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Obesity: Effects on bone marrow homeostasis and platelet activation

  • Alicia Vauclard
    Affiliations
    Inserm U1297 and Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France
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  • Marie Bellio
    Affiliations
    Inserm U1297 and Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France
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  • Colin Valet
    Affiliations
    Inserm U1297 and Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France
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  • Maxime Borret
    Affiliations
    Inserm U1297 and Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France
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  • Bernard Payrastre
    Affiliations
    Inserm U1297 and Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France

    Laboratoire d'Hématologie, Centre de Référence des Pathologies Plaquettaires, Centre Hospitalier Universitaire, Toulouse, France
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  • Sonia Severin
    Correspondence
    Corresponding author at: Inserm U1297 and Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires, 1 Avenue Jean Poulhes BP 84225, 31432 Toulouse Cedex 4, France.
    Affiliations
    Inserm U1297 and Université Paul Sabatier, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France
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Open AccessPublished:October 16, 2022DOI:https://doi.org/10.1016/j.thromres.2022.10.008

      Abstract

      Obesity is a major health issue that can increase the risk of cardiovascular morbidity and mortality. Obesity is characterized by an elevated prothrombotic state in which dysregulated platelet activation is a major component due to accumulation of adipose depots, insulin resistance, endothelial dysfunction, low-grade chronic inflammation and oxidative stress. Obesity also alters the homeostasis of the bone marrow, the site where megakaryopoiesis and platelet production take place, which include bone marrow adipose tissue as an important constituent of this microenvironment. Here, we provide an up-to-date review focusing on bone marrow adipose tissue and the influence of obesity on megakaryocytes and platelets that increases the cardiovascular risk.

      Keywords

      1. Introduction

      Platelets are known to play a major role in hemostasis and thrombosis. They are rapidly recruited at the site of vascular injury to prevent bleeding and are now recognized as key elements in many pathophysiological processes. Platelets originate from megakaryocytes (MKs) that arise from a complex process of hematopoietic stem cell (HSC) maturation in the bone marrow (BM). Any dysfunctions in the finely-regulated process of platelet production and activation could have side effects in humans. This is the case for the metabolic perturbations of obesity, in which BM homeostasis is altered by, for instance, an amplification of bone marrow adipose tissue (BMAT) and platelets are prone to hyperactivation due to multifactorial perturbations such as accumulation of adipose depots, insulin resistance, endothelial dysfunction, low-grade chronic inflammation and oxidative stress [
      • Van Gaal L.F.
      • Mertens I.L.
      • De Block C.E.
      Mechanisms linking obesity with cardiovascular disease.
      ]. Obesity is thus currently considered an important risk factor for cardiovascular morbidity and mortality due to platelet dysfunctions. Herein, we summarize the most recent and important findings regarding the impact of obesity on megakaryopoiesis and platelet production within the BM microenvironment and on platelet activation; all these increase the thrombotic risk in obesity.

      2. Megakaryopoiesis, thrombopoiesis and platelet activation

      2.1 Primary hemostasis involves the multistep activation of platelets

      Platelets are small enucleated discoid cells (ranging from 1 to 3 μm) and the second-most abundant cell lineage in the circulation (150,000 to 400,000 platelets per μL of blood in healthy individuals) [
      • Dilworth
      • Gyde O.H.
      • Ince A.J.
      Platelet estimation in whole blood.
      ]. The abundance of platelets in circulation allows for constant surveillance of the endothelium and facilitates their role in primary hemostasis, as was described in the 19th century [
      • de Gaetano G.
      • Cerletti C.
      Platelet adhesion and aggregation and fibrin formation in flowing blood: a historical contribution by giulio bizzozero.
      ]. Since the discovery of platelet function in hemostasis, numerous studies have described the complex mechanisms underlying platelet activation. In intact blood vasculature, the endothelium constitutes a non-thrombogenic surface and releases prostaglandin I2 (PGI2) and nitric oxide (NO) to maintain circulating platelets in a resting state [
      • Ruggeri Z.M.
      Platelets in atherothrombosis.
      ]. Following vascular injury, the wounded vessel wall leads to the initial and transient adhesion (rolling) of platelets, via the binding of the glycoprotein (GP) Ib-V-IX on platelets to the von Willebrand Factor (vWF) stabilized on collagen fibers, followed by platelet firm adhesion to collagen fibers through two collagen-specific platelet receptors: GPVI and GPIaIIa (also called integrin α2β1) [
      • Stegner D.
      • Nieswandt B.
      Platelet receptor signaling in thrombus formation.
      ]. When adhering, activated platelets release autocrine soluble mediators, by secreting the content of their granules or by generating thromboxane (TX) A2, to amplify the initial platelet responses, and recruit circulating platelets [
      • Gremmel T.
      • Frelinger 3rd, A.L.
      • Michelson A.D.
      Platelet physiology.
      ]. Platelet activation is reinforced by thrombin, which is locally produced by the coagulation cascade and binds to platelets through protease-activated receptors (PARs). The functional upregulation of GPIIb-IIIa, also called αIIbβ3 integrin, on activated platelets allows thrombi growth by fibrinogen binding to adjacent platelets. Platelet thrombi by sealing the vessel lesion arrest the hemorrhage [
      • Gremmel T.
      • Frelinger 3rd, A.L.
      • Michelson A.D.
      Platelet physiology.
      ].

      2.2 Platelets originate from MKs after a multistep maturation process

      In humans, approximately 1.1011 platelets are formed every day by MKs following a finely regulated and specific maturation process called megakaryopoiesis that occurs in the BM. MKs, with a size ranging from 15 to 100 μm, are rarest cells in the BM (0.01 % of nucleated cells among BM-resident cells) [
      • Pease D.C.
      An electron microscopic study of red bone marrow.
      ,
      • Nakeff A.
      • Maat B.
      Separation of megakaryocytes from mouse bone marrow by velocity sedimentation.
      ,
      • Nakeff A.
      • van Noord M.J.
      • Blansjaar N.
      Electron microscopy of megakaryocytes in thin-layer agar cultures of mouse bone marrow.
      ]. Although BM is considered the major site of platelet production, MKs found in the lungs participate in platelet production, as was shown by two-photon intravital microscopy in mice [
      • Lefrancais E.
      • Ortiz-Munoz G.
      • Caudrillier A.
      • Mallavia B.
      • Liu F.
      • Sayah D.M.
      • Thornton E.E.
      • Headley M.B.
      • David T.
      • Coughlin S.R.
      • Krummel M.F.
      • Leavitt A.D.
      • Passegue E.
      • Looney M.R.
      The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors.
      ]. Using the same technique, a recent study showed that in response to an inflammatory trigger such as sepsis, platelets can be produced from MKs localized in the spleen [
      • Valet C.
      • Magnen M.
      • Qiu L.
      • Cleary S.J.
      • Wang K.M.
      • Ranucci S.
      • Grockowiak E.
      • Boudra R.
      • Conrad C.
      • Seo Y.
      • Calabrese D.R.
      • Greenland J.R.
      • Leavitt A.D.
      • Passegue E.
      • Mendez-Ferrer S.
      • Swirski F.K.
      • Looney M.R.
      Sepsis promotes splenic production of a protective platelet pool with high CD40 ligand expression.
      ]. These recent findings unveil a newly comprehended complexity of the site of platelet production that can impact the future function of platelets. Beyond that, recent single-cell RNA sequencing analysis in human and mouse also showed that within the BM, MKs can be divided into three subpopulations due to transcriptional heterogeneity. The first subpopulation is specifically associated with thrombopoiesis functions (i.e., it is enriched for genes implicated in platelet production and functions), with a physical proximity to sinusoidal blood vessels. The second subpopulation expresses various inflammatory markers, such as CD40L, and appears to be involved in innate and adaptive immune functions. The third subpopulation is thought to be implicated in osteoblast and HSC niche maintenance [
      • Sun S.
      • Jin C.
      • Si J.
      • Lei Y.
      • Chen K.
      • Cui Y.
      • Liu Z.
      • Liu J.
      • Zhao M.
      • Zhang X.
      • Tang F.
      • Rondina M.T.
      • Li Y.
      • Wang Q.F.
      Single-cell analysis of ploidy and the transcriptome reveals functional and spatial divergency in murine megakaryopoiesis.
      ]. This recent advance in the knowledge of MK biology allows to decipher new functions for MKs beyond its first characterized role in platelet production.
      To allow platelet release, HSCs undergo a complex maturation process transforming them into mature MKs. This maturation process is regulated at multiple levels by different cytokines, the most important of which is thrombopoietin (TPO) that binds to its specific receptor, c-Mpl [
      • Lok S.
      • Foster D.C.
      The structure, biology and potential therapeutic applications of recombinant thrombopoietin.
      ,
      • Bartley T.D.
      • Bogenberger J.
      • Hunt P.
      • Li Y.S.
      • Lu H.S.
      • Martin F.
      • Chang M.S.
      • Samal B.
      • Nichol J.L.
      • Swift S.
      • et al.
      Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor mpl.
      ,
      • Kaushansky K.
      Thrombopoiesis.
      ]. During megakaryopoiesis, HSCs undergo successive endomitosis (DNA replication without cell division), resulting in a polyploid nucleus (16 N on average and 128 N maximum). In parallel, the cells amplify the number of organelles such as mitochondria and future platelet granules and create an invaginated membrane system (also known as the demarcation membrane system, DMS) that is continuous with the plasma membrane and provides a membrane reservoir for platelet production [
      • Eckly A.
      • Heijnen H.
      • Pertuy F.
      • Geerts W.
      • Proamer F.
      • Rinckel J.Y.
      • Leon C.
      • Lanza F.
      • Gachet C.
      Biogenesis of the demarcation membrane system (DMS) in megakaryocytes.
      ]. Once mature, MKs produce long and thin cytoplasmic extensions from the DMS, called proplatelets, which cross the endothelial cell barrier to release platelets into the circulation through a combination of cytoskeletal mechanical tensions and shear forces present in the blood vessel lumen [

      A.E. Geddis , Megakaryopoiesis, Semin. Hematol. 47(3) 212-9.

      ,
      • Noetzli L.J.
      • French S.L.
      • Machlus K.R.
      New insights into the differentiation of megakaryocytes from hematopoietic progenitors.
      ,
      • Machlus K.R.
      • Italiano Jr., J.E.
      The incredible journey: from megakaryocyte development to platelet formation.
      ,
      • Machlus K.R.
      • Thon J.N.
      • Italiano Jr., J.E.
      Interpreting the developmental dance of the megakaryocyte: a review of the cellular and molecular processes mediating platelet formation.
      ]. A recent study challenges the classic schema of proplatelet-dependent platelet production and describes MK membrane budding as a direct source of platelets for daily chronic needs [
      • Potts K.S.
      • Farley A.
      • Dawson C.A.
      • Rimes J.
      • Biben C.
      • de Graaf C.
      • Potts M.A.
      • Stonehouse O.J.
      • Carmagnac A.
      • Gangatirkar P.
      • Josefsson E.C.
      • Anttila C.
      • Amann-Zalcenstein D.
      • Naik S.
      • Alexander W.S.
      • Hilton D.J.
      • Hawkins E.D.
      • Taoudi S.
      Membrane budding is a major mechanism of in vivo platelet biogenesis.
      ]. In response to acute platelet needs, another mechanism of platelet production is the MK rupture-type thrombopoiesis, which appears to be interleukin (IL)-1α-dependent and allows a twenty times higher platelet release compared to the proplatelet-type thrombopoietic process [
      • Nishimura S.
      • Nagasaki M.
      • Kunishima S.
      • Sawaguchi A.
      • Sakata A.
      • Sakaguchi H.
      • Ohmori T.
      • Manabe I.
      • Italiano Jr., J.E.
      • Ryu T.
      • Takayama N.
      • Komuro I.
      • Kadowaki T.
      • Eto K.
      • Nagai R.
      IL-1alpha induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs.
      ]. It has been recently reported in humans and mouse models that microparticles originating from circulating platelets (PMPs) directly influence MKs and their progenitors. Under conditions associated with thromboinflammation, these PMPs can support megakaryopoiesis and platelet production [
      • French S.L.
      • Butov K.R.
      • Allaeys I.
      • Canas J.
      • Morad G.
      • Davenport P.
      • Laroche A.
      • Trubina N.M.
      • Italiano J.E.
      • Moses M.A.
      • Sola-Visner M.
      • Boilard E.
      • Panteleev M.A.
      • Machlus K.R.
      Platelet-derived extracellular vesicles infiltrate and modify the bone marrow during inflammation.
      ,
      • Qu M.
      • Zou X.
      • Fang F.
      • Wang S.
      • Xu L.
      • Zeng Q.
      • Fan Z.
      • Chen L.
      • Yue W.
      • Xie X.
      • Pei X.
      Platelet-derived microparticles enhance megakaryocyte differentiation and platelet generation via miR-1915-3p.
      ]. Any dysregulations in the maturation process of MKs can directly impact the quantity and/or the quality of platelets present in circulation. This is for example the case for obesity where metabolic/inflammatory dysfunctions and modification of the BM microenvironment, such as the accumulation of BMAT, dysregulates megakaryopoiesis and platelet production [
      • Valet C.
      • Batut A.
      • Vauclard A.
      • Dortignac A.
      • Bellio M.
      • Payrastre B.
      • Valet P.
      • Severin S.
      Adipocyte fatty acid transfer supports megakaryocyte maturation.
      ].

      3. Bone marrow adipose tissue (BMAT)

      In the BM cavity, hematopoietic cells, marrow stromal cells, nerves, blood vessels and adipocytes reside in close contact with bone. BM adipocytes have long been considered as silent bystanders that fill “empty space” in the BM when bone mass is low or when hematopoiesis is impaired. Recent studies on the functional role of BM adipocytes reveal that this adipose tissue, called BMAT, is a secretory and metabolically active organ distinct from extramedullary adipose depots [
      • Cawthorn W.P.
      • Scheller E.L.
      Editorial: bone marrow adipose tissue: formation, function, and impact on health and disease.
      ,
      • Veldhuis-Vlug A.G.
      • Rosen C.J.
      Clinical implications of bone marrow adiposity.
      ,
      • Sebo Z.L.
      • Rendina-Ruedy E.
      • Ables G.P.
      • Lindskog D.M.
      • Rodeheffer M.S.
      • Fazeli P.K.
      • Horowitz M.C.
      Bone marrow adiposity: basic and clinical implications.
      ,
      • Horowitz M.C.
      • Berry R.
      • Holtrup B.
      • Sebo Z.
      • Nelson T.
      • Fretz J.A.
      • Lindskog D.
      • Kaplan J.L.
      • Ables G.
      • Rodeheffer M.S.
      • Rosen C.J.
      Bone marrow adipocytes.
      ].

