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Revista Brasileira de Hematologia e Hemoterapia

Print version ISSN 1516-8484

Rev. Bras. Hematol. Hemoter. vol.36 no.2 São José do Rio Preto Mar./Apr. 2014 

Review Article

Obesity and inflammation and the effect on the hematopoietic system

Bruno Deltreggia Benites* 

Simone Cristina Olenscki Gilli

Sara Teresinha Olalla Saad

1Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil


Bone marrow is organized in specialized microenvironments known as 'marrow niches'. These are important for the maintenance of stem cells and their hematopoietic progenitors whose homeostasis also depends on other cell types present in the tissue. Extrinsic factors, such as infection and inflammatory states, may affect this system by causing cytokine dysregulation (imbalance in cytokine production) and changes in cell proliferation and self-renewal rates, and may also induce changes in the metabolism and cell cycle. Known to relate to chronic inflammation, obesity is responsible for systemic changes that are best studied in the cardiovascular system. Little is known regarding the changes in the hematopoietic system induced by the inflammatory state carried by obesity or the cell and molecular mechanisms involved. The understanding of the biological behavior of hematopoietic stem cells under obesity-induced chronic inflammation could help elucidate the pathophysiological mechanisms involved in other inflammatory processes, such as neoplastic diseases and bone marrow failure syndromes.

Key words: Obesity; Inflammation; Hematopoietic system


Bone marrow is an animal tissue with one of the highest cell proliferation rates. It gives rise to components of all hematopoietic and immune system lineages. In humans, approximately 1 × 1011 to 1 × 1012 mature blood cells are produced daily, due to the division and proliferation of a population of hematopoietic stem cells (HSCs), with a unique capacity for self-renewal and multilineage differentiation.1

The organization of bone marrow in specialized microenvironments, the 'marrow niches,' is important for the maintenance of hematopoietic stem and progenitor cells, as well as their intramedullary localization and cell cycle phase.2 Although the majority of HSCs were originally believed to be quiescent, many studies have demonstrated that these cells are actually cycling, although very slowly, suggesting a state of dormancy.3 They are activated for more intense proliferation and differentiation under stress conditions, when demands are higher (i.e. during infection) or for replacement of cells eliminated by cell death.2 In fact, many progenitors already committed to specific lineages appear to cycle actively. This condition strengthens the idea that the proliferation of HSCs and their progenitors is regulated by factors external to the cell itself, which must involve the action of different niches.4-6 Osteoblasts, endothelial cells, macrophages and other more primitive mesenchymal cells exert, by mechanisms not yet fully elucidated, a direct effect on the control of hematopoiesis.7

The identification and distribution of bone marrow niches has been the subject of intense scientific debate. For example, HSCs have been shown to be in direct contact with a population of osteoblasts, which delimit the bone marrow surface. Osteoblasts are characterized by their fusiform shape and high expression of N-cadherin, called SNO cells (spindle-shaped N-cadherin+ CD45- osteoplastic cells), which form the so-called 'endosteal niche'.8 Many HSCs are also close to the sinusoidal endothelium, suggesting that endothelial cells could also create clusters for HSCs (the vascular niche).9 Another recently discovered cell type that seems to play a key role in the maintenance of HSCs is the 'CAR cell' (CXCL12-abundant reticular cell), a small population of reticular cells expressing high amounts of CXCL12.10 CXCR4, the CXCL12 receptor, has been shown to be critical to maintain the HSCs pool and progenitor B cells in the bone marrow in direct contact with CAR cells, suggesting an important role of these cells in hematopoietic regulation.11

Knowledge of the different rates of stem cell proliferation and their regulation by other cell types in homeostasis has raised questions regarding possible changes in these mechanisms and the relationship between infection and the hematopoietic niche along with HSC modulation. Factors such as the association between HSC exposure to toll-like receptor (TLR) ligands and osteoclasts maturation,12 in addition to the increase in granulocyte-colony stimulating factor (G-CSF) expression and the increase in the peripheral mobilization of HSCs,13 reinforce the association between infection and modulation of HSC biology.

