Molecular Interaction of Bone Marrow Adipose Tissue with Energy Metabolism

Molecular Interaction of Bone Marrow Adipose Tissue with Energy Metabolism Purpose of Review The last decade has seen a resurgence in the study of bone marrow adipose tissue (BMAT) across diverse fields such as metabolism, haematopoiesis, skeletal biology and cancer. Herein, we review the most recent developments of BMAT research in both humans and rodents, including the distinct nature of BMAT; the autocrine, paracrine and endocrine interactions between BMAT and various tissues, both in physiological and pathological scenarios; how these interactions might impact energy metabolism; and the most recent technological advances to quantify BMAT. Recent Findings Though still dwarfed by research into white and brown adipose tissues, BMAT is now recognised as endocrine organ and is attracting increasing attention from biomedical researchers around the globe. Summary We are beginning to learn the importance of BMAT both within and beyond the bone, allowing us to better appreciate the role of BMAT in normal physiology and disease. . . Keywords Bone marrow adipocytes Bone marrow adipose tissue Endocrinology and metabolism Introduction marrow adipose tissue (BMAT) constitutes over 10% of total fat mass in lean, healthy humans. BMAT further increases in In humans white adipose tissue (WAT) forms in utero and per- diverse clinical conditions, including osteoporosis, ageing, type sists throughout life. Upon formation, adipose tissue is highly 2 diabetes, and radiotherapy, with recent studies also showing active and responds rapidly to external and internal cues [1]. BMAT regulation in mild spastic cerebral palsy, paediatric non- Most commonly, adipose tissue is defined as either WAT or alcoholic fatty liver disease, inflammatory bowel disease, brown adipose tissue (BAT) and is found in discrete and de- chronic kidney disease and macrodactyly [3–13]. In stark con- fined locations throughout the body. WAT and BAT depots trast to WAT, BMAT is also increased in caloric restriction and differ both in their developmental origin and function. WAT anorexia nervosa. These observations suggest that BMAT has stores excess energy as triglycerides and, when needed, systemic metabolic actions distinct to those of WAT and BAT. catabolises these stores to release fatty acids and glycerol. In Compared to WAT and BAT, knowledge of BMAT formation contrast, BAT expresses thermogenic proteins (e.g. uncoupling and function is extremely limited, despite BMAT being identi- protein 1, UCP1) that allow it to dissipate energy through the fied over a century ago. This is partly due to the challenges production of heat [2]. In addition to WAT and BAT, bone inherent in studying a tissue so diffuse and difficult to access. However, in the last decade BMAT has seen increasing atten- tion among several research fields, including metabolism, This article is part of the Topical Collection on Molecular Biology of Bone haematopoiesis, skeletal biology and cancer. Herein, we review Marrow Fat Adiposity the most recent developments of BMAT research in both * Karla J. Suchacki humans and rodents, including the distinct nature of BMAT; ksuchack@exseed.ed.ac.uk the autocrine, paracrine and endocrine interactions between BMAT and various tissues, both in physiological and patholog- ical scenarios; how these interactions impact energy metabo- University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of lism; and the most recent technological advances to quantify Edinburgh, Edinburgh EH16 4TJ, UK bone marrow (BM) adiposity (Fig. 1). 42 Curr Mol Bio Rep (2018) 4:41–49 Energy storage Further ? BMAT response to 1) Insulin 2) Catecholamines and release subtypes? Is BMAT cold responsive? 2 Thermogenesis ? rBMAT Adiponectin Altered muscle transcription Paracrine and ? Leptin Major contributor of circulating leptin? endocrine interactions FFA Support haematopoiesis and tumour progression? DPP4 Promote systemic insulin resistance? Bone interactions ? Impair osteoblast function? Promote bone resorption? Provide fuel for bone cells? cBMAT Regulation of haematopoiesis in physiological and pathological 5 Haematopoiesis ? conditions? Further subtypes? Fig. 1 Unknown functions of bone marrow adipose tissue (BMAT) Recent efforts have begun to uncover the role of BMAT in cells and increases or decreases in various conditions energy metabolism, including insulin responsiveness [14�� , (reviewed [18, 21]). Adipocytes within cBMAT and rBMAT 15], the response of BMAT to catecholamines [16� ], and po- were recently