      3.1 BM adipocytes originate from mesenchymal stromal cells (MSCs) and present characteristics that are both common to and distinct from white and brown adipocytes

      BM adipocytes are translucent, yellow elliptical cells with a large central lipid globule with smaller fat globules in the peripheral cytoplasm and are smaller than extramedullary adipocytes, with a diameter between 30 and 60 μm depending on the physiopathological context [
      • Allen J.E.
      • Henshaw D.L.
      • Keitch P.A.
      • Fews A.P.
      • Eatough J.P.
      Fat cells in red bone marrow of human rib: their size and spatial distribution with respect to the radon-derived dose to the haemopoietic tissue.
      ,
      • Rozman C.
      • Feliu E.
      • Berga L.
      • Reverter J.C.
      • Climent C.
      • Ferran M.J.
      Age-related variations of fat tissue fraction in normal human bone marrow depend both on size and number of adipocytes: a stereological study.
      ,
      • Hardouin P.
      • Marie P.J.
      • Rosen C.J.
      New insights into bone marrow adipocytes: report from the First European Meeting on Bone Marrow Adiposity (BMA 2015).
      ,
      • de Paula F.J.A.
      • Rosen C.J.
      Marrow adipocytes: origin, structure, and function.
      ]. Tavassoli first characterized the morphologic features of BM adipocytes in 1976 by histochemical staining of rat bones using performic acid-Schiff (PFAS) and distinguished two populations of fat cells within the bone cavity. One population was distributed throughout the hematopoietic red marrow and was positively stained by PFAS, and the other was packed in the yellow marrow and was not stained by PFAS [
      • Tavassoli M.
      Marrow adipose cells. Histochemical identification of labile and stable components.
      ]. Forty years later, using osmium tetroxide staining and microcomputed tomography (μCT), Scheller and colleagues confirmed the presence of two types of adipocytes within the mouse tibia cavity: constitutive adipocytes and regulated adipocytes [
      • Scheller E.L.
      • Doucette C.R.
      • Learman B.S.
      • Cawthorn W.P.
      • Khandaker S.
      • Schell B.
      • Wu B.
      • Ding S.Y.
      • Bredella M.A.
      • Fazeli P.K.
      • Khoury B.
      • Jepsen K.J.
      • Pilch P.F.
      • Klibanski A.
      • Rosen C.J.
      • MacDougald O.A.
      Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues.
      ,
      • Li Y.
      • Meng Y.
      • Yu X.
      The unique metabolic characteristics of bone marrow adipose tissue.
      ,
      • Scheller E.L.
      • Cawthorn W.P.
      • Burr A.A.
      • Horowitz M.C.
      • MacDougald O.A.
      Marrow adipose tissue: trimming the fat.
      ]. Constitutive adipocytes develop shortly after birth in the distal tibia and caudal vertebrae. They are compact and large in size (38 to 39 μm diameter), have little influence on hematopoiesis, contain more unsaturated than saturated lipids, have elevated levels of the adipogenic transcription factors CCAAT/enhancer binding protein α and β (Cebpa and Cebpb), and remain preserved upon systemic challenges. Regulated adipocytes develop with age within the red marrow, and have widespread localization and an active influence on hematopoiesis. They are smaller in size (31 to 33 μm diameter), contain more saturated lipids, express lower levels of Cebpa and Cebpb and are modulated by systemic changes (Fig. 1). Because of its bone location, it is complicated to structurally characterize BMAT compared to other adipose depots. Historically, bone biopsies at the iliac crest have allowed analysis of the marrow space where adipocytes are localized. More recently, noninvasive imaging techniques have been developed, such as μCT (single- or dual-energy) and magnetic resonance imaging (MRI) (conventional T1-weighted, water-fat or proton magnetic resonance spectroscopy (1H-MRS)). MRI is currently the best method to distinguish yellow fat marrow from hematopoietic red marrow, and 1H-MRS is considered the gold standard technique for both quantitative and qualitative characterization of BMAT in vivo [
      • Tratwal J.
      • Labella R.
      • Bravenboer N.
      • Kerckhofs G.
      • Douni E.
      • Scheller E.L.
      • Badr S.
      • Karampinos D.C.
      • Beck-Cormier S.
      • Palmisano B.
      • Poloni A.
      • Moreno-Aliaga M.J.
      • Fretz J.
      • Rodeheffer M.S.
      • Boroumand P.
      • Rosen C.J.
      • Horowitz M.C.
      • van der Eerden B.C.J.
      • Veldhuis-Vlug A.G.
      • Naveiras O.
      Reporting guidelines, review of methodological standards, and challenges toward harmonization in bone marrow adiposity research. report of the methodologies working group of the international bone marrow adiposity society.
      ,
      • Bravenboer N.
      • Bredella M.A.
      • Chauveau C.
      • Corsi A.
      • Douni E.
      • Ferris W.F.
      • Riminucci M.
      • Robey P.G.
      • Rojas-Sutterlin S.
      • Rosen C.
      • Schulz T.J.
      • Cawthorn W.P.
      Standardised nomenclature, abbreviations, and units for the study of bone marrow adiposity: report of the nomenclature working Group of the International Bone Marrow Adiposity Society.
      ,
      • Karampinos D.C.
      • Ruschke S.
      • Dieckmeyer M.
      • Diefenbach M.
      • Franz D.
      • Gersing A.S.
      • Krug R.
      • Baum T.
      Quantitative MRI and spectroscopy of bone marrow.
      ,
      • Jarraya M.
      • Bredella M.A.
      Clinical imaging of marrow adiposity.
      ].
      Fig. 1
      Fig. 1Bone marrow adipose tissue (BMAT). Schematic representation of BMAT origin, characteristics, regulation and functions. Lineage tracing studies demonstrate that BM adipocytes originate from mesenchymal stromal cells (MSCs) after a hierarchical process of differentiation. BM adipocytes can be classified into two distinct subtypes: regulated BMAT and constitutive BMAT, with different characteristics. In addition to physiological BMAT formation, various conditions are associated with BMAT loss or BMAT expansion, predominantly in regulated BMAT. BMAT can release adipokines such as adiponectin and leptin, chemokines/cytokines and lipids to exert both local and systemic effects on health and diseases such as bone homeostasis and hematopoiesis. IL: interleukin; TNFα: tumor necrosis factor α; G-CSF: granulocyte colony-stimulating factor; MIP1: macrophage inflammatory protein; GM-CSF: granulocyte macrophage colony-stimulating factor; RANKL: receptor activator of nuclear factor kappa-B ligand; CXCL: chemokine (C-X-C motif) ligand; FABP4: fatty acid-binding protein 4; Dpp4: dipeptidyl peptidase-4, Pref1: preadipocyte factor 1; Scf: stem cell factor; PPAR: peroxisome proliferator-activated receptor; C/EBP: CCAAT/enhancer binding protein.
      BM adipocytes originate from non-hematopoietic multipotent MSCs, which are common progenitors for adipogenic, osteoblastic and chondrocytic lineages and reside at the endosteal site of the BM space [
      • Tavassoli M.
      Ultrastructural development of bone marrow adipose cell.
      ,
      • Sivasubramaniyan K.
      • Lehnen D.
      • Ghazanfari R.
      • Sobiesiak M.
      • Harichandan A.
      • Mortha E.
      • Petkova N.
      • Grimm S.
      • Cerabona F.
      • de Zwart P.
      • Abele H.
      • Aicher W.K.
      • Faul C.
      • Kanz L.
      • Buhring H.J.
      Phenotypic and functional heterogeneity of human bone marrow- and amnion-derived MSC subsets.
      ,
      • Tencerova M.
      • Kassem M.
      The bone marrow-derived stromal cells: commitment and regulation of adipogenesis.
      ,
      • Berry R.
      • Rodeheffer M.S.
      • Rosen C.J.
      • Horowitz M.C.
      Adipose tissue residing progenitors (Adipocyte lineage progenitors and adipose derived stem cells (ADSC).
      ]. The differentiation process of BM adipocytes is finely tuned by transcription factors (such as peroxisome proliferator-activated receptor (PPAR) γ and CCAAT-enhancer-binding protein (c/EBP) α) and soluble mediators (such as adiponectin and leptin) [
      • Tencerova M.
      • Kassem M.
      The bone marrow-derived stromal cells: commitment and regulation of adipogenesis.
      ] (Fig. 1). Although the exact nature of BM adipocyte progenitor cells is still being investigated, it is now clear that BM adipocytes arise from a different lineage than extramedullary white and brown adipocytes [
      • Berry R.
      • Rodeheffer M.S.
      • Rosen C.J.
      • Horowitz M.C.
      Adipose tissue residing progenitors (Adipocyte lineage progenitors and adipose derived stem cells (ADSC).
      ]. Lineage tracing analysis in mice (by fluorescence-activated cell sorting or fluorescence imaging using lineage-specific mT/mG reporter mice) has been key to understanding the origin of BM adipocytes. Ambrosi and colleagues showed that MSCs follow a developmental hierarchy program of differentiation into BM adipocytes, starting from a multipotent perivascular osteogenic/adipocyte stem cell-like cell (CD45CD31Sca1+PdgfRα+CD24+) that unilaterally commits to either an adipogenic or osteoblastic lineage. An adipogenic fate-committed progenitor cell (CD45CD31Sca1+PdgfRα+CD24) then transforms into a mature CD45CD31Sca1Zfp423+ preadipocyte precursor cell [
      • Ambrosi T.H.
      • Scialdone A.
      • Graja A.
      • Gohlke S.
      • Jank A.M.
      • Bocian C.
      • Woelk L.
      • Fan H.
      • Logan D.W.
      • Schurmann A.
      • Saraiva L.R.
      • Schulz T.J.
      Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration.
      ]. BM adipocytes can also be derived from Osterix+, LrpR+, Nestin+, and Gremlin 1 MSC populations, as shown in human and murine BM [
      • Mizoguchi T.
      • Pinho S.
      • Ahmed J.
      • Kunisaki Y.
      • Hanoun M.
      • Mendelson A.
      • Ono N.
      • Kronenberg H.M.
      • Frenette P.S.
      Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development.
      ,
      • Zhou B.O.
      • Yue R.
      • Murphy M.M.
      • Peyer J.G.
      • Morrison S.J.
      Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow.
      ,
      • Pinho S.
      • Lacombe J.
      • Hanoun M.
      • Mizoguchi T.
      • Bruns I.
      • Kunisaki Y.
      • Frenette P.S.
      PDGFRalpha and CD51 mark human nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion.
      ]. The BM adipocyte lineage does not express the cell surface marker profile of white adipocyte progenitors (Lin; CD29+; CD34+; Sca1+; PdgfRα+; with or without CD24) [
      • Berry R.
      • Rodeheffer M.S.
      Characterization of the adipocyte cellular lineage in vivo.
      ].
      The medullary adipocyte phenotype combines some features of both white and brown adipocytes but is molecularly and functionally distinct from both types of adipocytes. The yellow color of BMAT is distinct from that of white or brown adipose tissue, especially in humans, probably because of differences in the number of mitochondria in each adipocyte type [
      • Krings A.
      • Rahman S.
      • Huang S.
      • Lu Y.
      • Czernik P.J.
      • Lecka-Czernik B.
      Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes.
      ]. As white adipose tissue, BM adipocytes secrete adipokines (such as leptin and adiponectin) and extracellular vesicles [
      • Attane C.
      • Esteve D.
      • Chaoui K.
      • Iacovoni J.S.
      • Corre J.
      • Moutahir M.
      • Valet P.
      • Schiltz O.
      • Reina N.
      • Muller C.
      Human bone marrow is comprised of adipocytes with specific lipid metabolism.
      ,
      • Cawthorn W.P.
      • Scheller E.L.
      • Learman B.S.
      • Parlee S.D.
      • Simon B.R.
      • Mori H.
      • Ning X.
      • Bree A.J.
      • Schell B.
      • Broome D.T.
      • Soliman S.S.
      • DelProposto J.L.
      • Lumeng C.N.
      • Mitra A.
      • Pandit S.V.
      • Gallagher K.A.
      • Miller J.D.
      • Krishnan V.
      • Hui S.K.
      • Bredella M.A.
      • Fazeli P.K.
      • Klibanski A.
      • Horowitz M.C.
      • Rosen C.J.
      • MacDougald O.A.
      Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction.
      ,
      • Martin P.J.
      • Haren N.
      • Ghali O.
      • Clabaut A.
      • Chauveau C.
      • Hardouin P.
      • Broux O.
      Adipogenic RNAs are transferred in osteoblasts via bone marrow adipocytes-derived extracellular vesicles (EVs).
      ]. Transcriptomic analysis of BM adipose tissue from rabbit tibia and radius and C57BL/6 mouse tibia showed that BM adipocytes express some markers of brown adipose tissue (such as Prdm16, deiodinase 2 (Dio2), PGC1α, Sfrp2, Ibsp and Pth1r) but do not express the brown adipose tissue-specific marker uncoupling protein (UCP) 1 [
      • Krings A.
      • Rahman S.
      • Huang S.
      • Lu Y.
      • Czernik P.J.
      • Lecka-Czernik B.
      Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes.
      ,
      • Craft C.S.
      • Robles H.
      • Lorenz M.R.
      • Hilker E.D.
      • Magee K.L.
      • Andersen T.L.
      • Cawthorn W.P.
      • MacDougald O.A.
      • Harris C.A.
      • Scheller E.L.
      Bone marrow adipose tissue does not express UCP1 during development or adrenergic-induced remodeling.
      ,
      • Pham T.T.
      • Ivaska K.K.
      • Hannukainen J.C.
      • Virtanen K.A.
      • Lidell M.E.
      • Enerback S.
      • Makela K.
      • Parkkola R.
      • Piirola S.
      • Oikonen V.
      • Nuutila P.
      • Kiviranta R.
      Human bone marrow adipose tissue is a metabolically active and insulin-sensitive distinct fat depot.
      ]. Additionally, BM adipocytes isolated from hip surgery patients show a different gene expression profile compared to subcutaneous white adipocytes collected from abdominal surgery patients, especially in terms of lipid metabolism regulation, HSC development and white-to-brown differentiation pathways. BM adipocytes seem to be more closely related to MSCs than to white adipocytes and play an active role in BM niche homeostasis [
      • Mattiucci D.
      • Maurizi G.
      • Izzi V.
      • Cenci L.
      • Ciarlantini M.
      • Mancini S.
      • Mensa E.
      • Pascarella R.
      • Vivarelli M.
      • Olivieri A.
      • Leoni P.
      • Poloni A.
      Bone marrow adipocytes support hematopoietic stem cell survival.
      ]. While cytokine/chemokine gene expression is upregulated in BM adipocytes compared to white adipocytes, these two types of adipocytes secrete IL-6, IL-1β, tumor necrosis factor (TNFα), macrophage inflammatory protein (MIP) 1, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF) and C-X-C motif chemokine ligand (CXCL) 1 and 2 [
      • de Paula F.J.A.
      • Rosen C.J.
      Marrow adipocytes: origin, structure, and function.
      ,
      • Li Y.
      • Meng Y.
      • Yu X.
      The unique metabolic characteristics of bone marrow adipose tissue.
      ,
      • Mattiucci D.
      • Maurizi G.
      • Izzi V.
      • Cenci L.
      • Ciarlantini M.
      • Mancini S.
      • Mensa E.
      • Pascarella R.
      • Vivarelli M.
      • Olivieri A.
      • Leoni P.
      • Poloni A.
      Bone marrow adipocytes support hematopoietic stem cell survival.
      ,
      • Shin E.
      • Koo J.S.
      The role of adipokines and bone marrow adipocytes in breast cancer bone metastasis.
      ]. Transcriptomic and functional studies of human BM adipocytes also have shown no activation by cold temperatures unlike the brown adipose tissue, and a different glucose metabolism and reduced insulin responsiveness compared with white adipose tissue [
      • Craft C.S.
      • Robles H.
      • Lorenz M.R.
      • Hilker E.D.
      • Magee K.L.
      • Andersen T.L.
      • Cawthorn W.P.
      • MacDougald O.A.
      • Harris C.A.
      • Scheller E.L.
      Bone marrow adipose tissue does not express UCP1 during development or adrenergic-induced remodeling.
      ,
      • Suchacki K.J.
      • Tavares A.A.S.
      • Mattiucci D.
      • Scheller E.L.
      • Papanastasiou G.
      • Gray C.
      • Sinton M.C.
      • Ramage L.E.
      • McDougald W.A.
      • Lovdel A.
      • Sulston R.J.
      • Thomas B.J.
      • Nicholson B.M.
      • Drake A.J.
      • Alcaide-Corral C.J.
      • Said D.
      • Poloni A.
      • Cinti S.
      • Macpherson G.J.
      • Dweck M.R.
      • Andrews J.P.M.
      • Williams M.C.
      • Wallace R.J.
      • van Beek E.J.R.
      • MacDougald O.A.
      • Morton N.M.
      • Stimson R.H.
      • Cawthorn W.P.
      Bone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis.
      ]. Proteomic and lipidomic analysis of BM adipocytes isolated from hip surgery patients revealed that compared to subcutaneous white adipocytes, BM adipocytes display a cholesterol-orientated lipid metabolic profile. They have a higher cholesterol content and upregulated expression levels of proteins involved in cholesterol transport, hydrolysis and synthesis, but a reduced fatty acid metabolism and lipolytic activity with an increased triglyceride and monoglyceride levels and a decreased expression of lipases involved in triglyceride hydrolysis, particularly monoglyceride lipase (MGLL), lipid droplet protein (PLIN1) and fatty acid binding protein 4 (FABP4) [
      • Attane C.
      • Esteve D.
      • Chaoui K.
      • Iacovoni J.S.
      • Corre J.
      • Moutahir M.
      • Valet P.
      • Schiltz O.
      • Reina N.
      • Muller C.
      Human bone marrow is comprised of adipocytes with specific lipid metabolism.
      ]. Thus, the main adipocyte function, liberating lipid reserves, appears to be less important for BM adipocytes than white adipocytes.