In addition to the direct effects caused by the pathogens or pathogenic particles, changes in the clusters of HSCs and their biological activity in response to infection may also indirectly be mediated by pro-inflammatory cytokines. In a recent study, Chen et al. demonstrated that HSCs exposed to a combination of lipopolysaccharide-induced proinflammatory cytokines, Interleukin (IL)-6, tumor necrosis factor (TNF) and chemokine ligand 2 (CCL2), showed a decrease in the potential of marrow repopulation and long-term engraftment, while maintaining the proliferation potential.14 In a Mycobacterium avium infection model in mice, activation of HSCs was initiated by interferon-gamma (INF-g) signaling.15 However, high levels of INF-g are known to be capable of inducing apoptosis in hematopoietic cells, leading to bone marrow hypocellularity. In fact, exposure of human CD34+ cells to INF-g leads to the expression of pro-apoptotic genes in vitro16 and continuous exposure to INF-g has also been related to a reduction in colony formation of human bone marrow cells in cultures.17

The duration and conditions of exposure to interferon and other inflammatory cytokines could be crucial factors regulating the biological activity of HSCs. Different responses to inflammatory cytokines may explain, for example, the mechanisms that lead to some bone marrow failure syndromes. It is because of this that these factors represent important areas for future scientific research.

Obesity and chronic inflammation and the hematopoietic system

The association between obesity and low-grade chronic inflammation has been demonstrated in numerous studies.18-20 Inflammation has been implicated in the pathophysiology of many morbid complications observed in most obese individuals, through mechanisms that go beyond a positive caloric balance, such as the release of adipokines and interleukins.21 Originally considered a mechanism of energy reservoir, adipose tissue is now recognized as one of the body's largest endocrine organs, secreting a variety of substances that exert multiple regulatory activities involving glucose homeostasis, immune function and metabolism.19 Given the systemic nature of this process, it is plausible that changes in the hematopoietic and immune systems may occur due to obesity.

Experiments involving animal models have demonstrated that high-fat diet (HFD)-induced obesity is associated with high levels of acute-phase reactants and leukocytosis, in addition to higher bone marrow cellularity, mainly due to polymorphonuclear expansion.22 One possible mechanism postulated to explain the augment in granulopoiesis is an increased production of G-CSF by bone marrow cells in the obese group compared to controls.23 Moreover, mesenchymal stem cells (MSC) of HFD rats express considerably higher amounts of nuclear Factor kappa β (NF-kβ) as well as tumor necrosis factor alpha (TNFα), IL-1 and IL-6, which can inhibit adipocyte differentiation of MSC thus shifting bone marrow differentiation towards osteoblasts. This mechanism could be responsible for niche alterations affecting marrow microenvironments and consequently destabilizing hematopoietic cell numbers and peripheral mobilization in the inflammatory state.22

In humans, obesity is associated with a peripheral blood increase of white blood cell counts, correlating with increased levels of C-reactive protein and decreased IL-10.24,25 Disturbances in erythropoiesis have also been described, including anemia and alterations in iron homeostasis.26 Interestingly, increased levels of IL-6 and leptin induced by inflammation result in the release of hepcidin from the liver and adipose tissue.27,28

Hepcidin is an important regulator of iron homeostasis, inhibiting iron absorption by enterocytes and the sequestration of iron by macrophages that result in restricted erythropoiesis leading to mild/moderate anemia.29 Obesity is associated with high levels of hepcidin, independently of the presence of liver alterations,27 suggesting that the anemia experienced by obese individuals may be secondary to the inflammatory status (anemia of chronic disease), in addition to the direct effects of cytokines on the proliferation and differentiation of erythroid progenitors.

In fact, studies involving patients undergoing bariatric surgery as treatment of obesity have clarified the fact that anemia in this population cannot be explained solely on the basis of iron availability and nutritional status.30,31 Drygalski et al. assessed 1125 obese patients before and after bariatric surgery for the prevalence of anemia and the depletion of body iron stores. The baseline incidence of anemia was higher than expected and increased significantly after surgery as the overall iron bioavailability improved significantly with pronounced weight loss, possibly following the reduction in inflammation.31 Gastric bypass surgery was also associated with a generalized decrease in the white blood cell and platelet counts, although not clinically important.32 These findings suggest that generalized suppression of hematopoiesis might occur after surgery, revealing a possible hyperproliferative state triggered by inflammation in obese patients.