shown to have different metabolic functions, tential BAT-like characteristics (see ‘BMAT—adistinctadi- with cBMAT being more resistant to lipolytic stimuli [16� ]. pose depot?’). However, it remains unclear to what extent Thus, cBMAT and rBMAT may have distinct impacts on met- BMAT acts as a site of energy storage and release, how para- abolic homeostasis. crine and endocrine actions of BMAT impact energy metabo- Beyond this potential heterogeneity between BMAT sub- lism, the ability of BMAT to interact with bone cells, and the types, a broader question is whether BMAT function overlaps role of BMAT in haematopoiesis. These topics are covered in with that of WAT or BAT. Establishing the pathophysiological the text. roles of BMAT will be crucial to determine whether it repre- sents a new target for disease treatment (reviewed in [22]). Histologically, BMAT adipocytes typically resemble those in BMAT—a Distinct Adipose Depot? WAT; however, whether BMAT is WAT- or BAT-like remains a subject of debate. Indeed, it has been reported that BM has a The development of BMAT is a normal physiological process mixed BAT/WAT population of adipocytes. Krings et al. tran- scriptionally analysed whole tibiae, revealing detectable ex- that progresses throughout the lifespan, such that by adult- hood (25 years) BMAT occupies 50 to 70% of the total bone pression of BAT markers including Prdm16, Dio2 and Pgc1α marrow volume [17]. This increase results from the BM un- [23]. Furthermore, they found that aged diabetic mice showed dergoing a red-to-yellow conversion occurring in a centripetal decreased expression of BAT markers in whole tibiae, sug- fashion [18, 19]. During normal development this red-to- gesting that BMAT function changes with ageing and diabe- yellow marrow conversion is independent of WAT accumula- tes. Most interestingly, administration of rosiglitazone, a syn- tion and slows during adulthood. However, in obesity, verte- thetic agonist for adipocyte-specific PPARγ and a potent in- bral BMAT is positively associated with visceral fat [20], sug- sulin sensitiser, significantly increased both BAT (Ucp1, gesting a relationship between BMAT and WAT development Pgc1α, Dio2, β3AR, Prdm16 and FoxC2)andWAT(Adipoq in this context. The conversion of red-to-yellow marrow in and Lep) markers in whole tibiae of normoglycemic mice, but rodents also occurs in a similar centripetal pattern and, in both not in diabetic mice [23]. More recently it has been reported that, compared with cBMAT, rBMAT is characterised by ele- rodents and humans, two distinct populations of BM adipo- cytes have been described: constitutive BMAT (cBMAT) is vated expression of beige fat markers, including Ucp1 [24]. situated in the distal long bones and (in rodents) caudal verte- However, we have shown that Ucp1 expression in whole tib- brae, while regulated BMAT (rBMAT) is situated in the prox- iae is 10,000- to 25,000-fold lower than in BAT [25]. This imal regions of long bones and in spinal vertebrae [21]. level of expression is similar to that observed by Krings cBMAT and rBMAT are not only anatomically distinct but et al. and clearly argues against BAT-like functions of also show different responses to age, weight, endocrine factors BMAT. However, these studies also highlight the technical and medical interventions. In brief, cBMAT appears in the limitations of using whole bones to represent BMAT. early postnatal period, histologically resembles WAT, and Efficient isolation of a pure population of adipocytes from mostly does not increase or decrease in response to external the bone marrow is technically very difficult, though methods stimuli or pathophysiological changes. Conversely rBMAT to achieve this have been reported [26]. Advanced imaging approaches are also allowing BMAT-specific analysis, with develops after cBMAT, is interspersed with haematopoietic Curr Mol Bio Rep (2018) 4:41–49 43 3D electron microscopy recently revealing a dense mitochon- as well as endosteum osteocytes, articular chondrocytes and drial network within BM adipocytes [27]. inguinal WAT. Furthermore, in Osx1-Cre:mT/mG mice, trac- This latter observation supports the possibility that BM ing occurred only in adipocytes in BMAT, and not those in adipocytes may have some brown- or beige-adipocyte-like WAT or BAT depots, suggesting that BMAT arises from a characteristics. Consistent with this, brown-like adipocytes mesenchymal-osteogenic lineage [36–38] (Comprehensively were observed in a BM core biopsy taken from a 74-year- reviewed in [14�� ]). Further unpublished lineage tracing stud- old