      3.2 BM adipocyte homeostasis is regulated by age, sex and metabolic conditions

      The development of BMAT is dependent on age, sex and metabolism. In humans, BMAT appears in the bone cavities shortly after birth and expands with skeletal growth throughout childhood and adolescence in a distal-to-proximal manner. In healthy adults, BMAT represents 70 % of the BM volume and accounts for approximately 5 % to 10 % of the total fat mass. It is found in trabecular bones such as long bones (tibia and femur), vertebrae, sternum and ribs. Throughout adulthood, BM conversion into BMAT progresses slowly with aging and often correlates with bone loss. In women, BMAT increases dramatically between the ages of 55 and 65, whereas in males, it increases gradually throughout life. Women have 10 % less BMAT than age-matched men, a phenomenon that reverses after menopause, as estradiol is a key player in BMAT endocrine regulation [
      • Kugel H.
      • Jung C.
      • Schulte O.
      • Heindel W.
      Age- and sex-specific differences in the 1H-spectrum of vertebral bone marrow.
      ,
      • Liney G.P.
      • Bernard C.P.
      • Manton D.J.
      • Turnbull L.W.
      • Langton C.M.
      Age, gender, and skeletal variation in bone marrow composition: a preliminary study at 3.0 tesla.
      ,
      • Pansini V.
      • Monnet A.
      • Salleron J.
      • Hardouin P.
      • Cortet B.
      • Cotten A.
      3 tesla (1) H MR spectroscopy of hip bone marrow in a healthy population, assessment of normal fat content values and influence of age and sex.
      ,
      • Griffith J.F.
      • Yeung D.K.
      • Ma H.T.
      • Leung J.C.
      • Kwok T.C.
      • Leung P.C.
      Bone marrow fat content in the elderly: a reversal of sex difference seen in younger subjects.
      ,
      • Sato C.
      • Miyakoshi N.
      • Kasukawa Y.
      • Nozaka K.
      • Tsuchie H.
      • Nagahata I.
      • Yuasa Y.
      • Abe K.
      • Saito H.
      • Shoji R.
      • Shimada Y.
      Teriparatide and exercise improve bone, skeletal muscle, and fat parameters in ovariectomized and tail-suspended rats.
      ,
      • Yang Y.
      • Luo X.
      • Xie X.
      • Yan F.
      • Chen G.
      • Zhao W.
      • Jiang Z.
      • Fang C.
      • Shen J.
      Influences of teriparatide administration on marrow fat content in postmenopausal osteopenic women using MR spectroscopy.
      ]. This adipose tissue shows a similar development pattern and distribution in rodents, predominantly located in the arms and legs and spreaded across the spine and central skeleton. However, the BM adiposity is lower in rodents than in humans and varies by mouse strain. As an example, C3H/HeJ (C3H) mice have very high endogenous levels of BMAT, while C57BL/6 mice have very low endogenous levels [
      • Suchacki K.J.
      • Cawthorn W.P.
      • Rosen C.J.
      Bone marrow adipose tissue: formation, function and regulation.
      ].
      BMAT consistently expands with obesity and decreases with weight loss in clinically obese patients; these trends have also been seen in diet-induced obese rodents [
      • Valet C.
      • Batut A.
      • Vauclard A.
      • Dortignac A.
      • Bellio M.
      • Payrastre B.
      • Valet P.
      • Severin S.
      Adipocyte fatty acid transfer supports megakaryocyte maturation.
      ,
      • Tencerova M.
      • Figeac F.
      • Ditzel N.
      • Taipaleenmaki H.
      • Nielsen T.K.
      • Kassem M.
      High-fat diet-induced obesity promotes expansion of bone marrow adipose tissue and impairs skeletal stem cell functions in mice.
      ,
      • Doucette C.R.
      • Horowitz M.C.
      • Berry R.
      • MacDougald O.A.
      • Anunciado-Koza R.
      • Koza R.A.
      • Rosen C.J.
      A high fat diet increases bone marrow adipose tissue (MAT) but does not Alter trabecular or cortical bone mass in C57BL/6J mice.
      ,
      • Blom-Hogestol I.K.
      • Mala T.
      • Kristinsson J.A.
      • Brunborg C.
      • Gulseth H.L.
      • Eriksen E.F.
      Changes in bone quality after roux-en-Y gastric bypass: a prospective cohort study in subjects with and without type 2 diabetes.
      ,
      • Scheller E.L.
      • Khoury B.
      • Moller K.L.
      • Wee N.K.
      • Khandaker S.
      • Kozloff K.M.
      • Abrishami S.H.
      • Zamarron B.F.
      • Singer K.
      Changes in skeletal integrity and marrow adiposity during high-fat diet and after weight loss.
      ,
      • de Araujo I.M.
      • Salmon C.E.
      • Nahas A.K.
      • Nogueira-Barbosa M.H.
      • Elias Jr., J.
      • de Paula F.J.
      Marrow adipose tissue spectrum in obesity and type 2 diabetes mellitus.
      ]. It remains controversial whether type 1 and 2 diabetes influence BMAT fate; however, BMAT is positively associated with glycated hemoglobin HbA1c levels and lower lipid unsaturation in diabetic patients [
      • de Araujo I.M.
      • Salmon C.E.
      • Nahas A.K.
      • Nogueira-Barbosa M.H.
      • Elias Jr., J.
      • de Paula F.J.
      Marrow adipose tissue spectrum in obesity and type 2 diabetes mellitus.
      ,
      • Botolin S.
      • McCabe L.R.
      Bone loss and increased bone adiposity in spontaneous and pharmacologically induced diabetic mice.
      ,
      • Santopaolo M.
      • Gu Y.
      • Spinetti G.
      • Madeddu P.
      Bone marrow fat: friend or foe in people with diabetes mellitus?.
      ,
      • Baum T.
      • Yap S.P.
      • Karampinos D.C.
      • Nardo L.
      • Kuo D.
      • Burghardt A.J.
      • Masharani U.B.
      • Schwartz A.V.
      • Li X.
      • Link T.M.
      Does vertebral bone marrow fat content correlate with abdominal adipose tissue, lumbar spine bone mineral density, and blood biomarkers in women with type 2 diabetes mellitus?.
      ]. BMAT volume increases in chronic caloric restricted patients with anorexia nervosa and decreases with exercise, acute caloric restriction and in late stages of anorexia nervosa when marrow becomes gelatinous [
      • Sato C.
      • Miyakoshi N.
      • Kasukawa Y.
      • Nozaka K.
      • Tsuchie H.
      • Nagahata I.
      • Yuasa Y.
      • Abe K.
      • Saito H.
      • Shoji R.
      • Shimada Y.
      Teriparatide and exercise improve bone, skeletal muscle, and fat parameters in ovariectomized and tail-suspended rats.
      ,
      • Abella E.
      • Feliu E.
      • Granada I.
      • Milla F.
      • Oriol A.
      • Ribera J.M.
      • Sanchez-Planell L.
      • Berga L.I.
      • Reverter J.C.
      • Rozman C.
      Bone marrow changes in anorexia nervosa are correlated with the amount of weight loss and not with other clinical findings.
      ,
      • Cawthorn W.P.
      • Scheller E.L.
      • Parlee S.D.
      • Pham H.A.
      • Learman B.S.
      • Redshaw C.M.
      • Sulston R.J.
      • Burr A.A.
      • Das A.K.
      • Simon B.R.
      • Mori H.
      • Bree A.J.
      • Schell B.
      • Krishnan V.
      • MacDougald O.A.
      Expansion of bone marrow adipose tissue during caloric restriction is associated with increased circulating glucocorticoids and not with hypoleptinemia.
      ,
      • Bathija A.
      • Davis S.
      • Trubowitz S.
      Bone marrow adipose tissue: response to acute starvation.
      ,
      • Ghali O.
      • Al Rassy N.
      • Hardouin P.
      • Chauveau C.
      Increased bone marrow adiposity in a context of energy deficit: the tip of the iceberg?.
      ,
      • Styner M.
      • Pagnotti G.M.
      • McGrath C.
      • Wu X.
      • Sen B.
      • Uzer G.
      • Xie Z.
      • Zong X.
      • Styner M.A.
      • Rubin C.T.
      • Rubin J.
      Exercise decreases marrow adipose tissue through ss-oxidation in obese running mice.
      ]. Glucocorticoids and parathyroid hormone (PTH), a potent osteoanabolic drug, increased BMAT in postmenopausal osteopenic women and ovariectomized rats [
      • Sato C.
      • Miyakoshi N.
      • Kasukawa Y.
      • Nozaka K.
      • Tsuchie H.
      • Nagahata I.
      • Yuasa Y.
      • Abe K.
      • Saito H.
      • Shoji R.
      • Shimada Y.
      Teriparatide and exercise improve bone, skeletal muscle, and fat parameters in ovariectomized and tail-suspended rats.
      ,
      • Yang Y.
      • Luo X.
      • Xie X.
      • Yan F.
      • Chen G.
      • Zhao W.
      • Jiang Z.
      • Fang C.
      • Shen J.
      Influences of teriparatide administration on marrow fat content in postmenopausal osteopenic women using MR spectroscopy.
      ] (Fig. 1).

      3.3 BM adipocytes are critical for bone homeostasis and hematopoiesis

      3.3.1 Bone homeostasis

      The correlation between BMAT and bone mineral density is often cited as a negative regulator of bone mass, and BMAT expansion appears to be a relevant marker of compromised bone integrity. In African and Caucasian healthy adults, μCT and MRI measurements have shown an inverse correlation between BMAT mass and bone quality/density [
      • Ambrosi T.H.
      • Schulz T.J.
      The emerging role of bone marrow adipose tissue in bone health and dysfunction.
      ,
      • Di Iorgi N.
      • Mo A.O.
      • Grimm K.
      • Wren T.A.
      • Dorey F.
      • Gilsanz V.
      Bone acquisition in healthy young females is reciprocally related to marrow adiposity.
      ,
      • Di Iorgi N.
      • Rosol M.
      • Mittelman S.D.
      • Gilsanz V.
      Reciprocal relation between marrow adiposity and the amount of bone in the axial and appendicular skeleton of young adults.
      ,
      • Shen W.
      • Chen J.
      • Punyanitya M.
      • Shapses S.
      • Heshka S.
      • Heymsfield S.B.
      MRI-measured bone marrow adipose tissue is inversely related to DXA-measured bone mineral in caucasian women.
      ,
      • Shen W.
      • Scherzer R.
      • Gantz M.
      • Chen J.
      • Punyanitya M.
      • Lewis C.E.
      • Grunfeld C.
      Relationship between MRI-measured bone marrow adipose tissue and hip and spine bone mineral density in african-american and caucasian participants: the CARDIA study.
      ]. In elderly individuals, increased BM adiposity is inversely associated with bone loss and fracture risk [
      • Justesen J.
      • Stenderup K.
      • Ebbesen E.N.
      • Mosekilde L.
      • Steiniche T.
      • Kassem M.
      Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis.
      ,
      • Schwartz A.V.
      • Sigurdsson S.
      • Hue T.F.
      • Lang T.F.
      • Harris T.B.
      • Rosen C.J.
      • Vittinghoff E.
      • Siggeirsdottir K.
      • Sigurdsson G.
      • Oskarsdottir D.
      • Shet K.
      • Palermo L.
      • Gudnason V.
      • Li X.
      Vertebral bone marrow fat associated with lower trabecular BMD and prevalent vertebral fracture in older adults.
      ]. In postmenopausal women, bone fractures are associated with a low unsaturation and a high saturation of marrow fat [
      • Shen W.
      • Chen J.
      • Punyanitya M.
      • Shapses S.
      • Heshka S.
      • Heymsfield S.B.
      MRI-measured bone marrow adipose tissue is inversely related to DXA-measured bone mineral in caucasian women.
      ,
      • Patsch J.M.
      • Li X.
      • Baum T.
      • Yap S.P.
      • Karampinos D.C.
      • Schwartz A.V.
      • Link T.M.
      Bone marrow fat composition as a novel imaging biomarker in postmenopausal women with prevalent fragility fractures.
      ]. Increased marrow adiposity in diabetic mice is also associated with bone loss [
      • Botolin S.
      • McCabe L.R.
      Bone loss and increased bone adiposity in spontaneous and pharmacologically induced diabetic mice.
      ]. Caloric restriction or starvation in growing mice leads to an increased accumulation of BM fat, decreased bone density, and increased bone resorption [
      • Devlin M.J.
      • Cloutier A.M.
      • Thomas N.A.
      • Panus D.A.
      • Lotinun S.
      • Pinz I.
      • Baron R.
      • Rosen C.J.
      • Bouxsein M.L.
      Caloric restriction leads to high marrow adiposity and low bone mass in growing mice.
      ]. Although strain-, sex-, age- and diet-dependent, the expansion of BMAT is associated with decreased bone quality with reduced bone mass and impaired bone strength in experimental models of obesity in rodents [
      • Tencerova M.
      • Figeac F.
      • Ditzel N.
      • Taipaleenmaki H.
      • Nielsen T.K.
      • Kassem M.
      High-fat diet-induced obesity promotes expansion of bone marrow adipose tissue and impairs skeletal stem cell functions in mice.
      ,
      • Devlin M.J.
      • Robbins A.
      • Cosman M.N.
      • Moursi C.A.
      • Cloutier A.M.
      • Louis L.
      • Vliet M.Van
      • Conlon C.
      • Bouxsein M.L.
      Differential effects of high fat diet and diet-induced obesity on skeletal acquisition in female C57BL/6J vs. FVB/NJ mice.
      ]. However, diet-induced obesity in rodents, that increases BMAT volume, appears to be responsible for an initial increase in bone mass followed by an impaired bone formation [
      • Lecka-Czernik B.
      • Stechschulte L.A.
      • Czernik P.J.
      • Dowling A.R.
      High bone mass in adult mice with diet-induced obesity results from a combination of initial increase in bone mass followed by attenuation in bone formation; implications for high bone mass and decreased bone quality in obesity.
      ]. The increased BMAT that contributes to bone deterioration appears not to be necessary for obesity-induced bone loss [
      • Scheller E.L.
      • Khoury B.
      • Moller K.L.
      • Wee N.K.
      • Khandaker S.
      • Kozloff K.M.
      • Abrishami S.H.
      • Zamarron B.F.
      • Singer K.
      Changes in skeletal integrity and marrow adiposity during high-fat diet and after weight loss.
      ], and BMAT loss through exercise does not completely restore the defective skeletal morphology and biomechanics in obese mice [
      • Styner M.
      • Pagnotti G.M.
      • McGrath C.
      • Wu X.
      • Sen B.
      • Uzer G.
      • Xie Z.
      • Zong X.
      • Styner M.A.
      • Rubin C.T.
      • Rubin J.
      Exercise decreases marrow adipose tissue through ss-oxidation in obese running mice.
      ]. Doucette et al. also reported that BMAT expansion in obese mice occurs without any changes in bone phenotype [
      • Doucette C.R.
      • Horowitz M.C.
      • Berry R.
      • MacDougald O.A.
      • Anunciado-Koza R.
      • Koza R.A.
      • Rosen C.J.
      A high fat diet increases bone marrow adipose tissue (MAT) but does not Alter trabecular or cortical bone mass in C57BL/6J mice.
      ].
      The link between BM adipocytes and bone might be attributed to the common origin of their BM progenitors, MSCs, and to the involvement of PTH1 and leptin signaling pathways, which are known regulators of the balance between adipogenesis and osteogenesis, as shown in Prx1-Cre; Lepr(fl/fl) and leptin-deficient ob/ob mice [
      • Yue R.
      • Zhou B.O.
      • Shimada I.S.
      • Zhao Z.
      • Morrison S.J.
      Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow.
      ,
      • Fan Y.
      • Hanai J.I.
      • Le P.T.
      • Bi R.
      • Maridas D.
      • DeMambro V.
      • Figueroa C.A.
      • Kir S.
      • Zhou X.
      • Mannstadt M.
      • Baron R.
      • Bronson R.T.
      • Horowitz M.C.
      • Wu J.Y.
      • Bilezikian J.P.
      • Dempster D.W.
      • Rosen C.J.
      • Lanske B.
      Parathyroid hormone directs bone marrow mesenchymal cell fate.
      ,
      • Hamrick M.W.
      • Della-Fera M.A.
      • Choi Y.H.
      • Pennington C.
      • Hartzell D.
      • Baile C.A.
      Leptin treatment induces loss of bone marrow adipocytes and increases bone formation in leptin-deficient ob/ob mice.
      ]. Additionally, BM adipocytes secrete factors that directly regulate bone remodeling, such as extracellular vesicles, adipokines (leptin and adiponectin) and inflammatory factors, such as IL-6 and TNFα [
      • de Paula F.J.A.
      • Rosen C.J.
      Marrow adipocytes: origin, structure, and function.
      ,
      • Li Y.
      • Meng Y.
      • Yu X.
      The unique metabolic characteristics of bone marrow adipose tissue.
      ,
      • Martin P.J.
      • Haren N.
      • Ghali O.
      • Clabaut A.
      • Chauveau C.
      • Hardouin P.
      • Broux O.
      Adipogenic RNAs are transferred in osteoblasts via bone marrow adipocytes-derived extracellular vesicles (EVs).
      ,
      • Shin E.
      • Koo J.S.
      The role of adipokines and bone marrow adipocytes in breast cancer bone metastasis.
      ,
      • Laharrague P.
      • Fontanilles A.M.
      • Tkaczuk J.
      • Corberand J.X.
      • Penicaud L.
      • Casteilla L.
      Inflammatory/haematopoietic cytokine production by human bone marrow adipocytes.
      ]. In vitro studies have revealed that BMAT-derived fatty acids can directly inhibit human primary osteoblast proliferation and induce apoptosis [
      • Maurin A.C.
      • Chavassieux P.M.
      • Frappart L.
      • Delmas P.D.
      • Serre C.M.
      • Meunier P.J.
      Influence of mature adipocytes on osteoblast proliferation in human primary cocultures.
      ,
      • Elbaz A.
      • Wu X.
      • Rivas D.
      • Gimble J.M.
      • Duque G.
      Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro.
      ]. BMAT also contributes to osteoclast-like cell differentiation and secretes the chemokines CXCL 1 and 2, promoting osteoclast maturation in metastatic prostate cancer [
      • Kelly K.A.
      • Tanaka S.
      • Baron R.
      • Gimble J.M.
      Murine bone marrow stromally derived BMS2 adipocytes support differentiation and function of osteoclast-like cells in vitro.
      ,
      • Hardaway A.L.
      • Herroon M.K.
      • Rajagurubandara E.
      • Podgorski I.
      Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer.
      ] (Fig. 1). Through a three-dimensional analysis of the ultrastructure of the BMAT niche using focused ion beam scanning electron microscopy (FIB-SEM), Scheller and colleagues showed that in mouse tibia, BM adipocytes extend organelle- and lipid-rich cytoplasmic regions toward areas of active osteoblasts at the bone surface, allowing reception of lipid and protein signals from adipocytes to osteoblasts, and therefore linking BM adipocytes and bone [
      • Robles H.
      • Park S.
      • Joens M.S.
      • Fitzpatrick J.A.J.
      • Craft C.S.
      • Scheller E.L.
      Characterization of the bone marrow adipocyte niche with three-dimensional electron microscopy.
      ]. The role of BMAT in the progression of cancer derived from bones has been described in a recent review (as reviewed in [
      • Reagan M.R.
      • Fairfield H.
      • Rosen C.J.
      Bone marrow adipocytes: a link between obesity and bone cancer.
      ]).