Bioenergetic organization of stem cells in obesity

One of the striking features of the HSC niche is its low oxygen tension, yielding the term 'hypoxic niche.' This microenvironment of low O2 concentrations appears not only to be well tolerated by HSCs but also essential for keeping their self-renewal and differentiating properties.33-36

Through mitochondrial metabolism, O2 generates reactive oxygen species (ROS) that, at increased levels, lead to cell dysfunction and aging, disrupting tissue homeostasis. The aberrant production of large quantities of ROS in mitochondria has been implicated in the pathophysiology of several chronic degenerative processes, such as Parkinson and Alzheimer's diseases,37 and this seems to act in deleterious ways also in obesity, diabetes and metabolic syndrome.38 Thus, the distribution of stem cells in hypoxic niches with reduced ROS production seems clearly advantageous.39 Maintaining viability in a hypoxic environment, however, could require HSCs to have great metabolic adaptions; these mechanisms however are not yet fully known.

Cellular bioenergetic homeostasis is determined by the fraction of cellular adenosine triphosphate (ATP) produced by glycolysis or mitochondrial oxidative phosphorylation (OXPHOS). In some situations, as previously described in tumors, bioenergetic organization is different from normal cells', wherein the method of ATP production switches progressively from oxidative phosphorylation to glycolysis, which is called the 'Warburg effect'.40 This distinct metabolism results from the dysregulation of multiple oncogenes and tumor suppressor genes, whose final target is the glycolytic pathway,41 in addition to defects in the mitochondria itself. This mechanism may be responsible for better adaptation of tumor cells to microenvironments with chronic or intermittent hypoxia, in addition to reducing mitochondria-dependent cell death, facilitating invasion and metastasis.42

Suppression of oxidative phosphorylation generates signals to adenosine monophosphate-activated protein kinases (AMPK), which reprogram cellular metabolism, stimulating glycolysis through increased cellular glucose uptake and activating 6-fosfofruto-2-kinase. Meanwhile, activated AMPK also inactivates enzymes responsible for ATP consumption including, for example, those involved in fatty acid and cholesterol synthesis.43 In addition to these effects, activation of AMPK also suppresses cell proliferation in normal and neoplastic tissues.44

Increased AMPK after oxidative phosphorylation suppression is known to be transient. However, whether the maintenance of anaerobic conditions after normalization of AMPK could lead to the death of these cells, or whether any such mechanism would be only the initial part of an adaptive process by giving more advantage to these tissues, is not clear yet .45

An important mechanism of adaptation to hypoxia involves hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor composed of an O2-regulated subunit (HIF-1α) and a constitutional subunit (HIF-1b).46 The two subunits are present in all human and murine tissues and are activated by O2-dependent hydroxylases. The final action occurs primarily through modulation of transcription of other genes involved in the cell metabolism.47

Another event that appears to be important for adaptation to hypoxia is the exchange of the regulatory subunit of the cytochrome c oxidase from cyclooxygenase COX4-1 to COX4-2; the latter being activated by HIF-1. Other mitochondrial proteases are also activated by HIF-1, leading to enhanced degradation of COX4-1.48 This mechanism appears to be essential for the optimal function of cytochrome c oxidase in situations of hypoxia and to reduce ROS production.

Recently, a mechanism to minimize cell damage caused by excess ROS production, dependent on the action of uncoupling proteins (UCP) has been elucidated. Part of the proton gradient used to drive the synthesis of ATP is deflected from the membrane back into the mitochondrial matrix, thereby reducing the emission of ROS, this transport is carried out by UCP 'uncoupling' the oxidative phosphorylation process.49 Three isoforms of UCP (UCP-1, -2 and -3) have been described and all appear to be activated by ROS molecules themselves, setting up a negative feedback loop.

Thus, we can speculate that obesity and its related deregulations in metabolism and inflammation may alter bone marrow niches and the energetic organization of marrow cells through pathways that have not been fully investigated until now.