man with untreated lymphoplasmacytic lymphoma. ies have shown that insulin signalling is not required for lipid The authors reported that these adipocytes were UCP1- accumulation in BMAT, but is required in WAT, providing positive and largely separated from the surrounding mar- evidence for the functional differences in regulation of adipose row, suggesting that the observed BBAT^ maybe aninci- depots [14�� ]. dental intraosseous hibernoma [22, 28]. Furthermore, 18F- FDG-PET/CT imagining of healthy young human subjects, with or without cold stimuli, identified cold-stimulated BMAT Autocrine, Paracrine and Endocrine 18F-FDG uptake in vertebral bone marrow that significant- Interactions ly correlated with 18F-FDG uptake into BAT [29]. The authors further identified expression of UCP1 and Sexual Dimorphism PRDM16 in BM from two male subjects, while histologi- cal assessment of vertebral BM from 3-week-old mice The distribution of WAT and BAT shows a clear sexual dimor- highlighted the presence of multilocular, brown-like adipo- phism [39, 40] that seems to also apply to BMAT. We have cytes that were positive for UCP1. Taken together, these found that female mice tend to have a higher volume of data suggest the presence of functional brown adipocytes rBMAT in the proximal tibial diaphysis [41], whereas in in vertebral BM of mammals. The authors suggest that the humans BM fat is higher in males than in females, at least in presence of brown adipocytes in the BM seems plausible younger adults [42]. To further explore such sex differences, given that Myf5-positive cells emerge at the juxtaspinal, Lecka-Czernik et al. investgiated the impact of sex steroids on prospectively paravertebral, regions within somites [30, BMAT [24]. While no sexual divergence in the volume and 31], and it has been well documented that BAT is derived transcriptional profile of distal BMAT was observed, ovariec- from Myf5-positive myoblastic cells [32]. tomy led to increased BMAT, increased Adipoq (adiponectin) A recent study provided further evidence for a mixed BAT/ and decreased beige fat gene markers. Orchidectomy in males WAT phenotype of BMAT both in vitro and in vivo. The also tended to increase BMAT, consistent with previous ob- authors showed that treatment of BM mesenchymal stromal servations that testosterone can decrease BMAT in female rats cells or stromal ST2 cells with triiodothyronine or a thyroid [43]. However, unlike ovariectomy, orchidectomy did not hormone receptor beta-specific agonist (GC-1) significantly change expression of Adipoq or beige fat gene markers [24]. increased expression of brown and beige fat markers. Thus, males and females may differ in how their sex steroid Furthermore, administration of GC-1 in vivo in thyroid deficiency affects BMAT formation and endocrine function −/− hormone-deficient (Tshr ) mice showed a 149-fold increase [24]. in Ucp1 expression in skeletal tissue (femoral and tibial epiph- In humans, the impact of testosterone on BMAT remains to yses). Whether this translates into detectable UCP1 protein be established, but the effects of oestrogen are similar to those expression remains to be confirmed; however, these data sug- observed in rodent studies. For example, Limonard et al. used gest not only that thyroid hormone induces the expression of MRI to measure vertebral BM fat in postmenopausal women BAT genes in mouse BMAT but, importantly, that like WAT, before, during, and following a two-week treatment with 17-β BMAT has the potential to beige [33]. estradiol. Even in such a short timescale, this treatment was Murine tracer models are crucial in search of the origin of found to rapidly decrease the BM fat fraction [44]. Consistent BMAT. In contrast with the above data, recent research has with this, in younger adults vertebral BM fat tends to be higher shown that the origin of BMAT is likely to be distinct to that of in males than in females, whereas, post-menopause, females − − WAT and BAT. WAT is derived from Myf5 /Pax7 progeni- have greater vertebral BM fat content [42]. Thus, oestrogen + + tors, while BAT is derived from Myf5 /Pax7 progenitors clearly has a profound ability to suppress BMAT formation, [14�� , 32, 34]. Strikingly, BM adipocytes are also derived which likely contributes to the sex differences in BMAT con- from progenitors that express Osterix. Once thought to be tent across the lifecourse. More recent studies suggest that osteoblast-specific, Osterix is a transcription factor that acts BMAT is also regulated by follicle-stimulating hormone downstream of Runx2/Cbfa1 and is