      3.3.2 Hematopoiesis

      BMAT was first described as a negative regulator of hematopoiesis in mice. In genetically modified lipoatrophic A-ZIP/F1 “fatless” mice and in C57BL/6 J mice treated with the adipogenesis PPARγ inhibitor bisphenol A diglycidyl ether (BADGE), BMAT loss improves hematopoietic recovery by enhancing HSC engraftment in marrow transplantation experiments after lethal irradiation or chemotherapy [
      • Naveiras O.
      • Nardi V.
      • Wenzel P.L.
      • Hauschka P.V.
      • Fahey F.
      • Daley G.Q.
      Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment.
      ,
      • 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.
      ]. Additionally, aging and obesity, which increase BM adiposity, reduce hematopoietic reconstitution capacities, whereas reduced marrow adiposity following exercise restores hematopoiesis capacity in mice [
      • Ambrosi T.H.
      • Scialdone A.
      • Graja A.
      • Gohlke S.
      • Jank A.M.
      • Bocian C.
      • Woelk L.
      • Fan H.
      • Logan D.W.
      • Schurmann A.
      • Saraiva L.R.
      • Schulz T.J.
      Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration.
      ,
      • Patel V.S.
      • Ete Chan M.
      • Rubin J.
      • Rubin C.T.
      Marrow adiposity and hematopoiesis in aging and obesity: exercise as an intervention.
      ]. While excessive medullary adiposity is considered deleterious for hematopoiesis, adipocytes can support primitive hematopoiesis in vitro and are required for in vivo BM HSC mobilization or retention through the regulation of the retention factor CXCL12/CXCR4 pathway in steady-state hematopoiesis [
      • Wilson A.
      • Fu H.
      • Schiffrin M.
      • Winkler C.
      • Koufany M.
      • Jouzeau J.Y.
      • Bonnet N.
      • Gilardi F.
      • Renevey F.
      • Luther S.A.
      • Moulin D.
      • Desvergne B.
      Lack of adipocytes alters hematopoiesis in lipodystrophic mice.
      ,
      • 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.
      ]. Other studies have also revealed that BM adipocytes, as a source of stem cell factor (SCF), are positive regulators of HSC survival and hematopoietic regeneration in steady-state hematopoiesis and in metabolic stress contexts such as obesity and aging [
      • Mattiucci D.
      • Maurizi G.
      • Izzi V.
      • Cenci L.
      • Ciarlantini M.
      • Mancini S.
      • Mensa E.
      • Pascarella R.
      • Vivarelli M.
      • Olivieri A.
      • Leoni P.
      • Poloni A.
      Bone marrow adipocytes support hematopoietic stem cell survival.
      ,
      • Zhou B.O.
      • Yu H.
      • Yue R.
      • Zhao Z.
      • Rios J.J.
      • Naveiras O.
      • Morrison S.J.
      Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF.
      ,
      • Zhang Z.
      • Huang Z.
      • Ong B.
      • Sahu C.
      • Zeng H.
      • Ruan H.B.
      Bone marrow adipose tissue-derived stem cell factor mediates metabolic regulation of hematopoiesis.
      ]. Ambrosi and colleagues demonstrated in mice that adipogenic transplants of adipogenic-committed progenitor cells (CD45CD31Sca1+PdgfRα+CD24) or mature CD45CD31Sca1Zfp423+ preadipocytes in irradiated mice reduced lineage-sca1+ c-kit+ (LSK) frequencies and impaired hematopoietic repopulation. However, the transplantation of multipotent CD45CD31Sca1+CD24+ cells to generate adipocytes increases LSK BM recovery, suggesting that according to their differentiation stage, adipocyte precursors can exert distinct effects on hematopoiesis [
      • Ambrosi T.H.
      • Scialdone A.
      • Graja A.
      • Gohlke S.
      • Jank A.M.
      • Bocian C.
      • Woelk L.
      • Fan H.
      • Logan D.W.
      • Schurmann A.
      • Saraiva L.R.
      • Schulz T.J.
      Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration.
      ]. Therefore, whether BMAT plays a beneficial or detrimental role in hematopoiesis requires further study but appears to be dependent on the experimental model, differentiation state, location and disease. A three-dimensional analysis of BMAT niche ultrastructure using FIB-SEM showed that in mouse tibia, BM adipocytes extensively interact with maturing myeloid/granulocyte cell lineages and with erythroblast islands (macrophage-like nurse cells that provide support for maturing erythroblasts and traffic mature erythrocytes to sinusoids) [
      • Robles H.
      • Park S.
      • Joens M.S.
      • Fitzpatrick J.A.J.
      • Craft C.S.
      • Scheller E.L.
      Characterization of the bone marrow adipocyte niche with three-dimensional electron microscopy.
      ], emphasizing the role of BM adipocytes in erythropoiesis and myelopoiesis through direct cell contact and indirect signals through adjacent cell membrane communication. The disruption of the BMAT niche during acute myeloid leukemia results in impaired myeloerythroid maturation [
      • Boyd A.L.
      • Reid J.C.
      • Salci K.R.
      • Aslostovar L.
      • Benoit Y.D.
      • Shapovalova Z.
      • Nakanishi M.
      • Porras D.P.
      • Almakadi M.
      • Campbell C.J.V.
      • Jackson M.F.
      • Ross C.A.
      • Foley R.
      • Leber B.
      • Allan D.S.
      • Sabloff M.
      • Xenocostas A.
      • Collins T.J.
      • Bhatia M.
      Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche.
      ]. A rapid decrease in BM adipocyte size occurs during reactive red blood cell formation after phenylhydrazine-induced anemia or severe blood loss [
      • Tavassoli M.
      Marrow adipose cells. Histochemical identification of labile and stable components.
      ,
      • Bathija A.
      • Davis S.
      • Trubowitz S.
      Marrow adipose tissue: response to erythropoiesis.
      ]. In vitro culturing of BM cells with adiponectin, a BMAT-secreted hormone, enhances myelopoiesis and is associated with an inhibitory effect on B lymphopoiesis [
      • Yokota T.
      • Meka C.S.
      • Kouro T.
      • Medina K.L.
      • Igarashi H.
      • Takahashi M.
      • Oritani K.
      • Funahashi T.
      • Tomiyama Y.
      • Matsuzawa Y.
      • Kincade P.W.
      Adiponectin, a fat cell product, influences the earliest lymphocyte precursors in bone marrow cultures by activation of the cyclooxygenase-prostaglandin pathway in stromal cells.
      ]. Diet-induced obesity in rodents also rapidly suppresses B lymphopoiesis in vivo by disrupting the supportive capacity of the BM niche, upregulating myelopoiesis [
      • Patel V.S.
      • Ete Chan M.
      • Rubin J.
      • Rubin C.T.
      Marrow adiposity and hematopoiesis in aging and obesity: exercise as an intervention.
      ,
      • 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.
      ,
      • Singer K.
      • DelProposto J.
      • Morris D.L.
      • Zamarron B.
      • Mergian T.
      • Maley N.
      • Cho K.W.
      • Geletka L.
      • Subbaiah P.
      • Muir L.
      • Martinez-Santibanez G.
      • Lumeng C.N.
      Diet-induced obesity promotes myelopoiesis in hematopoietic stem cells.
      ] and inducing a shift of lymphoid to myeloid cell differentiation with enhanced canonical myeloid gene (Csf1r, Spi1, Runx1) expression and decreased lymphoid gene (Flt3, Tcf3, Ebf1) expression [
      • Luo Y.
      • Chen G.L.
      • Hannemann N.
      • Ipseiz N.
      • Kronke G.
      • Bauerle T.
      • Munos L.
      • Wirtz S.
      • Schett G.
      • Bozec A.
      Microbiota from obese mice regulate hematopoietic stem cell differentiation by altering the bone niche.
      ]. Conversely, Trottier and colleagues showed that diet-induced obesity in mice enhanced lymphopoiesis [
      • Trottier M.D.
      • Naaz A.
      • Li Y.
      • Fraker P.J.
      Enhancement of hematopoiesis and lymphopoiesis in diet-induced obese mice.
      ] (Fig. 1). Despite discrepancies in the impact of BMAT on hematopoiesis, additional investigation is needed to elucidate the soluble signals involved in the communication between BM adipocytes and hematopoietic cells.

      4. Obesity influences megakaryopoiesis and platelet production

      4.1 Obesity enhances megakaryopoiesis and alters platelet production

      To date, no study linking megakaryopoiesis and obesity in humans has been reported. Nevertheless, some studies have shown an increased mean platelet volume (MPV) in humans positively correlated with body mass index (BMI), while others have reported no correlation [
      • Furuncuoglu Y.
      • Tulgar S.
      • Dogan A.N.
      • Cakar S.
      • Tulgar Y.K.
      • Cakiroglu B.
      How obesity affects the neutrophil/lymphocyte and platelet/lymphocyte ratio, systemic immune-inflammatory index and platelet indices: a retrospective study.
      ,
      • Han S.
      • Gan D.
      • Wang G.
      • Ru Y.
      • Huang C.
      • Lin J.
      • Zhang L.
      • Meng Z.
      • Zhu S.
      Associations of platelet indices with body fat mass and fat distribution.
      ,
      • Coban E.
      • Ozdogan M.
      • Yazicioglu G.
      • Akcit F.
      The mean platelet volume in patients with obesity.
      ]. Some studies have also shown a normal platelet count in the obese population compared to healthy individuals, while others reported that the platelet count is slightly higher in obese individuals, particularly in women with visceral adiposity, and is positively correlated with BMI [
      • Furuncuoglu Y.
      • Tulgar S.
      • Dogan A.N.
      • Cakar S.
      • Tulgar Y.K.
      • Cakiroglu B.
      How obesity affects the neutrophil/lymphocyte and platelet/lymphocyte ratio, systemic immune-inflammatory index and platelet indices: a retrospective study.
      ,
      • Han S.
      • Gan D.
      • Wang G.
      • Ru Y.
      • Huang C.
      • Lin J.
      • Zhang L.
      • Meng Z.
      • Zhu S.
      Associations of platelet indices with body fat mass and fat distribution.
      ,
      • Coban E.
      • Ozdogan M.
      • Yazicioglu G.
      • Akcit F.
      The mean platelet volume in patients with obesity.
      ,
      • Samocha-Bonet D.
      • Justo D.
      • Rogowski O.
      • Saar N.
      • Abu-Abeid S.
      • Shenkerman G.
      • Shapira I.
      • Berliner S.
      • Tomer A.
      Platelet counts and platelet activation markers in obese subjects.
      ,
      • Erdal E.
      • Inanir M.
      Platelet-to-lymphocyte ratio (PLR) and Plateletcrit (PCT) in young patients with morbid obesity.
      ,
      • Farhangi M.A.
      • Keshavarz S.A.
      • Eshraghian M.
      • Ostadrahimi A.
      • Saboor-Yaraghi A.A.
      White blood cell count in women: relation to inflammatory biomarkers, haematological profiles, visceral adiposity, and other cardiovascular risk factors.
      ]. Weight loss can induce a decrease in MPV and platelet count in obese individuals [
      • Coban E.
      • Yilmaz A.
      • Sari R.
      The effect of weight loss on the mean platelet volume in obese patients.
      ,
      • Raoux L.
      • Moszkowicz D.
      • Vychnevskaia K.
      • Poghosyan T.
      • Beauchet A.
      • Clauser S.
      • Bretault M.
      • Czernichow S.
      • Carette C.
      • Bouillot J.L.
      Effect of bariatric surgery-induced weight loss on platelet count and mean platelet volume: a 12-month follow-up study.
      ]. The mechanism behind the increased MPV and platelet count in obese individuals is poorly understood, but it appears to be a reflection of an increased percentage of reticulated young platelets that is linked to BMI [
      • Goudswaard L.J.
      • Corbin L.J.
      • Burley K.L.
      • Mumford A.
      • Akbari P.
      • Soranzo N.
      • Butterworth A.S.
      • Watkins N.A.
      • Pournaras D.J.
      • Harris J.
      • Timpson N.J.
      • Hers I.
      Higher body mass index raises immature platelet count: potential contribution to obesity-related thrombosis.
      ].
      In an experimental high-fat diet-fed male murine model that induced obesity, platelets released into the circulation have an increased MPV and a normal lifespan [
      • Valet C.
      • Batut A.
      • Vauclard A.
      • Dortignac A.
      • Bellio M.
      • Payrastre B.
      • Valet P.
      • Severin S.
      Adipocyte fatty acid transfer supports megakaryocyte maturation.
      ]. In this mouse model, obesity influenced BM megakaryopoiesis by increasing the MK size and enhancing their nuclear maturation and DMS formation. This enhanced MK maturation induced by obesity in mice, accelerates proplatelet formation, and is responsible for the ectopic platelet release outside the sinusoidal vessels in the BM and the slight decreased in circulating platelet count. However, in male rats, diet-induced obesity induces a slightly increase in platelet count [
      • Barrachina M.N.
      • Moran L.A.
      • Izquierdo I.
      • Casanueva F.F.
      • Pardo M.
      • Garcia A.
      Analysis of platelets from a diet-induced obesity rat model: elucidating platelet dysfunction in obesity.
      ]. These current differences in platelet count observed in obese men/women and male rodent models of obesity might be attributed to interspecies differences or/and to sex dysmorphism. Whether the slight decrease or increase in platelet count in different species has an impact on thrombotic risk needs to be further investigated.