Biologically, obesity is characterized by a state of chronic inflammation and its effects on the hematopoietic system, in particular on the stem cell compartment, are poorly understood. Therefore, further studies are needed to clarify the specific impact of this state at molecular and cellular levels, as well as the mechanisms involved. Long-term activation of hematopoietic stem cells during chronic inflammation may lead to the depletion of these cells or development of functional defects, such as those seen in aplastic anemia. Therefore, this area of research may also provide new evidence to understand other situations involving chronic inflammation, such as normal aging, neoplastic diseases and bone marrow failure syndromes.

The evaluation of the proliferative and self-renewal potential of hematopoietic cells, the cytokine and hematopoietic growth factor profiles of obese individuals and the bioenergetic organization of stem cells in obesity are some key points for future investigation.


Molofsky AV, Pardal R, Morrison SJ. Diverse mechanisms regulate stem cell self-renewal. Curr Opin Cell Biol. 2004;16:700-7. [ Links ]

Morrison SJ, Spradling AC. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell. 2008;132:598-611. [ Links ]

Yamazaki S, Iwama A, Takayanagi S, Eto K, Ema H, Nakauchi H. TGF-beta as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. Blood. 2009;113:1250-6. [ Links ]

Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008;135:1118-29. [ Links ]

Omatsu Y, Sugiyama T, Kohara H, Kondoh G, Fujii N, Kohno K, et al. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity. 2010;33:387-99. [ Links ]

Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118:149-61. [ Links ]

Zipori D, Duksin D, Tamir M, Argaman A, Toledo J, Malik Z. Cultured mouse marrow stromal cell lines. II. Distinct subtypes differing in morphology, collagen types, myelopoietic factors, and leukemic cell growth modulating activities. J Cell Physiol. 1985;122:81-90. [ Links ]

Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425:836-41. [ Links ]

Kiel MJ, Yilmaz OH, Iwashita T, Terhorst C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121:1109-21. [ Links ]

Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25:977-88. [ Links ]

Nagasawa T. The chemokine CXCL12 and regulation of HSC and B lymphocyte development in the bone marrow niche. Adv Exp Med Biol. 2007;602:69-75. [ Links ]

Hayashi S, Yamada T, Tsuneto M, Yamane T, Takahashi M, Shultz LD, et al. Distinct osteoclast precursors in the bone marrow and extramedullary organs characterized by responsiveness to Toll-like receptor ligands and TNF-alpha. J Immunol. 2003;171:5130-9. [ Links ]

Christopher MJ, Liu F, Hilton MJ, Long F, Link DC. Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization. Blood. 2009;114:1331-9. [ Links ]

Chen C, Liu Y, Zheng P. Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice. J Clin Invest. 2010;120:4091-101. [ Links ]

Baldridge MT, King KY, Boles NC, Weksberg DC, Goodell MA. Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature. 2010;465:793-7. [ Links ]

Zeng W, Miyazato A, Chen G, Kajigaya S, Young NS, Maciejewski JP. Interferon-gamma-induced gene expression in CD34 cells: identification of pathologic cytokine-specific signature profiles. Blood. 2006;107:167-75. [ Links ]

Selleri C, Sato T, Anderson S, Young NS, Maciejewski JP. Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol. 1995;165:538-46. [ Links ]

Ferrante AW Jr. Obesity-induced inflammation: a metabolic dialogue in the language of inflammation. J Intern Med. 2007;262:408-14. [ Links ]

Hevener AL, Febbraio MA. The 2009 stock conference report: inflammation, obesity and metabolic disease. Obes Rev. 2010;11:635-44. [ Links ]

Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860-7. [ Links ]

Bluher M. The distinction of metabolically 'healthy' from 'unhealthy' obese individuals. Curr Opin Lipidol. 2010;21:38-43. [ Links ]

Cortez M, Carmo LS, Rogero MM, Borelli P, Fock RA. A high-fat diet increases IL-1, IL-6, and TNF-alpha production by increasing NF-kappaB and attenuating PPAR-gamma expression in bone marrow mesenchymal stem cells. Inflammation. 2013;36:379-86. [ Links ]

do Carmo LS, Rogero MM, Paredes-Gamero EJ, Nogueira-Pedro A, Xavier JG, Cortez M, 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 (Maywood). 2013;238:375-84. [ Links ]