required for osteoblast (FSH). Specifically, mice that underwent ovariectomy and differentiation [35]. Lineage tracing studies using Prx1- were then given an FSH antibody had decreased BMAT vol- Cre:mT/mG and Osx1-Cre:mT/mG showed that tibial and ume coupled with decreased fat mass and the production of UCP1-positive adipose tissue [45]. Thus, beyond oestrogen femoral BM adipocytes were traced in Prx1-Cre:mT/mG mice 44 Curr Mol Bio Rep (2018) 4:41–49 and testosterone, it will be important to determine if other sex in cases of failed bone regeneration, such as non-union frac- hormones can also regulate BMAT formation and function in ture, it remains unclear if BMAT has a positive or negative humans. impact on bone healing [57]. Most recently, Ambrosi et al. elegantly showed that BMAT exerts direct negative effects Adiponectin on bone healing and haematopoiesis in mouse models, with BM adipocytes secreting dipeptidyl peptidase-4 (DPP4) to BMAT is known to increase in caloric restriction (CR), con- inhibit fracture repair [58]. Given that DPP4 is a target of tributing to increases in circulating adiponectin [46, 47]. anti-diabetic therapies, this finding raises the intriguing possi- Adiponectin is the most abundant adipokine in the circulation bility that BMAT-derived DPP4 might impact not only skele- and can be used as a clinical biomarker for early detection of tal remodelling, but also systemic insulin resistance. conditions such as type 2 diabetes, cardiovascular diseases, Osteoarthritis (OA) is a heterogeneous disease that leads to and certain cancers. Although we have recently reviewed this the progressive loss of normal joint function and related elsewhere [47], many questions remain regarding adiponectin subchondral bone changes. OA is the most common form of secretion from BMAT and how this is altered by disease. For arthritis and represents the world’s leading cause of physical example, recent human data suggest that adiponectin may disability in adults. At a time when the population is ageing regulate the relationship between BMAT and insulin sensitiv- and the prevalence of obesity is increasing, there has never ity in obese and non-obese premenopausal women [48]. It been a greater need for the prevention of OA. Currently, OA is remains unclear if adiponectin secretion from BMAT directly routinely managed therapeutically and patients are offered influences cardiac function or the risk of cardiovascular dis- physiotherapy [59]. Traditionally, OA was considered to be a ease. Studies in rats showed that bone marrow and adipose disease of the cartilage, but more recently has been shown to mesenchymal stem cells attenuated cardiac fibrosis [49]. affect the entire joint, including the bone, synovium, tendons, However, far more research effort is required to understand and muscles [60]. The location of BMAT suggests that BM if BMAT directly impacts cardiac function or impacts other adipocytes may play a role in the pathology of OA. A recent tissues, such as the liver and pancreas, that are known to be study found increased BMAT in postmenopausal women with targeted by adiponectin [50]. both OA and osteoporosis (OP), and the authors suggested that a subgroup of OA subjects with elevated BMAT may Bone Trauma and Pathology have a high risk of developing OP [61]. Given the close proximity of BMAT to the bone, researchers Interaction of BMAT with Bone Cells have suggested that BMAT directly regulates bone metabo- lism. In the last decade, bone has emerged as a highly meta- BMAT has recently been shown to be responsive to parathy- bolic organ that contributes to the regulation of whole-body roid hormone and to secrete receptor activator of nuclear fac- metabolism [51]. Indeed, bone has the capability to regenerate tor kappa-Β ligand (RANKL), a key regulator of osteoclast without scar formation following mechanical and structural differentiation and activation [26]. This suggests that BMAT failure. This occurs typically by secondary endochondral exhibits unique osteo-resorptive characteristics. Furthermore, healing, which consists of both endochondral and murine models with decreased sclerostin (SOST) have signif- intramembranous ossification. The process of secondary en- icantly decreased BMAT [62], suggesting that BMAT forma- dochondral healing begins with haematoma formation; then tion is governed directly by osteocytes, which secrete SOST. an acute inflammatory response with pro-inflammatory sig- Currently, there is much interest in anti-SOST therapy for nalling; primary callus formation (soft callus), which un- treatment of