      4.2 Molecular mechanisms of the impact of obesity on megakaryopoiesis and platelet production

      The molecular impact of obesity on megakaryopoiesis and platelet production remains ill-defined, but it appears to be multifactorial (Fig. 2). In the BM from obese mice, where the BM adipocyte mass increased, no direct interaction between BM adipocytes and MKs has been observed [
      • Valet C.
      • Batut A.
      • Vauclard A.
      • Dortignac A.
      • Bellio M.
      • Payrastre B.
      • Valet P.
      • Severin S.
      Adipocyte fatty acid transfer supports megakaryocyte maturation.
      ], strongly suggesting the involvement of soluble factors in the influence of obesity on megakaryopoiesis and platelet production.
      Fig. 2
      Fig. 2Factors influencing megakaryocyte and platelet biology in obesity. Obesity can influence megakaryopoiesis, the production of platelets, and platelet activation by increasing the level of circulating thrombopoietin (TPO), increasing free fatty acid uptake and synthesis, upregulating reactive oxygen species (ROS) production, inducing a chronic low-grade inflammatory state, and stimulating adipokine secretion. In obesity, the platelet size is correlated with platelet activation, BMI, and circulating levels of platelet activation markers such as soluble P-selectin, soluble CD40L, soluble GPVI and TXA2 and platelet-derived microparticles (PMPs). Platelets have higher surface expression of GPVI and CLEC-2 and display upregulated GPVI and αIIbβ3 signaling pathways that make platelets prone to GPVI-dependent adhesion and aggregation and less sensitive to anti-aggregating agents. ROS: reactive oxygen species; DNL: de novo lipogenesis; DMS: demarcation membrane system; TXA2: thromboxane A2; TPO: thrombopoietin, IL: interleukin; TNFα: tumor necrosis factor α; PMP: platelet microparticles, CCL5: chemokine (C C motif) ligand 5.

      4.2.1 Free fatty acids

      Several studies have highlighted an important role for fatty acids in MK differentiation and platelet production. Recent studies using human and murine MKs have shown that free fatty acids (released by adipocytes or generated by de novo lipogenesis) can directly improve MK maturation. In vitro coculture of adipocytes with murine BM hematopoietic progenitors committed to MK differentiation with TPO showed a direct dialog between MKs and adipocytes through which MK maturation is enhanced and adipocytes are delipidated. This dialog clearly involves a direct free fatty acid transfer from adipocytes to MKs, through the MK fatty acid translocase CD36, which increases ploidy levels by upregulating MK maturation-related signaling pathways, enhances DMS formation and accelerates proplatelet formation [
      • Valet C.
      • Batut A.
      • Vauclard A.
      • Dortignac A.
      • Bellio M.
      • Payrastre B.
      • Valet P.
      • Severin S.
      Adipocyte fatty acid transfer supports megakaryocyte maturation.
      ]. Therefore, excessive adipocyte accumulation and excessive fatty acid release in obesity could explain the enhanced MK maturation induced by obesity. In the same line of evidence, adding free fatty acids (docosahexaenoic acid, arachidonic acid and polyunsaturated fatty acids) to CD34+ human hematopoietic progenitor cells committed toward the MK lineage increases the number of differentiated MKs and reduces their apoptosis and reactive oxygen species (ROS) production, resulting in higher platelet production [
      • Siddiqui N.F.
      • Shabrani N.C.
      • Kale V.P.
      • Limaye L.S.
      Enhanced generation of megakaryocytes from umbilical cord blood-derived CD34(+) cells expanded in the presence of two nutraceuticals, docosahexanoic acid and arachidonic acid, as supplements to the cytokine-containing medium.
      ,
      • Dhenge A.
      • Limbkar K.
      • Melinkeri S.
      • Kale V.P.
      • Limaye L.
      Arachidonic acid and docosahexanoic acid enhance platelet formation from human apheresis-derived CD34(+) cells.
      ]. A study by Kelly and colleagues demonstrated that abolishing free fatty acid production in MKs by inhibiting acetyl-CoA carboxylase (ACC) or fatty acid synthase (FASN), two enzymes involved in de novo lipogenesis from non-lipid substrates (such as glucose), impaired DMS formation and platelet production in humans and monkeys but not in rodents or dogs [
      • Kelly K.L.
      • Reagan W.J.
      • Sonnenberg G.E.
      • Clasquin M.
      • Hales K.
      • Asano S.
      • Amor P.A.
      • Carvajal-Gonzalez S.
      • Shirai N.
      • Matthews M.D.
      • Li K.W.
      • Hellerstein M.K.
      • Vera N.B.
      • Ross T.T.
      • Cappon G.
      • Bergman A.
      • Buckeridge C.
      • Sun Z.
      • Qejvanaj E.Z.
      • Schmahai T.
      • Beebe D.
      • Pfefferkorn J.A.
      • Esler W.P.
      De novo lipogenesis is essential for platelet production in humans.
      ]. Although it is unclear why MK DMS formation and platelet production in humans and primates would be more dependent on de novo lipogenesis than rodents, the interspecies differences observed in the importance of de novo lipogenesis in other tissues could explain this phenomenon. This suggests that in mice, adipocytes from BM are the major source of fatty acids for MK maturation. Nevertheless, further work is needed to define the signals of megakaryocytic origin that regulate fatty acid release by adipocytes.

      4.2.2 Adipokines

      Excessive fat accumulation in obese individuals strongly increases adipokine secretion by adipocytes [
      • Hajer G.R.
      • van Haeften T.W.
      • Visseren F.L.
      Adipose tissue dysfunction in obesity, diabetes, and vascular diseases.
      ], which has a direct impact on megakaryopoiesis. Resistin, leptin, plasminogen activator inhibitor-1 (PAI-1) and retinol binding protein (RBP) 4 secreted by adipocytes induce insulin resistance in human MKs by interfering with insulin receptor substrate (IRS) 1 [
      • Gerrits A.J.
      • Gitz E.
      • Koekman C.A.
      • Visseren F.L.
      • van Haeften T.W.
      • Akkerman J.W.
      Induction of insulin resistance by the adipokines resistin, leptin, plasminogen activator inhibitor-1 and retinol binding protein 4 in human megakaryocytes.
      ]. Leptin enhances ADP-induced cytosolic Ca2+ activation in the megakaryocytic MEG-01 cell line [
      • Nakata M.
      • Maruyama I.
      • Yada T.
      Leptin potentiates ADP-induced [Ca(2+)](i) increase via JAK2 and tyrosine kinases in a megakaryoblast cell line.
      ]. Adiponectin hinders the maturation of human CD34+ hematopoietic progenitor cells into MKs [
      • Sun S.
      • Wang W.
      • Latchman Y.
      • Gao D.
      • Aronow B.
      • Reems J.A.
      Expression of plasma membrane receptor genes during megakaryocyte development.
      ]. Adipose tissue accumulation can also influence megakaryocytic progenitor proliferation and differentiation into MKs by oversecreting TPO, the main cytokine regulator of megakaryopoiesis and thrombopoiesis, as observed in the serum of obese women [
      • Maury E.
      • Brichard S.M.
      • Pataky Z.
      • Carpentier A.
      • Golay A.
      • Bobbioni-Harsch E.
      Effect of obesity on growth-related oncogene factor-alpha, thrombopoietin, and tissue inhibitor metalloproteinase-1 serum levels.
      ].

      4.2.3 Oxidative stress

      Oxidative stress is dysregulated during obesity, with increased ROS production and decreased NO bioavailability. A high ROS environment (20 % O2) enhances nuclear MK maturation and proplatelet-forming MKs in CD34+ cultures from human BM samples [
      • Mostafa S.S.
      • Miller W.M.
      • Papoutsakis E.T.
      Oxygen tension influences the differentiation, maturation and apoptosis of human megakaryocytes.
      ]. In MKs from human CD34+ cells or from murine BM cultures, when ROS production is prevented by the addition of different antioxidants (such as N-acetyl cysteine, Trolox, quercetin) or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) inhibitors, the activation of the main signaling pathways required for megakaryopoiesis, such as ERK, AKT and JAK2, is partly inhibited and MK polyploidization is affected [
      • Sardina J.L.
      • Lopez-Ruano G.
      • Sanchez-Abarca L.I.
      • Perez-Simon J.A.
      • Gaztelumendi A.
      • Trigueros C.
      • Llanillo M.
      • Sanchez-Yague J.
      • Hernandez-Hernandez A.
      p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation.
      ,
      • McCrann D.J.
      • Eliades A.
      • Makitalo M.
      • Matsuno K.
      • Ravid K.
      Differential expression of NADPH oxidases in megakaryocytes and their role in polyploidy.
      ]. Additionally, human MKs treated with antioxidant compounds extend fewer proplatelets, whereas MKs treated with prooxidant molecules produce more proplatelets [
      • Poirault-Chassac S.
      • Nivet-Antoine V.
      • Houvert A.
      • Kauskot A.
      • Lauret E.
      • Lai-Kuen R.
      • Dusanter-Fourt I.
      • Baruch D.
      Mitochondrial dynamics and reactive oxygen species initiate thrombopoiesis from mature megakaryocytes.
      ]. The role of ROS in MK maturation and platelet production has also been shown by the effect of antioxidant molecules on counteracting the role of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand called 15-deoxy-delta(12,14)-PGJ(2) (15d-PGJ(2)), which is known to promote megakaryocytic maturation in the MEG-01 megakaryoblastic cell line and primary human and mouse MKs and to accelerate platelet production after in vivo radiation-induced BM injury in mice [
      • O'Brien J.J.
      • Baglole C.J.
      • Garcia-Bates T.M.
      • Blumberg N.
      • Francis C.W.
      • Phipps R.P.
      15-deoxy-Delta 12,14 prostaglandin J2-induced heme oxygenase-1 in megakaryocytes regulates thrombopoiesis.
      ,
      • O'Brien J.J.
      • Spinelli S.L.
      • Tober J.
      • Blumberg N.
      • Francis C.W.
      • Taubman M.B.
      • Palis J.
      • Seweryniak K.E.
      • Gertz J.M.
      • Phipps R.P.
      15-deoxy-delta12,14-PGJ2 enhances platelet production from megakaryocytes.
      ]. Thus, in obesity, increased ROS production could lead to increased MK maturation and platelet production. For NO, both exogenous and endogenous sources of NO suppress the growth and differentiation of MKs by promoting apoptosis in the megakaryoblastic cell lines MEG-01 and HEL, and conversely, superoxide inhibitors suppress NO-induced MK apoptosis. Treatment with NO facilitates platelet production by MEG-01 cells, which is enhanced in combination with TPO [
      • Battinelli E.
      • Loscalzo J.
      Nitric oxide induces apoptosis in megakaryocytic cell lines.
      ,
      • Battinelli E.
      • Willoughby S.R.
      • Foxall T.
      • Valeri C.R.
      • Loscalzo J.
      Induction of platelet formation from megakaryocytoid cells by nitric oxide.
      ]. This suggests that MK apoptosis induced by NO is essential for platelet release and that a decrease in NO bioavailability could lead to an increase in MK maturation but not an increase in platelet release.

      4.2.4 Inflammatory cytokines

      Obesity is also characterized by a chronic low-grade inflammatory state with increased plasma levels of inflammatory cytokines such as IL-6, IL-1β, and CCL5 that enhance megakaryopoiesis. In vitro, in human CD34+ cells and murine hematopoietic progenitor cells, IL-6 alone stimulates MK maturation by enhancing MK number, size, ploidy levels and proplatelet formation. In synergy with SCF, TPO and IL-11 or low doses of IL-3 and IL-1, IL-6 allows the proliferation of MK progenitors differentiated from purified CD34+ cells. In vivo, IL-6 administration in mice and primates induces an increase in the size, number, ploidy and protein synthesis of MKs, and an increased platelet count [
      • Baatout S.
      Interleukin-6 and megakaryocytopoiesis: an update.
      ,
      • Lazzari L.
      • Henschler R.
      • Lecchi L.
      • Rebulla P.
      • Mertelsmann R.
      • Sirchia G.
      Interleukin-6 and interleukin-11 act synergistically with thrombopoietin and stem cell factor to modulate ex vivo expansion of human CD41+ and CD61+ megakaryocytic cells.
      ]. IL-1β activates nuclear factor-κB and mitogen-activated protein kinase (MAP) signaling pathways, which increases the ploidy of MKs from obese high-fat diet-fed mice [
      • Beaulieu L.M.
      • Lin E.
      • Mick E.
      • Koupenova M.
      • Weinberg E.O.
      • Kramer C.D.
      • Genco C.A.
      • Tanriverdi K.
      • Larson M.G.
      • Benjamin E.J.
      • Freedman J.E.
      Interleukin 1 receptor 1 and interleukin 1beta regulate megakaryocyte maturation, platelet activation, and transcript profile during inflammation in mice and humans.
      ]. CCL5 also enhances polyploidization and proplatelet formation of MKs differentiated from murine fetal liver cells [
      • Machlus K.R.
      • Johnson K.E.
      • Kulenthirarajan R.
      • Forward J.A.
      • Tippy M.D.
      • Soussou T.S.
      • El-Husayni S.H.
      • Wu S.K.
      • Wang S.
      • Watnick R.S.
      • Italiano Jr., J.E.
      • Battinelli E.M.
      CCL5 derived from platelets increases megakaryocyte proplatelet formation.
      ].

      5. Obesity influences platelet activation and thrombosis

      5.1 Platelet activation is enhanced during obesity increasing the thrombosis risk

      It is now well known that obesity is associated with increased thrombosis risk due to platelet activation (Fig. 2). In humans, obesity leads to higher circulating levels of activated platelet markers such as soluble P-selectin, soluble CD40L and soluble GPVI and TXA2 [
      • De Pergola G.
      • Pannacciulli N.
      • Coviello M.
      • Scarangella A.
      • Di Roma P.
      • Caringella M.
      • Venneri M.T.
      • Quaranta M.
      • Giorgino R.
      sP-selectin plasma levels in obesity: association with insulin resistance and related metabolic and prothrombotic factors.
      ,
      • Angelico F.
      • Alessandri C.
      • Ferro D.
      • Pignatelli P.
      • Del Ben M.
      • Fiorello S.
      • Cangemi R.
      • Loffredo L.
      • Violi F.
      Enhanced soluble CD40L in patients with the metabolic syndrome: relationship with in vivo thrombin generation.
      ,
      • Basili S.
      • Pacini G.
      • Guagnano M.T.
      • Manigrasso M.R.
      • Santilli F.
      • Pettinella C.
      • Ciabattoni G.
      • Patrono C.
      • Davi G.
      Insulin resistance as a determinant of platelet activation in obese women.
      ,
      • Barrachina M.N.
      • Hermida-Nogueira L.
      • Moran L.A.
      • Casas V.
      • Hicks S.M.
      • Sueiro A.M.
      • Di Y.
      • Andrews R.K.
      • Watson S.P.
      • Gardiner E.E.
      • Abian J.
      • Carrascal M.
      • Pardo M.
      • Garcia A.
      Phosphoproteomic analysis of platelets in severe obesity uncovers platelet reactivity and signaling pathways alterations.
      ,
      • Desideri G.
      • Ferri C.
      Effects of obesity and weight loss on soluble CD40L levels.
      ,
      • Unek I.T.
      • Bayraktar F.
      • Solmaz D.
      • Ellidokuz H.
      • Yuksel F.
      • Sisman A.R.
      • Yesil S.
      Enhanced levels of soluble CD40 ligand and C-reactive protein in a total of 312 patients with metabolic syndrome.
      ]. The level of another marker of platelet activation, PMP, increases with obesity and decreases with weight loss [
      • Murakami T.
      • Horigome H.
      • Tanaka K.
      • Nakata Y.
      • Ohkawara K.
      • Katayama Y.
      • Matsui A.
      Impact of weight reduction on production of platelet-derived microparticles and fibrinolytic parameters in obesity.
      ,
      • Suades R.
      • Padro T.
      • Vilahur G.
      • Badimon L.
      Circulating and platelet-derived microparticles in human blood enhance thrombosis on atherosclerotic plaques.
      ]. A proteomic analysis of platelets from individuals with severe obesity showed higher expression levels of GPVI and CLEC-2 that correlated with BMI, and upregulated levels of αIIb integrin and fibrinogen isoforms. Deep phosphoproteomic analysis of these platelets revealed upregulated phosphorylation of the active form of the tyrosine kinase Src (pTyr418) in the basal state and hyperphosphorylation of proteins involved in αIIbβ3 integrin-, GPIb-IX-V complex-, GPVI- and CLEC-2-related signaling pathways, in cytoskeleton remodeling, in platelet degranulation and in ROS production [
      • Barrachina M.N.
      • Hermida-Nogueira L.
      • Moran L.A.
      • Casas V.
      • Hicks S.M.
      • Sueiro A.M.
      • Di Y.
      • Andrews R.K.
      • Watson S.P.
      • Gardiner E.E.
      • Abian J.
      • Carrascal M.
      • Pardo M.
      • Garcia A.
      Phosphoproteomic analysis of platelets in severe obesity uncovers platelet reactivity and signaling pathways alterations.
      ,
      • Barrachina M.N.
      • Sueiro A.M.
      • Izquierdo I.
      • Hermida-Nogueira L.
      • Guitian E.
      • Casanueva F.F.
      • Farndale R.W.
      • Moroi M.
      • Jung S.M.
      • Pardo M.
      • Garcia A.
      GPVI surface expression and signalling pathway activation are increased in platelets from obese patients: elucidating potential anti-atherothrombotic targets in obesity.
      ]. An in vitro analysis of platelet features showed that obesity, both in humans and rodents, increases GPVI-dependent platelet aggregation and platelet adhesion to the collagen surface but not to the fibrinogen surface and induces the formation of larger thrombi on the collagen surface under arterial shear conditions, making GPVI a potential anti-thrombotic target in the context of obesity [
      • Valet C.
      • Batut A.
      • Vauclard A.
      • Dortignac A.
      • Bellio M.
      • Payrastre B.
      • Valet P.
      • Severin S.
      Adipocyte fatty acid transfer supports megakaryocyte maturation.
      ,
      • Barrachina M.N.
      • Moran L.A.
      • Izquierdo I.
      • Casanueva F.F.
      • Pardo M.
      • Garcia A.
      Analysis of platelets from a diet-induced obesity rat model: elucidating platelet dysfunction in obesity.
      ,
      • Barrachina M.N.
      • Hermida-Nogueira L.
      • Moran L.A.
      • Casas V.
      • Hicks S.M.
      • Sueiro A.M.
      • Di Y.
      • Andrews R.K.
      • Watson S.P.
      • Gardiner E.E.
      • Abian J.
      • Carrascal M.
      • Pardo M.
      • Garcia A.
      Phosphoproteomic analysis of platelets in severe obesity uncovers platelet reactivity and signaling pathways alterations.
      ].