Nanji AA, Freeman JB. Relationship between body weight and total leukocyte count in morbid obesity. Am J Clin Pathol. 1985;84:346-7. [ Links ]

Pratley RE, Wilson C, Bogardus C. Relation of the white blood cell count to obesity and insulin resistance: effect of race and gender. Obes Res. 1995;3:563-71. [ Links ]

Yanoff LB, Menzie CM, Denkinger B, Sebring NG, McHugh T, Remaley AT, et al. Inflammation and iron deficiency in the hypoferremia of obesity. Int J Obes (Lond). 2007;31:1412-9. [ Links ]

Vuppalanchi R, Troutt JS, Konrad RJ, Ghabril M, Saxena R, Bell LN, et al. Serum hepcidin levels are associated with obesity but not liver disease. Obesity (Silver Spring). 2014;22:836-41. [ Links ]

Chung B, Matak P, McKie AT, Sharp P. Leptin increases the expression of the iron regulatory hormone hepcidin in HuH7 human hepatoma cells. J Nutr. 2007;137:2366-70. [ Links ]

Ganz T. Hepcidin--a regulator of intestinal iron absorption and iron recycling by macrophages. Best Pract Res Clin Haematol. 2005;18:171-82. [ Links ]

Chen M, Krishnamurthy A, Mohamed AR, Green R. Hematological disorders following gastric bypass surgery: emerging concepts of the interplay between nutritional deficiency and inflammation. Biomed Res Int. 2013;2013:205467. [ Links ]

von Drygalski A, Andris DA, Nuttleman PR, Jackson S, Klein J, Wallace JR. Anemia after bariatric surgery cannot be explained by iron deficiency alone: results of a large cohort study. Surg Obes Relat Dis. 2011;7:151-6. [ Links ]

Dallal RM, Leighton J, Trang A. Analysis of leukopenia and anemia after gastric bypass surgery. Surg Obes Relat Dis. 2012;8:164-8. [ Links ]

Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci U S A. 2007;104:5431-6. [ Links ]

Danet GH, Pan Y, Luongo JL, Bonnet DA, Simon MC. Expansion of human SCID-repopulating cells under hypoxic conditions. J Clin Invest. 2003;112:126-35. [ Links ]

Eliasson P, Jonsson JI. The hematopoietic stem cell niche: low in oxygen but a nice place to be. J Cell Physiol. 2010;222:17-22. [ Links ]

Simsek T, Kocabas F, Zheng J, Deberardinis RJ, Mahmoud AI, Olson EN, et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell. 2010;7:380-90. [ Links ]

Patten DA, Germain M, Kelly MA, Slack RS. Reactive oxygen species: stuck in the middle of neurodegeneration. J Alzheimers Dis. 2010;20(Suppl 2):S357-67. [ Links ]

Ando K, Fujita T. Metabolic syndrome and oxidative stress. Free Radic Biol Med. 2009;47:213-8. [ Links ]

Jang YY, Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood. 2007;110:3056-63. [ Links ]

Warburg O. On respiratory impairment in cancer cells. Science. 1956;124:269-70. [ Links ]

DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7:11-20. [ Links ]

Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4:891-9. [ Links ]

Almeida A, Moncada S, Bolanos JP. Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nat Cell Biol. 2004;6:45-51. [ Links ]

Motoshima H, Goldstein BJ, Igata M, Araki E. AMPK and cell proliferation--AMPK as a therapeutic target for atherosclerosis and cancer. J Physiol. 2006;574(Pt 1):63-71. [ Links ]

Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, et al. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol. 2000;10:1247-55. [ Links ]

Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92:5510-4. [ Links ]

Semenza GL. Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta. 2011;1813:1263-8. [ Links ]

Received: July 19, 2013; Accepted: November 11, 2013

*Corresponding author at: Universidade de Campinas (Unicamp) Hemocentro, 6198, Cidade Universitária Zeferino Vaz Barão Geraldo, 13081-970, Campinas, SP, Brazil E-mail address: (B.D. Benites)

Conflicts of interest The authors declare no conflicts of interest.

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