OP. This is driving a greater consideration of dergoes revascularisation and calcification to form the hard the clinicalimplications ofBMAT, which shouldhelptofur- callus; and finally bone remodelling [52]. This process of ther our knowledge of this complex adipose depot [62, 63]. In fracture healing is highly metabolically demanding and re- murine models and human patients with low bone mineral quires the cooperation between different cell types, as recently density (BMD) and bone formation, BMAT has been shown reviewed elsewhere [53]. BM adipocytes secrete adipokines to be elevated (reviewed [64�� , 65]). Mice with a loss of func- (e.g. adiponectin), cytokines (e.g. RANKL), and free fatty tion mutation in the Dock7 gene, which results in low BMD acids that act to promote bone resorption, haematopoietic re- and reduced bone formation, have very few osteoblasts but covery and supply energy. Indeed, BMAT has been reported BMAT is increased 3.5-fold compared to wild-type controls. to be increased in subjects with prevalent vertebral fracture However, it is important to highlight that other studies have [54, 55] and prevalent vertebral deformities [56]. Despite re- not found an inverse relationship between BMD and BMAT. cent efforts, it remains unclear why BMAT increases in frac- For example, BMAT was significantly increased following ture and, specifically, why there is an intricate relationship 12 weeks of high-fat diet feeding in mice, while BMD was between bone and BMAT during bone pathology. Moreover, unchanged [66]. Furthermore, C3H/HeJ mice have increased Curr Mol Bio Rep (2018) 4:41–49 45 bone mass and BMAT compared to C57BL/6 mice [67], and worth highlighting the developments in BMAT imaging that we have shown that during CR in rabbits, bone loss can occur are particularly relevant to its metabolic characteristics and independently of BMAT expansion [41]. functions. For example, ex vivo high-resolution magic angle spinning (HRMAS) proton nuclear magnetic resonance ( H Metastasis, Myeloma and BMAT NMR) spectroscopy has recently been used in humans to de- termine the (un)saturation level of fatty acids in BMAT [75]. The interplay between tumour cells, osteoclasts and osteo- A novel, dual-energy computed tomography (DECT) method blasts is well documented, but despite occupying 50 to has also been described to assess both BMAT and marrow- 70% of the total BM volume, the relationship between corrected volumetric BMD (mcvBMD) [76]. Hopefully, these BMAT, multiple myeloma, and metastasis of breast and developments in new clinical techniques will allow re- prostate has only just begun to be understood. While be- searchers to more accurately assess BMAT’s lipid composi- yond the scope of this review, others have recently provid- tion and relationship with skeletal parameters. ed elegant overviews of the growing evidence linking Finally, imaging studies are beginning to shed light on the BMAT to tumour growth and the development of associat- metabolic functions of BMAT. Positron emission tomogra- ed bone disease [68–71]. phy–computed tomography (PETCT) is a non-invasive tech- nique allowing the visualisation of biological processes. Most simply, compounds are radiolabelled with positron-emitting 11 15 18 Technological Advances to Assess BMAT radioisotopes (e.g. C, O, and F). These radiolabelled Quantity and Metabolic Function compounds emit positrons which annihilate with electrons and produce two annihilation photons that travel in opposite As reviewed elsewhere in this issue, techniques for BMAT directions and are detected by the PET scanner. Upon detec- imaging are improving and expanding. Standard histological tion, the PETCT scanner uses various algorithms and attenu- approaches, such as haematoxylin and eosin staining of ation correction factors to hybridise the PET data with the CT paraffin-embedded sections, have been used routinely to de- images, allowing the user to visualise and analyse the anatom- tect adipocytes within BM. More recently, osmium tetroxide ical locations of the tracer. PET imaging can be conducted staining followed by micro-computed tomography (μCT) has either dynamically or statically. Clinically, static imaging is been used to visualise and quantify BMAT in situ [72]. New most common as dynamic analysis requires kinetic modelling, μCT contrast agents are currently being developed to assess which is complex and time consuming [77]. The most com- 18 18 BMAT, vasculature and nerves without the requirement for monly used radiotracer is F-fluorodeoxyglucoe ( F-FDG), time-consuming decalcification. The