      5.2 Molecular mechanisms of the impact of obesity on platelet hyperactivity

      The causes for enhanced platelet activation in obesity appear to be multifactorial and are probably caused by hereditary (intrinsic) changes in platelets due to the influence of obesity on MKs and by acquired (extrinsic) changes within platelets due to systemic modifications such as increased inflammatory cytokine and adipokine plasmatic levels.

      5.2.1 Intrinsic causes

      Several studies have shown that increased thrombosis risk is related to hereditary changes in platelets from altered megakaryopoiesis and platelet production caused by obesity. Increased MPV is associated with an increased number of mRNA rich-reticulated young platelets in obese individuals, which correlates with upregulated adenosine diphosphate (ADP) and P-selectin expression in platelets, increased aggregation, and resistance to antiplatelet therapy. Increased MPV during obesity appears to be a good predictor of increased thrombotic risk [
      • Goudswaard L.J.
      • Corbin L.J.
      • Burley K.L.
      • Mumford A.
      • Akbari P.
      • Soranzo N.
      • Butterworth A.S.
      • Watkins N.A.
      • Pournaras D.J.
      • Harris J.
      • Timpson N.J.
      • Hers I.
      Higher body mass index raises immature platelet count: potential contribution to obesity-related thrombosis.
      ,
      • Guthikonda S.
      • Lev E.I.
      • Patel R.
      • DeLao T.
      • Bergeron A.L.
      • Dong J.F.
      • Kleiman N.S.
      Reticulated platelets and uninhibited COX-1 and COX-2 decrease the antiplatelet effects of aspirin.
      ,
      • Vizioli L.
      • Muscari S.
      • Muscari A.
      The relationship of mean platelet volume with the risk and prognosis of cardiovascular diseases.
      ,
      • Bath P.M.
      • Butterworth R.J.
      Platelet size: measurement, physiology and vascular disease.
      ]. Recent transcriptomic studies also showed that in obese women, obesity is associated with an altered platelet transcriptome and increased platelet activation, which partly returns to normal after weight loss following bariatric surgery. The changes observed in platelet gene expression in obese individuals after surgical weight loss implicate pathways improving cardiometabolic risk post-weight loss [
      • Ezzaty Mirhashemi M.
      • Shah R.V.
      • Kitchen R.R.
      • Rong J.
      • Spahillari A.
      • Pico A.R.
      • Vitseva O.
      • Levy D.
      • Demarco D.
      • Shah S.
      • Iafrati M.D.
      • Larson M.G.
      • Tanriverdi K.
      • Freedman J.E.
      The dynamic platelet transcriptome in obesity and weight loss.
      ,
      • Heffron S.P.
      • Marier C.
      • Parikh M.
      • Fisher E.A.
      • Berger J.S.
      Severe obesity and bariatric surgery alter the platelet mRNA profile.
      ]. Although the mechanism behind this transcriptomic modification needs to be further analyzed, it appears that the altered platelet production by MKs in obesity impacts platelet activation by increasing thrombotic risk. In mice, the platelet ultrastructure as analyzed by transmission electron microscopy is unaltered by obesity [
      • Valet C.
      • Batut A.
      • Vauclard A.
      • Dortignac A.
      • Bellio M.
      • Payrastre B.
      • Valet P.
      • Severin S.
      Adipocyte fatty acid transfer supports megakaryocyte maturation.
      ].

      5.2.2 Extrinsic causes

      Several systemic factors have a direct impact on platelets by increasing their activation and thrombosis. Insulin resistance, commonly linked with obesity, is responsible for reduced platelet sensitivity to insulin, leading to increased platelet aggregation in obese individuals [
      • Basili S.
      • Pacini G.
      • Guagnano M.T.
      • Manigrasso M.R.
      • Santilli F.
      • Pettinella C.
      • Ciabattoni G.
      • Patrono C.
      • Davi G.
      Insulin resistance as a determinant of platelet activation in obese women.
      ,
      • Anfossi G.
      • Russo I.
      • Trovati M.
      Platelet resistance to the anti-aggregating agents in the insulin resistant states.
      ,
      • Anfossi G.
      • Russo I.
      • Trovati M.
      Platelet dysfunction in central obesity.
      ,
      • Anfossi G.
      • Trovati M.
      Pathophysiology of platelet resistance to anti-aggregating agents in insulin resistance and type 2 diabetes: implications for anti-aggregating therapy.
      ]. In obese individuals, the increased plasma level of leptin leads to a prothrombotic effect and contributes to arterial thrombosis [
      • Bodary P.F.
      • Westrick R.J.
      • Wickenheiser K.J.
      • Shen Y.
      • Eitzman D.T.
      Effect of leptin on arterial thrombosis following vascular injury in mice.
      ,
      • Dellas C.
      • Schafer K.
      • Rohm I.
      • Lankeit M.
      • Ellrott T.
      • Faustin V.
      • Riggert J.
      • Hasenfuss G.
      • Konstantinides S.
      Absence of leptin resistance in platelets from morbidly obese individuals may contribute to the increased thrombosis risk in obesity.
      ,
      • Konstantinides S.
      • Schafer K.
      • Koschnick S.
      • Loskutoff D.J.
      Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity.
      ,
      • Konstantinides S.
      • Schafer K.
      • Loskutoff D.J.
      The prothrombotic effects of leptin possible implications for the risk of cardiovascular disease in obesity.
      ]. Conversely, the plasma level of adiponectin is inversely correlated with soluble P-selectin and CD40L in obese patients, acting as an antithrombotic factor [
      • Kato H.
      • Kashiwagi H.
      • Shiraga M.
      • Tadokoro S.
      • Kamae T.
      • Ujiie H.
      • Honda S.
      • Miyata S.
      • Ijiri Y.
      • Yamamoto J.
      • Maeda N.
      • Funahashi T.
      • Kurata Y.
      • Shimomura I.
      • Tomiyama Y.
      • Kanakura Y.
      Adiponectin acts as an endogenous antithrombotic factor.
      ,
      • Restituto P.
      • Colina I.
      • Varo J.J.
      • Varo N.
      Adiponectin diminishes platelet aggregation and sCD40L release. Potential role in the metabolic syndrome, american journal of physiology.
      ]. The upregulated levels of platelet protein disulfide isomerase (PDI) and NOX-1 that increase platelet ROS generation in obese individuals contribute to platelet activation dependent on the GPVI signaling pathway and increase the thrombotic risk of obesity [
      • Gaspar R.S.
      • Sage T.
      • Little G.
      • Kriek N.
      • Pula G.
      • Gibbins J.M.
      Protein disulphide isomerase and NADPH oxidase 1 cooperate to control platelet function and are associated with cardiometabolic disease risk factors.
      ]. In individuals with visceral obesity, a higher plasma level of 8-isoPGF2α, the most abundant isoprostane produced through a ROS-dependent mechanism, is positively correlated with circulating levels of soluble CD40L, 11-dehydro TXB2 and PMP and is able to dysregulate platelet functions such as adhesive functions and TXA2 receptor-dependent activation [
      • Helal O.
      • Defoort C.
      • Robert S.
      • Marin C.
      • Lesavre N.
      • Lopez-Miranda J.
      • Riserus U.
      • Basu S.
      • Lovegrove J.
      • McMonagle J.
      • Roche H.M.
      • Dignat-George F.
      • Lairon D.
      Increased levels of microparticles originating from endothelial cells, platelets and erythrocytes in subjects with metabolic syndrome: relationship with oxidative stress.
      ,
      • Patrono C.
      • Falco A.
      • Davi G.
      Isoprostane formation and inhibition in atherothrombosis.
      ,
      • Audoly L.P.
      • Rocca B.
      • Fabre J.E.
      • Koller B.H.
      • Thomas D.
      • Loeb A.L.
      • Coffman T.M.
      • FitzGerald G.A.
      Cardiovascular responses to the isoprostanes iPF(2alpha)-III and iPE(2)-III are mediated via the thromboxane A(2) receptor in vivo.
      ]. Obese patients also have higher circulating levels of C-reactive protein, which correlate with BMI (as adipose tissue is a source of C-reactive protein) and return to normal levels after weight loss [
      • Unek I.T.
      • Bayraktar F.
      • Solmaz D.
      • Ellidokuz H.
      • Yuksel F.
      • Sisman A.R.
      • Yesil S.
      Enhanced levels of soluble CD40 ligand and C-reactive protein in a total of 312 patients with metabolic syndrome.
      ,
      • Ruminska M.
      • Witkowska-Sedek E.
      • Artemniak-Wojtowicz D.
      • Krajewska M.
      • Majcher A.
      • Sobol M.
      • Pyrzak B.
      Changes in leukocyte profile and C-reactive protein concentration in overweight and obese adolescents after reduction of body weight.
      ,
      • de Dios O.
      • Gavela-Perez T.
      • Aguado-Roncero P.
      • Perez-Tejerizo G.
      • Ricote M.
      • Gonzalez N.
      • Garces C.
      • Soriano-Guillen L.
      C-reactive protein expression in adipose tissue of children with acute appendicitis.
      ]. The dissociation of pentameric C-reactive protein at the platelet surface into monomeric C-reactive protein enhances platelet activation and adhesion, thus promoting thrombosis and thrombus growth [
      • Danenberg H.D.
      • Szalai A.J.
      • Swaminathan R.V.
      • Peng L.
      • Chen Z.
      • Seifert P.
      • Fay W.P.
      • Simon D.I.
      • Edelman E.R.
      Increased thrombosis after arterial injury in human C-reactive protein-transgenic mice.
      ,
      • Molins B.
      • Pena E.
      • de la Torre R.
      • Badimon L.
      Monomeric C-reactive protein is prothrombotic and dissociates from circulating pentameric C-reactive protein on adhered activated platelets under flow.
      ,
      • Molins B.
      • Pena E.
      • Vilahur G.
      • Mendieta C.
      • Slevin M.
      • Badimon L.
      C-reactive protein isoforms differ in their effects on thrombus growth.
      ]. C-reactive protein is also implicated in the fibrinolytic system by enhancing PAI-1 in human endothelial cells; this enhancement is known to decrease fibrin clearance and thus promotes thrombotic risk [
      • Nagai N.
      • Van Hoef B.
      • Lijnen H.R.
      Plasminogen activator inhibitor-1 contributes to the deleterious effect of obesity on the outcome of thrombotic ischemic stroke in mice.
      ]. The increased circulating TNFα level in obese individuals leads to increased platelet adhesion to the endothelium and is responsible for platelet hyperactivity, TXA2 biosynthesis and CD40L shedding [
      • Pignatelli P.
      • De Biase L.
      • Lenti L.
      • Tocci G.
      • Brunelli A.
      • Cangemi R.
      • Riondino S.
      • Grego S.
      • Volpe M.
      • Violi F.
      Tumor necrosis factor-alpha as trigger of platelet activation in patients with heart failure.
      ,
      • Davizon-Castillo P.
      • McMahon B.
      • Aguila S.
      • Bark D.
      • Ashworth K.
      • Allawzi A.
      • Campbell R.A.
      • Montenont E.
      • Nemkov T.
      • D'Alessandro A.
      • Clendenen N.
      • Shih L.
      • Sanders N.A.
      • Higa K.
      • Cox A.
      • Padilla-Romo Z.
      • Hernandez G.
      • Wartchow E.
      • Trahan G.D.
      • Nozik-Grayck E.
      • Jones K.
      • Pietras E.M.
      • DeGregori J.
      • Rondina M.T.
      • Di Paola J.
      TNF-alpha-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.
      ,
      • Lou J.
      • Donati Y.R.
      • Juillard P.
      • Giroud C.
      • Vesin C.
      • Mili N.
      • Grau G.E.
      Platelets play an important role in TNF-induced microvascular endothelial cell pathology.
      ]. Finally, obese individuals display a decreased platelet sensitivity to physiological anti-aggregating agents such as glyceryl trinitrate (GTN) and sodium nitroprusside (SNP), PGI2, adenosine and cyclic nucleotides [
      • Anfossi G.
      • Russo I.
      • Massucco P.
      • Mattiello L.
      • Doronzo G.
      • De Salve A.
      • Trovati M.
      Impaired synthesis and action of antiaggregating cyclic nucleotides in platelets from obese subjects: possible role in platelet hyperactivation in obesity.
      ,
      • Anfossi G.
      • Mularoni E.M.
      • Burzacca S.
      • Ponziani M.C.
      • Massucco P.
      • Mattiello L.
      • Cavalot F.
      • Trovati M.
      Platelet resistance to nitrates in obesity and obese NIDDM, and normal platelet sensitivity to both insulin and nitrates in lean NIDDM.
      ] and to pharmacological anti-platelet molecules such as aspirin, clopidogrel and prasugrel [
      • Deharo P.
      • Pankert M.
      • Bonnet G.
      • Quilici J.
      • Bassez C.
      • Morange P.
      • Alessi M.C.
      • Bonnet J.L.
      • Cuisset T.
      Body mass index has no impact on platelet inhibition induced by ticagrelor after acute coronary syndrome, conversely to prasugrel.
      ,
      • Pankert M.
      • Quilici J.
      • Loundou A.D.
      • Verdier V.
      • Lambert M.
      • Deharo P.
      • Bonnet G.
      • Gaborit B.
      • Morange P.E.
      • Valero R.
      • Dutour A.
      • Bonnet J.L.
      • Alessi M.C.
      • Cuisset T.
      Impact of obesity and the metabolic syndrome on response to clopidogrel or prasugrel and bleeding risk in patients treated after coronary stenting.
      ,
      • Grinstein J.
      • Cannon C.P.
      Aspirin resistance: current status and role of tailored therapy.
      ]. However, sensitivity to these molecules is restored after weight loss [
      • Russo I.
      • Traversa M.
      • Bonomo K.
      • De Salve A.
      • Mattiello L.
      • Del Mese P.
      • Doronzo G.
      • Cavalot F.
      • Trovati M.
      • Anfossi G.
      In central obesity, weight loss restores platelet sensitivity to nitric oxide and prostacyclin.
      ].

      6. Conclusions

      Complications arising from obesity, particularly thromboembolic incidents, lead to increased risks of cardiovascular morbidity and mortality. There is significant interplays between endothelial dysfunction, hypercoagulability, altered megakaryopoiesis and platelet production, platelet hyperactivity, inflammation and the accumulation of adipose tissue. While some diagnostic and treatment options are available, further research is necessary to increase our knowledge in the underlying pathophysiology of obesity in cardiovascular diseases involving platelets.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work was supported by Fondation de France (grant number 00075817 ), Fondation pour la Recherche Médicale (grant number DEQ20170336737 ) and Inserm / Région Occitanie ( R21100BB ).

