Adler, B., Kaushansky, K. & Rubin, C. Obesity-driven disruption of haematopoiesis and the bone marrow niche. Nat Rev Endocrinol 10, 737–748 (2014). https://doi.org/10.1038/nrendo.2014.169

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