most recent of these a glucose analogue that is actively transported into the cell by stains, for use in contrast-enhanced microfocus computed to- glucose transporters. After import, F-FDG can be phosphor- mography (CE-CT), is a Hafnium-based Wells-Dawson ylated by hexokinase to form 2-deoxyglucose-6-phosphate; polyoxometalate (Hf-POM) [73, 74]. Hf-POM has been vali- however, unlike endogenous glucose, once phosphorylated dated in murine long bones and provides the researcher with a F-FDG is unable to continue along the glycolytic pathway and 3D representation of the mineralised bone, vasculature and instead accumulates in the cell as F-labelled 2- BMAT. These developments in contrast agents allow novel deoxyglucose-6-phosphate. This intracellular accumulation of insights into the interaction between the bone, vasculature F allows the user to calculate the standardised uptake value and BMAT. However, as for osmium μCT, specialist high- (SUV, the concentration of radioactivity in a specific anatomic resolution CT scanners are required. region, normalised to body weight and the injected dose of the One relatively simple technique has been developed by the radiotracer), which allows for the quantification of glucose Horowitz laboratory, allowing BMAT to be visualised ex vivo utilisation, commonly in sites of inflammation, tissue repair by confocal microscopy (described in [14�� ]). Briefly, the and cancer [78]. One study in humans assessed F-FDG up- BMAT is extracted from long bones by using a needle to take into femoral and vertebral BM during a punch through the length of the diaphysis. This BMAT plug hyperinsulinaemic-euglycaemic clamp, the gold-standard in is then gently ejected onto a slide, immersed in Fluoromount- assessing insulin sensitivity [15]. This revealed that insulin G (eBioscience), cover-slipped and then visualised. This sensitivity in femoral BM, but not in vertebral BM, correlates method does not affect intrinsic fluorescence (e.g. mT/mG with whole-body insulin sensitivity and is improved by exer- reporter mice) and allows staining of neutral lipids within cise. However, it is unclear if this reflects insulin action in the BM adipocytes. BMAT or in other BM components. Indeed, in another study Studies in human subjects routinely use CT and magnetic this group used F-FDG PET/CT, combined with MRI anal- resonance spectroscopy (MRS) and imaging (MRI) methods ysis of BMAT, to further characterise BMAT metabolic func- to measure BMAT. A comprehensive review of these tech- tions. They found that vertebral BM uptake was inversely niques can be found elsewhere in this issue; however, it is associated with BMAT content in both diabetic and healthy 46 Curr Mol Bio Rep (2018) 4:41–49 Open Access This article is distributed under the terms of the Creative pigs [79]. This suggests that BMAT itself may not be highly Commons Attribution 4.0 International License (http:// insulin responsive. In addition to F-FDG, other tracers that creativecommons.org/licenses/by/4.0/), which permits unrestricted use, target, for example, translocator protein 18 kDa (TSPO) may distribution, and reproduction in any medium, provided you give appro- be useful in dissecting BMAT function. TSPO is an outer priate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. mitochondrial membrane transporter that is downregulated in both WAT and BAT during obesity [80] and can be used to image human BAT mass under thermoneutral conditions [81]. Therefore, TSPO may be useful to further understand References the phenotypic WAT/BAT properties of BMAT. 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Molecular Interaction of Bone Marrow Adipose Tissue with Energy Metabolism

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Abstract

Purpose of Review The last decade has seen a resurgence in the study of bone marrow adipose tissue (BMAT) across diverse fields such as metabolism, haematopoiesis, skeletal biology and cancer. Herein, we review the most recent developments of BMAT research in both humans and rodents, including the distinct nature of BMAT; the autocrine, paracrine and endocrine interactions between BMAT and various tissues, both in physiological and pathological scenarios; how these interactions might impact energy metabolism; and the most recent technological advances to quantify BMAT. Recent Findings Though still dwarfed by research into white and brown adipose tissues, BMAT is now recognised as endocrine organ and is attracting increasing attention from biomedical researchers around the globe. Summary We are beginning to learn