      References

        • Van Gaal L.F.
        • Mertens I.L.
        • De Block C.E.
        Mechanisms linking obesity with cardiovascular disease.
        Nature. 2006; 444: 875-880
        • Dilworth
        • Gyde O.H.
        • Ince A.J.
        Platelet estimation in whole blood.
        Phys. Med. Biol. 1978; 23: 127-133
        • de Gaetano G.
        • Cerletti C.
        Platelet adhesion and aggregation and fibrin formation in flowing blood: a historical contribution by giulio bizzozero.
        Platelets. 2002; 13: 85-89
        • Ruggeri Z.M.
        Platelets in atherothrombosis.
        Nat. Med. 2002; 8: 1227-1234
        • Stegner D.
        • Nieswandt B.
        Platelet receptor signaling in thrombus formation.
        J. Mol. Med. (Berl). 2011; 89: 109-121
        • Gremmel T.
        • Frelinger 3rd, A.L.
        • Michelson A.D.
        Platelet physiology.
        Semin. Thromb. Hemost. 2016; 42: 191-204
        • Pease D.C.
        An electron microscopic study of red bone marrow.
        Blood. 1956; 11: 501-526
        • Nakeff A.
        • Maat B.
        Separation of megakaryocytes from mouse bone marrow by velocity sedimentation.
        Blood. 1974; 43: 591-595
        • Nakeff A.
        • van Noord M.J.
        • Blansjaar N.
        Electron microscopy of megakaryocytes in thin-layer agar cultures of mouse bone marrow.
        J. Ultrastruct. Res. 1974; 49: 1-10
        • Lefrancais E.
        • Ortiz-Munoz G.
        • Caudrillier A.
        • Mallavia B.
        • Liu F.
        • Sayah D.M.
        • Thornton E.E.
        • Headley M.B.
        • David T.
        • Coughlin S.R.
        • Krummel M.F.
        • Leavitt A.D.
        • Passegue E.
        • Looney M.R.
        The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors.
        Nature. 2017; 544: 105-109
        • Valet C.
        • Magnen M.
        • Qiu L.
        • Cleary S.J.
        • Wang K.M.
        • Ranucci S.
        • Grockowiak E.
        • Boudra R.
        • Conrad C.
        • Seo Y.
        • Calabrese D.R.
        • Greenland J.R.
        • Leavitt A.D.
        • Passegue E.
        • Mendez-Ferrer S.
        • Swirski F.K.
        • Looney M.R.
        Sepsis promotes splenic production of a protective platelet pool with high CD40 ligand expression.
        J. Clin. Invest. 2022; 132
        • Sun S.
        • Jin C.
        • Si J.
        • Lei Y.
        • Chen K.
        • Cui Y.
        • Liu Z.
        • Liu J.
        • Zhao M.
        • Zhang X.
        • Tang F.
        • Rondina M.T.
        • Li Y.
        • Wang Q.F.
        Single-cell analysis of ploidy and the transcriptome reveals functional and spatial divergency in murine megakaryopoiesis.
        Blood. 2021; 138: 1211-1224
        • Lok S.
        • Foster D.C.
        The structure, biology and potential therapeutic applications of recombinant thrombopoietin.
        Stem Cells. 1994; 12: 586-598
        • Bartley T.D.
        • Bogenberger J.
        • Hunt P.
        • Li Y.S.
        • Lu H.S.
        • Martin F.
        • Chang M.S.
        • Samal B.
        • Nichol J.L.
        • Swift S.
        • et al.
        Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor mpl.
        Cell. 1994; 77: 1117-1124
        • Kaushansky K.
        Thrombopoiesis.
        Semin. Hematol. 2015; 52: 4-11
        • Eckly A.
        • Heijnen H.
        • Pertuy F.
        • Geerts W.
        • Proamer F.
        • Rinckel J.Y.
        • Leon C.
        • Lanza F.
        • Gachet C.
        Biogenesis of the demarcation membrane system (DMS) in megakaryocytes.
        Blood. 2014; 123: 921-930
      1. A.E. Geddis , Megakaryopoiesis, Semin. Hematol. 47(3) 212-9.