the importance of BMAT both within and beyond the bone, allowing us to better appreciate the role of BMAT in normal physiology and disease. . . Keywords Bone marrow adipocytes Bone marrow adipose tissue Endocrinology and metabolism Introduction marrow adipose tissue (BMAT) constitutes over 10% of total fat mass in lean, healthy humans. BMAT further increases in In humans white adipose tissue (WAT) forms in utero and per- diverse clinical conditions, including osteoporosis, ageing, type sists throughout life. Upon formation, adipose tissue is highly 2 diabetes, and radiotherapy, with recent studies also showing active and responds rapidly to external and internal cues [1]. BMAT regulation in mild spastic cerebral palsy, paediatric non- Most commonly, adipose tissue is defined as either WAT or alcoholic fatty liver disease, inflammatory bowel disease, brown adipose tissue (BAT) and is found in discrete and de- chronic kidney disease and macrodactyly [3–13]. In stark con- fined locations throughout the body. WAT and BAT depots trast to WAT, BMAT is also increased in caloric restriction and differ both in their developmental origin and function. WAT anorexia nervosa. These observations suggest that BMAT has stores excess energy as triglycerides and, when needed, systemic metabolic actions distinct to those of WAT and BAT. catabolises these stores to release fatty acids and glycerol. In Compared to WAT and BAT, knowledge of BMAT formation contrast, BAT expresses thermogenic proteins (e.g. uncoupling and function is extremely limited, despite BMAT being identi- protein 1, UCP1) that allow it to dissipate energy through the fied over a century ago. This is partly due to the challenges production of heat [2]. In addition to WAT and BAT, bone inherent in studying a tissue so diffuse and difficult to access. However, in the last decade BMAT has seen increasing atten- tion among several research fields, including metabolism, This article is part of the Topical Collection on Molecular Biology of Bone haematopoiesis, skeletal biology and cancer. Herein, we review Marrow Fat Adiposity the most recent developments of BMAT research in both * Karla J. Suchacki humans and rodents, including the distinct nature of BMAT; ksuchack@exseed.ed.ac.uk the autocrine, paracrine and endocrine interactions between BMAT and various tissues, both in physiological and patholog- ical scenarios; how these interactions impact energy metabo- University/British Heart Foundation Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of lism; and the most recent technological advances to quantify Edinburgh, Edinburgh EH16 4TJ, UK bone marrow (BM) adiposity (Fig. 1). 42 Curr Mol Bio Rep (2018) 4:41–49 Energy storage Further ? BMAT response to 1) Insulin 2) Catecholamines and release subtypes? Is BMAT cold responsive? 2 Thermogenesis ? rBMAT Adiponectin Altered muscle transcription Paracrine and ? Leptin Major contributor of circulating leptin? endocrine interactions FFA Support haematopoiesis and tumour progression? DPP4 Promote systemic insulin resistance? Bone interactions ? Impair osteoblast function? Promote bone resorption? Provide fuel for bone cells? cBMAT Regulation of haematopoiesis in physiological and pathological 5 Haematopoiesis ? conditions? Further subtypes? Fig. 1 Unknown functions of bone marrow adipose tissue (BMAT) Recent efforts have begun to uncover the role of BMAT in cells and increases or decreases in various conditions energy metabolism, including insulin responsiveness [14�� , (reviewed [18, 21]). Adipocytes within cBMAT and rBMAT 15], the response of BMAT to catecholamines [16� ], and po- were recently shown to have different metabolic functions, tential BAT-like characteristics (see ‘BMAT—adistinctadi- with cBMAT being more resistant to lipolytic stimuli [16� ]. pose depot?’). However, it remains unclear to what extent Thus, cBMAT and rBMAT may have distinct impacts on met- BMAT acts as a site of energy storage and release, how para- abolic homeostasis. crine and endocrine actions of BMAT impact energy metabo- Beyond this potential heterogeneity between BMAT sub- lism, the ability of BMAT to interact with bone cells, and the types, a broader question is whether BMAT function overlaps role of BMAT in haematopoiesis. These topics are covered in with that of WAT or BAT. Establishing the pathophysiological the text. roles of BMAT will be crucial to determine whether it repre- sents a new target for disease treatment (reviewed in [22]). Histologically, BMAT adipocytes typically resemble those in BMAT—a Distinct Adipose Depot? WAT; however, whether