        • Noetzli L.J.
        • French S.L.
        • Machlus K.R.
        New insights into the differentiation of megakaryocytes from hematopoietic progenitors.
        Arterioscler. Thromb. Vasc. Biol. 2019; 39: 1288-1300
        • Machlus K.R.
        • Italiano Jr., J.E.
        The incredible journey: from megakaryocyte development to platelet formation.
        J. Cell Biol. 2013; 201: 785-796
        • Machlus K.R.
        • Thon J.N.
        • Italiano Jr., J.E.
        Interpreting the developmental dance of the megakaryocyte: a review of the cellular and molecular processes mediating platelet formation.
        Br. J. Haematol. 2014; 165: 227-236
        • Potts K.S.
        • Farley A.
        • Dawson C.A.
        • Rimes J.
        • Biben C.
        • de Graaf C.
        • Potts M.A.
        • Stonehouse O.J.
        • Carmagnac A.
        • Gangatirkar P.
        • Josefsson E.C.
        • Anttila C.
        • Amann-Zalcenstein D.
        • Naik S.
        • Alexander W.S.
        • Hilton D.J.
        • Hawkins E.D.
        • Taoudi S.
        Membrane budding is a major mechanism of in vivo platelet biogenesis.
        J. Exp. Med. 2020; 217
        • Nishimura S.
        • Nagasaki M.
        • Kunishima S.
        • Sawaguchi A.
        • Sakata A.
        • Sakaguchi H.
        • Ohmori T.
        • Manabe I.
        • Italiano Jr., J.E.
        • Ryu T.
        • Takayama N.
        • Komuro I.
        • Kadowaki T.
        • Eto K.
        • Nagai R.
        IL-1alpha induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs.
        J. Cell Biol. 2015; 209: 453-466
        • French S.L.
        • Butov K.R.
        • Allaeys I.
        • Canas J.
        • Morad G.
        • Davenport P.
        • Laroche A.
        • Trubina N.M.
        • Italiano J.E.
        • Moses M.A.
        • Sola-Visner M.
        • Boilard E.
        • Panteleev M.A.
        • Machlus K.R.
        Platelet-derived extracellular vesicles infiltrate and modify the bone marrow during inflammation.
        Blood Adv. 2020; 4: 3011-3023
        • Qu M.
        • Zou X.
        • Fang F.
        • Wang S.
        • Xu L.
        • Zeng Q.
        • Fan Z.
        • Chen L.
        • Yue W.
        • Xie X.
        • Pei X.
        Platelet-derived microparticles enhance megakaryocyte differentiation and platelet generation via miR-1915-3p.
        Nat. Commun. 2020; 11: 4964
        • Valet C.
        • Batut A.
        • Vauclard A.
        • Dortignac A.
        • Bellio M.
        • Payrastre B.
        • Valet P.
        • Severin S.
        Adipocyte fatty acid transfer supports megakaryocyte maturation.
        Cell Rep. 2020; 32107875
        • Cawthorn W.P.
        • Scheller E.L.
        Editorial: bone marrow adipose tissue: formation, function, and impact on health and disease.
        Front. Endocrinol. 2017; 8: 112
        • Veldhuis-Vlug A.G.
        • Rosen C.J.
        Clinical implications of bone marrow adiposity.
        J. Intern. Med. 2018; 283: 121-139
        • Sebo Z.L.
        • Rendina-Ruedy E.
        • Ables G.P.
        • Lindskog D.M.
        • Rodeheffer M.S.
        • Fazeli P.K.
        • Horowitz M.C.
        Bone marrow adiposity: basic and clinical implications.
        Endocr. Rev. 2019; 40: 1187-1206
        • Horowitz M.C.
        • Berry R.
        • Holtrup B.
        • Sebo Z.
        • Nelson T.
        • Fretz J.A.
        • Lindskog D.
        • Kaplan J.L.
        • Ables G.
        • Rodeheffer M.S.
        • Rosen C.J.
        Bone marrow adipocytes.
        Adipocyte. 2017; 6: 193-204
        • Allen J.E.
        • Henshaw D.L.
        • Keitch P.A.
        • Fews A.P.
        • Eatough J.P.
        Fat cells in red bone marrow of human rib: their size and spatial distribution with respect to the radon-derived dose to the haemopoietic tissue.
        Int. J. Radiat. Biol. 1995; 68: 669-678
        • Rozman C.
        • Feliu E.
        • Berga L.
        • Reverter J.C.
        • Climent C.
        • Ferran M.J.
        Age-related variations of fat tissue fraction in normal human bone marrow depend both on size and number of adipocytes: a stereological study.
        Exp. Hematol. 1989; 17: 34-37
        • Hardouin P.
        • Marie P.J.
        • Rosen C.J.
        New insights into bone marrow adipocytes: report from the First European Meeting on Bone Marrow Adiposity (BMA 2015).
        Bone. 2016; 93: 212-215
        • de Paula F.J.A.
        • Rosen C.J.
        Marrow adipocytes: origin, structure, and function.
        Annu. Rev. Physiol. 2020; 82: 461-484
        • Tavassoli M.
        Marrow adipose cells. Histochemical identification of labile and stable components.
        Arch. Pathol. Lab. Med. 1976; 100: 16-18
        • Scheller E.L.
        • Doucette C.R.
        • Learman B.S.
        • Cawthorn W.P.
        • Khandaker S.
        • Schell B.
        • Wu B.
        • Ding S.Y.
        • Bredella M.A.
        • Fazeli P.K.
        • Khoury B.
        • Jepsen K.J.
        • Pilch P.F.
        • Klibanski A.
        • Rosen C.J.
        • MacDougald O.A.
        Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues.
        Nat. Commun. 2015; 6: 7808
        • Li Y.
        • Meng Y.
        • Yu X.
        The unique metabolic characteristics of bone marrow adipose tissue.
        Front. Endocrinol. 2019; 10: 69
        • Scheller E.L.
        • Cawthorn W.P.
        • Burr A.A.
        • Horowitz M.C.
        • MacDougald O.A.
        Marrow adipose tissue: trimming the fat.
        Trends Endocrinol. Metab. 2016; 27: 392-403
        • Tratwal J.
        • Labella R.
        • Bravenboer N.
        • Kerckhofs G.
        • Douni E.
        • Scheller E.L.
        • Badr S.
        • Karampinos D.C.
        • Beck-Cormier S.
        • Palmisano B.
        • Poloni A.
        • Moreno-Aliaga M.J.
        • Fretz J.
        • Rodeheffer M.S.
        • Boroumand P.
        • Rosen C.J.
        • Horowitz M.C.
        • van der Eerden B.C.J.
        • Veldhuis-Vlug A.G.
        • Naveiras O.
        Reporting guidelines, review of methodological standards, and challenges toward harmonization in bone marrow adiposity research. report of the methodologies working group of the international bone marrow adiposity society.
        Front. Endocrinol. 2020; 11: 65
        • Bravenboer N.
        • Bredella M.A.
        • Chauveau C.
        • Corsi A.
        • Douni E.
        • Ferris W.F.
        • Riminucci M.
        • Robey P.G.
        • Rojas-Sutterlin S.
        • Rosen C.
        • Schulz T.J.
        • Cawthorn W.P.
        Standardised nomenclature, abbreviations, and units for the study of bone marrow adiposity: report of the nomenclature working Group of the International Bone Marrow Adiposity Society.
        Front. Endocrinol. 2019; 10: 923
        • Karampinos D.C.
        • Ruschke S.
        • Dieckmeyer M.
        • Diefenbach M.
        • Franz D.
        • Gersing A.S.
        • Krug R.
        • Baum T.
        Quantitative MRI and spectroscopy of bone marrow.
        J. Magn. Reson. Imaging. 2018; 47: 332-353
        • Jarraya M.
        • Bredella M.A.
        Clinical imaging of marrow adiposity.
        Best Pract. Res. Clin. Endocrinol. Metab. 2021; 35101511
        • Tavassoli M.
        Ultrastructural development of bone marrow adipose cell.
        Acta Anat. (Basel). 1976; 94: 65-77
        • Sivasubramaniyan K.
        • Lehnen D.
        • Ghazanfari R.
        • Sobiesiak M.
        • Harichandan A.
        • Mortha E.
        • Petkova N.
        • Grimm S.
        • Cerabona F.
        • de Zwart P.
        • Abele H.
        • Aicher W.K.
        • Faul C.
        • Kanz L.
        • Buhring H.J.
        Phenotypic and functional heterogeneity of human bone marrow- and amnion-derived MSC subsets.
        Ann. N. Y. Acad. Sci. 2012; 1266: 94-106
        • Tencerova M.
        • Kassem M.
        The bone marrow-derived stromal cells: commitment and regulation of adipogenesis.
        Front. Endocrinol. 2016; 7: 127
        • Berry R.
        • Rodeheffer M.S.
        • Rosen C.J.
        • Horowitz M.C.
        Adipose tissue residing progenitors (Adipocyte lineage progenitors and adipose derived stem cells (ADSC).
        Curr. Mol. Biol. Rep. 2015; 1: 101-109
        • Ambrosi T.H.
        • Scialdone A.
        • Graja A.
        • Gohlke S.
        • Jank A.M.
        • Bocian C.
        • Woelk L.
        • Fan H.
        • Logan D.W.
        • Schurmann A.
        • Saraiva L.R.
        • Schulz T.J.
        Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration.
        Cell Stem Cell. 2017; 20 (e6): 771-784
        • Mizoguchi T.
        • Pinho S.
        • Ahmed J.
        • Kunisaki Y.
        • Hanoun M.
        • Mendelson A.
        • Ono N.
        • Kronenberg H.M.
        • Frenette P.S.
        Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development.
        Dev. Cell. 2014; 29: 340-349
        • Zhou B.O.
        • Yue R.
        • Murphy M.M.
        • Peyer J.G.
        • Morrison S.J.
        Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow.
        Cell Stem Cell. 2014; 15: 154-168
        • Pinho S.
        • Lacombe J.
        • Hanoun M.
        • Mizoguchi T.
        • Bruns I.
        • Kunisaki Y.
        • Frenette P.S.
        PDGFRalpha and CD51 mark human nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion.
        J. Exp. Med. 2013; 210: 1351-1367
        • Berry R.
        • Rodeheffer M.S.
        Characterization of the adipocyte cellular lineage in vivo.
        Nat. Cell Biol. 2013; 15: 302-308
        • Krings A.
        • Rahman S.
        • Huang S.
        • Lu Y.
        • Czernik P.J.
        • Lecka-Czernik B.
        Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes.
        Bone. 2012; 50: 546-552
        • Attane C.
        • Esteve D.
        • Chaoui K.
        • Iacovoni J.S.
        • Corre J.
        • Moutahir M.
        • Valet P.
        • Schiltz O.
        • Reina N.
        • Muller C.
        Human bone marrow is comprised of adipocytes with specific lipid metabolism.
        Cell Rep. 2020; 30 (e6): 949-958
        • Cawthorn W.P.
        • Scheller E.L.
        • Learman B.S.
        • Parlee S.D.
        • Simon B.R.
        • Mori H.
        • Ning X.
        • Bree A.J.
        • Schell B.
        • Broome D.T.
        • Soliman S.S.
        • DelProposto J.L.
        • Lumeng C.N.
        • Mitra A.
        • Pandit S.V.
        • Gallagher K.A.
        • Miller J.D.
        • Krishnan V.
        • Hui S.K.
        • Bredella M.A.
        • Fazeli P.K.
        • Klibanski A.
        • Horowitz M.C.
        • Rosen C.J.
        • MacDougald O.A.
        Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction.
        Cell Metab. 2014; 20: 368-375
        • Martin P.J.
        • Haren N.
        • Ghali O.
        • Clabaut A.
        • Chauveau C.
        • Hardouin P.
        • Broux O.
        Adipogenic RNAs are transferred in osteoblasts via bone marrow adipocytes-derived extracellular vesicles (EVs).
        BMC Cell Biol. 2015; 16: 10
        • Craft C.S.
        • Robles H.
        • Lorenz M.R.
        • Hilker E.D.
        • Magee K.L.
        • Andersen T.L.
        • Cawthorn W.P.
        • MacDougald O.A.
        • Harris C.A.
        • Scheller E.L.
        Bone marrow adipose tissue does not express UCP1 during development or adrenergic-induced remodeling.
        Sci. Rep. 2019; 9: 17427
        • Pham T.T.
        • Ivaska K.K.
        • Hannukainen J.C.
        • Virtanen K.A.
        • Lidell M.E.
        • Enerback S.
        • Makela K.
        • Parkkola R.
        • Piirola S.
        • Oikonen V.
        • Nuutila P.
        • Kiviranta R.
        Human bone marrow adipose tissue is a metabolically active and insulin-sensitive distinct fat depot.
        J. Clin. Endocrinol. Metab. 2020; 105
        • Mattiucci D.
        • Maurizi G.
        • Izzi V.
        • Cenci L.
        • Ciarlantini M.
        • Mancini S.
        • Mensa E.
        • Pascarella R.
        • Vivarelli M.
        • Olivieri A.
        • Leoni P.
        • Poloni A.
        Bone marrow adipocytes support hematopoietic stem cell survival.
        J. Cell. Physiol. 2018; 233: 1500-1511
        • Shin E.
        • Koo J.S.
        The role of adipokines and bone marrow adipocytes in breast cancer bone metastasis.
        Int. J. Mol. Sci. 2020; 21
        • Suchacki K.J.
        • Tavares A.A.S.
        • Mattiucci D.
        • Scheller E.L.
        • Papanastasiou G.
        • Gray C.
        • Sinton M.C.
        • Ramage L.E.
        • McDougald W.A.
        • Lovdel A.
        • Sulston R.J.
        • Thomas B.J.
        • Nicholson B.M.
        • Drake A.J.
        • Alcaide-Corral C.J.
        • Said D.
        • Poloni A.
        • Cinti S.
        • Macpherson G.J.
        • Dweck M.R.
        • Andrews J.P.M.
        • Williams M.C.
        • Wallace R.J.
        • van Beek E.J.R.
        • MacDougald O.A.
        • Morton N.M.
        • Stimson R.H.
        • Cawthorn W.P.
        Bone marrow adipose tissue is a unique adipose subtype with distinct roles in glucose homeostasis.
        Nat. Commun. 2020; 11: 3097
        • Kugel H.
        • Jung C.
        • Schulte O.
        • Heindel W.
        Age- and sex-specific differences in the 1H-spectrum of vertebral bone marrow.
        J. Magn. Reson. Imaging. 2001; 13: 263-268
        • Liney G.P.
        • Bernard C.P.
        • Manton D.J.
        • Turnbull L.W.
        • Langton C.M.
        Age, gender, and skeletal variation in bone marrow composition: a preliminary study at 3.0 tesla.
        J. Magn. Reson. Imaging. 2007; 26: 787-793
        • Pansini V.
        • Monnet A.
        • Salleron J.
        • Hardouin P.
        • Cortet B.
        • Cotten A.
        3 tesla (1) H MR spectroscopy of hip bone marrow in a healthy population, assessment of normal fat content values and influence of age and sex.
        J. Magn. Reson. Imaging. 2014; 39: 369-376
        • Griffith J.F.
        • Yeung D.K.
        • Ma H.T.
        • Leung J.C.
        • Kwok T.C.
        • Leung P.C.
        Bone marrow fat content in the elderly: a reversal of sex difference seen in younger subjects.
        J. Magn. Reson. Imaging. 2012; 36: 225-230
        • Sato C.
        • Miyakoshi N.
        • Kasukawa Y.
        • Nozaka K.
        • Tsuchie H.
        • Nagahata I.
        • Yuasa Y.
        • Abe K.
        • Saito H.
        • Shoji R.
        • Shimada Y.
        Teriparatide and exercise improve bone, skeletal muscle, and fat parameters in ovariectomized and tail-suspended rats.
        J. Bone Miner. Metab. 2021; 39: 385-395
        • Yang Y.
        • Luo X.
        • Xie X.
        • Yan F.
        • Chen G.
        • Zhao W.
        • Jiang Z.
        • Fang C.
        • Shen J.
        Influences of teriparatide administration on marrow fat content in postmenopausal osteopenic women using MR spectroscopy.
        Climacteric. 2016; 19: 285-291
        • Suchacki K.J.
        • Cawthorn W.P.
        • Rosen C.J.
        Bone marrow adipose tissue: formation, function and regulation.
        Curr. Opin. Pharmacol. 2016; 28: 50-56
        • Tencerova M.
        • Figeac F.
        • Ditzel N.
        • Taipaleenmaki H.
        • Nielsen T.K.
        • Kassem M.
        High-fat diet-induced obesity promotes expansion of bone marrow adipose tissue and impairs skeletal stem cell functions in mice.
        J. Bone Miner. Res. 2018; 33: 1154-1165
        • Doucette C.R.
        • Horowitz M.C.
        • Berry R.
        • MacDougald O.A.
        • Anunciado-Koza R.
        • Koza R.A.
        • Rosen C.J.
        A high fat diet increases bone marrow adipose tissue (MAT) but does not Alter trabecular or cortical bone mass in C57BL/6J mice.
        J. Cell. Physiol. 2015; 230: 2032-2037
        • Blom-Hogestol I.K.
        • Mala T.
        • Kristinsson J.A.
        • Brunborg C.
        • Gulseth H.L.
        • Eriksen E.F.
        Changes in bone quality after roux-en-Y gastric bypass: a prospective cohort study in subjects with and without type 2 diabetes.
        Bone. 2020; 130115069
        • Scheller E.L.
        • Khoury B.
        • Moller K.L.
        • Wee N.K.
        • Khandaker S.
        • Kozloff K.M.
        • Abrishami S.H.
        • Zamarron B.F.
        • Singer K.
        Changes in skeletal integrity and marrow adiposity during high-fat diet and after weight loss.
        Front. Endocrinol. 2016; 7: 102
        • de Araujo I.M.
        • Salmon C.E.
        • Nahas A.K.
        • Nogueira-Barbosa M.H.
        • Elias Jr., J.
        • de Paula F.J.
        Marrow adipose tissue spectrum in obesity and type 2 diabetes mellitus.
        Eur. J. Endocrinol. 2017; 176: 21-30
        • Botolin S.
        • McCabe L.R.
        Bone loss and increased bone adiposity in spontaneous and pharmacologically induced diabetic mice.
        Endocrinology. 2007; 148: 198-205
        • Santopaolo M.
        • Gu Y.
        • Spinetti G.
        • Madeddu P.
        Bone marrow fat: friend or foe in people with diabetes mellitus?.
        Clin. Sci. (Lond.). 2020; 134: 1031-1048
        • Baum T.
        • Yap S.P.
        • Karampinos D.C.
        • Nardo L.
        • Kuo D.
        • Burghardt A.J.
        • Masharani U.B.
        • Schwartz A.V.
        • Li X.
        • Link T.M.
        Does vertebral bone marrow fat content correlate with abdominal adipose tissue, lumbar spine bone mineral density, and blood biomarkers in women with type 2 diabetes mellitus?.
        J. Magn. Reson. Imaging. 2012; 35: 117-124
        • Abella E.
        • Feliu E.
        • Granada I.
        • Milla F.
        • Oriol A.
        • Ribera J.M.
        • Sanchez-Planell L.
        • Berga L.I.
        • Reverter J.C.
        • Rozman C.
        Bone marrow changes in anorexia nervosa are correlated with the amount of weight loss and not with other clinical findings.
        Am. J. Clin. Pathol. 2002; 118: 582-588
        • Cawthorn W.P.
        • Scheller E.L.
        • Parlee S.D.
        • Pham H.A.
        • Learman B.S.
        • Redshaw C.M.
        • Sulston R.J.
        • Burr A.A.
        • Das A.K.
        • Simon B.R.
        • Mori H.
        • Bree A.J.
        • Schell B.
        • Krishnan V.
        • MacDougald O.A.
        Expansion of bone marrow adipose tissue during caloric restriction is associated with increased circulating glucocorticoids and not with hypoleptinemia.
        Endocrinology. 2016; 157: 508-521
        • Bathija A.
        • Davis S.
        • Trubowitz S.
        Bone marrow adipose tissue: response to acute starvation.
        Am. J. Hematol. 1979; 6: 191-198
        • Ghali O.
        • Al Rassy N.
        • Hardouin P.
        • Chauveau C.
        Increased bone marrow adiposity in a context of energy deficit: the tip of the iceberg?.
        Front. Endocrinol. 2016; 7: 125
        • Styner M.
        • Pagnotti G.M.
        • McGrath C.
        • Wu X.
        • Sen B.
        • Uzer G.
        • Xie Z.
        • Zong X.
        • Styner M.A.
        • Rubin C.T.
        • Rubin J.
        Exercise decreases marrow adipose tissue through ss-oxidation in obese running mice.
        J. Bone Miner. Res. 2017; 32: 1692-1702
        • Ambrosi T.H.
        • Schulz T.J.
        The emerging role of bone marrow adipose tissue in bone health and dysfunction.
        J. Mol. Med. (Berl). 2017; 95: 1291-1301
        • Di Iorgi N.
        • Mo A.O.
        • Grimm K.
        • Wren T.A.
        • Dorey F.
        • Gilsanz V.
        Bone acquisition in healthy young females is reciprocally related to marrow adiposity.
        J. Clin. Endocrinol. Metab. 2010; 95: 2977-2982
        • Di Iorgi N.
        • Rosol M.
        • Mittelman S.D.
        • Gilsanz V.
        Reciprocal relation between marrow adiposity and the amount of bone in the axial and appendicular skeleton of young adults.
        J. Clin. Endocrinol. Metab. 2008; 93: 2281-2286
        • Shen W.
        • Chen J.
        • Punyanitya M.
        • Shapses S.
        • Heshka S.
        • Heymsfield S.B.
        MRI-measured bone marrow adipose tissue is inversely related to DXA-measured bone mineral in caucasian women.
        Osteoporos. Int. 2007; 18: 641-647
        • Shen W.
        • Scherzer R.
        • Gantz M.
        • Chen J.
        • Punyanitya M.
        • Lewis C.E.
        • Grunfeld C.
        Relationship between MRI-measured bone marrow adipose tissue and hip and spine bone mineral density in african-american and caucasian participants: the CARDIA study.
        J. Clin. Endocrinol. Metab. 2012; 97: 1337-1346
        • Justesen J.
        • Stenderup K.
        • Ebbesen E.N.
        • Mosekilde L.
        • Steiniche T.
        • Kassem M.
        Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis.
        Biogerontology. 2001; 2: 165-171
        • Schwartz A.V.
        • Sigurdsson S.
        • Hue T.F.
        • Lang T.F.
        • Harris T.B.
        • Rosen C.J.
        • Vittinghoff E.
        • Siggeirsdottir K.
        • Sigurdsson G.
        • Oskarsdottir D.
        • Shet K.
        • Palermo L.
        • Gudnason V.
        • Li X.
        Vertebral bone marrow fat associated with lower trabecular BMD and prevalent vertebral fracture in older adults.
        J. Clin. Endocrinol. Metab. 2013; 98: 2294-2300
        • Patsch J.M.
        • Li X.
        • Baum T.
        • Yap S.P.
        • Karampinos D.C.
        • Schwartz A.V.
        • Link T.M.
        Bone marrow fat composition as a novel imaging biomarker in postmenopausal women with prevalent fragility fractures.
        J. Bone Miner. Res. 2013; 28: 1721-1728
        • Devlin M.J.
        • Cloutier A.M.
        • Thomas N.A.
        • Panus D.A.
        • Lotinun S.
        • Pinz I.
        • Baron R.
        • Rosen C.J.
        • Bouxsein M.L.
        Caloric restriction leads to high marrow adiposity and low bone mass in growing mice.
        J. Bone Miner. Res. 2010; 25: 2078-2088
        • Devlin M.J.
        • Robbins A.
        • Cosman M.N.
        • Moursi C.A.
        • Cloutier A.M.
        • Louis L.
        • Vliet M.Van
        • Conlon C.
        • Bouxsein M.L.
        Differential effects of high fat diet and diet-induced obesity on skeletal acquisition in female C57BL/6J vs. FVB/NJ mice.
        Bone Rep. 2018; 8: 204-214
        • Lecka-Czernik B.
        • Stechschulte L.A.
        • Czernik P.J.
        • Dowling A.R.
        High bone mass in adult mice with diet-induced obesity results from a combination of initial increase in bone mass followed by attenuation in bone formation; implications for high bone mass and decreased bone quality in obesity.
        Mol. Cell. Endocrinol. 2015; 410: 35-41
        • Yue R.
        • Zhou B.O.
        • Shimada I.S.
        • Zhao Z.
        • Morrison S.J.
        Leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow.
        Cell Stem Cell. 2016; 18: 782-796
        • Fan Y.
        • Hanai J.I.
        • Le P.T.
        • Bi R.
        • Maridas D.
        • DeMambro V.
        • Figueroa C.A.
        • Kir S.
        • Zhou X.
        • Mannstadt M.
        • Baron R.
        • Bronson R.T.
        • Horowitz M.C.
        • Wu J.Y.
        • Bilezikian J.P.
        • Dempster D.W.
        • Rosen C.J.
        • Lanske B.
        Parathyroid hormone directs bone marrow mesenchymal cell fate.
        Cell Metab. 2017; 25: 661-672
        • Hamrick M.W.
        • Della-Fera M.A.
        • Choi Y.H.
        • Pennington C.
        • Hartzell D.
        • Baile C.A.
        Leptin treatment induces loss of bone marrow adipocytes and increases bone formation in leptin-deficient ob/ob mice.
        J. Bone Miner. Res. 2005; 20: 994-1001
        • Laharrague P.
        • Fontanilles A.M.
        • Tkaczuk J.
        • Corberand J.X.
        • Penicaud L.
        • Casteilla L.
        Inflammatory/haematopoietic cytokine production by human bone marrow adipocytes.
        Eur. Cytokine Netw. 2000; 11: 634-639
        • Maurin A.C.
        • Chavassieux P.M.
        • Frappart L.
        • Delmas P.D.
        • Serre C.M.
        • Meunier P.J.
        Influence of mature adipocytes on osteoblast proliferation in human primary cocultures.
        Bone. 2000; 26: 485-489
        • Elbaz A.
        • Wu X.
        • Rivas D.
        • Gimble J.M.
        • Duque G.
        Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro.
        J. Cell. Mol. Med. 2010; 14: 982-991
        • Kelly K.A.
        • Tanaka S.
        • Baron R.
        • Gimble J.M.
        Murine bone marrow stromally derived BMS2 adipocytes support differentiation and function of osteoclast-like cells in vitro.
        Endocrinology. 1998; 139: 2092-2101
        • Hardaway A.L.
        • Herroon M.K.
        • Rajagurubandara E.
        • Podgorski I.
        Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer.
        Clin. Exp. Metastasis. 2015; 32: 353-368
        • Robles H.
        • Park S.
        • Joens M.S.
        • Fitzpatrick J.A.J.
        • Craft C.S.
        • Scheller E.L.
        Characterization of the bone marrow adipocyte niche with three-dimensional electron microscopy.
        Bone. 2019; 118: 89-98
        • Reagan M.R.
        • Fairfield H.
        • Rosen C.J.
        Bone marrow adipocytes: a link between obesity and bone cancer.
        Cancers (Basel). 2021; 13
        • Naveiras O.
        • Nardi V.
        • Wenzel P.L.
        • Hauschka P.V.
        • Fahey F.
        • Daley G.Q.
        Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment.
        Nature. 2009; 460: 259-263
        • 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. 2013; 97: 58-72
        • Patel V.S.
        • Ete Chan M.
        • Rubin J.
        • Rubin C.T.
        Marrow adiposity and hematopoiesis in aging and obesity: exercise as an intervention.
        Curr. Osteoporos. Rep. 2018; 16: 105-115
        • Wilson A.
        • Fu H.
        • Schiffrin M.
        • Winkler C.
        • Koufany M.
        • Jouzeau J.Y.
        • Bonnet N.
        • Gilardi F.
        • Renevey F.
        • Luther S.A.
        • Moulin D.
        • Desvergne B.
        Lack of adipocytes alters hematopoiesis in lipodystrophic mice.
        Front. Immunol. 2018; 9: 2573
        • 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. 2014; 23: 434-441
        • Zhou B.O.
        • Yu H.
        • Yue R.
        • Zhao Z.
        • Rios J.J.
        • Naveiras O.
        • Morrison S.J.
        Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF.
        Nat. Cell Biol. 2017; 19: 891-903
        • Zhang Z.
        • Huang Z.
        • Ong B.
        • Sahu C.
        • Zeng H.
        • Ruan H.B.
        Bone marrow adipose tissue-derived stem cell factor mediates metabolic regulation of hematopoiesis.
        Haematologica. 2019; 104: 1731-1743
        • Boyd A.L.
        • Reid J.C.
        • Salci K.R.
        • Aslostovar L.
        • Benoit Y.D.
        • Shapovalova Z.
        • Nakanishi M.
        • Porras D.P.
        • Almakadi M.
        • Campbell C.J.V.
        • Jackson M.F.
        • Ross C.A.
        • Foley R.
        • Leber B.
        • Allan D.S.
        • Sabloff M.
        • Xenocostas A.
        • Collins T.J.
        • Bhatia M.
        Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche.
        Nat. Cell Biol. 2017; 19: 1336-1347
        • Bathija A.
        • Davis S.
        • Trubowitz S.
        Marrow adipose tissue: response to erythropoiesis.
        Am. J. Hematol. 1978; 5: 315-321
        • Yokota T.
        • Meka C.S.
        • Kouro T.
        • Medina K.L.
        • Igarashi H.