BMAT is WAT- or BAT-like remains a subject of debate. Indeed, it has been reported that BM has a The development of BMAT is a normal physiological process mixed BAT/WAT population of adipocytes. Krings et al. tran- scriptionally analysed whole tibiae, revealing detectable ex- that progresses throughout the lifespan, such that by adult- hood (25 years) BMAT occupies 50 to 70% of the total bone pression of BAT markers including Prdm16, Dio2 and Pgc1α marrow volume [17]. This increase results from the BM un- [23]. Furthermore, they found that aged diabetic mice showed dergoing a red-to-yellow conversion occurring in a centripetal decreased expression of BAT markers in whole tibiae, sug- fashion [18, 19]. During normal development this red-to- gesting that BMAT function changes with ageing and diabe- yellow marrow conversion is independent of WAT accumula- tes. Most interestingly, administration of rosiglitazone, a syn- tion and slows during adulthood. However, in obesity, verte- thetic agonist for adipocyte-specific PPARγ and a potent in- bral BMAT is positively associated with visceral fat [20], sug- sulin sensitiser, significantly increased both BAT (Ucp1, gesting a relationship between BMAT and WAT development Pgc1α, Dio2, β3AR, Prdm16 and FoxC2)andWAT(Adipoq in this context. The conversion of red-to-yellow marrow in and Lep) markers in whole tibiae of normoglycemic mice, but rodents also occurs in a similar centripetal pattern and, in both not in diabetic mice [23]. More recently it has been reported that, compared with cBMAT, rBMAT is characterised by ele- rodents and humans, two distinct populations of BM adipo- cytes have been described: constitutive BMAT (cBMAT) is vated expression of beige fat markers, including Ucp1 [24]. situated in the distal long bones and (in rodents) caudal verte- However, we have shown that Ucp1 expression in whole tib- brae, while regulated BMAT (rBMAT) is situated in the prox- iae is 10,000- to 25,000-fold lower than in BAT [25]. This imal regions of long bones and in spinal vertebrae [21]. level of expression is similar to that observed by Krings cBMAT and rBMAT are not only anatomically distinct but et al. and clearly argues against BAT-like functions of also show different responses to age, weight, endocrine factors BMAT. However, these studies also highlight the technical and medical interventions. In brief, cBMAT appears in the limitations of using whole bones to represent BMAT. early postnatal period, histologically resembles WAT, and Efficient isolation of a pure population of adipocytes from mostly does not increase or decrease in response to external the bone marrow is technically very difficult, though methods stimuli or pathophysiological changes. Conversely rBMAT to achieve this have been reported [26]. Advanced imaging approaches are also allowing BMAT-specific analysis, with develops after cBMAT, is interspersed with haematopoietic Curr Mol Bio Rep (2018) 4:41–49 43 3D electron microscopy recently revealing a dense mitochon- as well as endosteum osteocytes, articular chondrocytes and drial network within BM adipocytes [27]. inguinal WAT. Furthermore, in Osx1-Cre:mT/mG mice, trac- This latter observation supports the possibility that BM ing occurred only in adipocytes in BMAT, and not those in adipocytes may have some brown- or beige-adipocyte-like WAT or BAT depots, suggesting that BMAT arises from a characteristics. Consistent with this, brown-like adipocytes mesenchymal-osteogenic lineage [36–38] (Comprehensively were observed in a BM core biopsy taken from a 74-year- reviewed in [14�� ]). Further unpublished lineage tracing stud- old man with untreated lymphoplasmacytic lymphoma. ies have shown that insulin signalling is not required for lipid The authors reported that these adipocytes were UCP1- accumulation in BMAT, but is required in WAT, providing positive and largely separated from the surrounding mar- evidence for the functional differences in regulation of adipose row, suggesting that the observed BBAT^ maybe aninci- depots [14�� ]. dental intraosseous hibernoma [22, 28]. Furthermore, 18F- FDG-PET/CT imagining of healthy young human subjects, with or without cold stimuli, identified cold-stimulated BMAT Autocrine, Paracrine and Endocrine 18F-FDG uptake in vertebral bone marrow that significant- Interactions ly correlated with 18F-FDG uptake into BAT [29]. The authors further identified expression of UCP1 and Sexual Dimorphism PRDM16 in BM from two male subjects, while histologi- cal assessment of vertebral BM from 3-week-old mice The distribution of WAT and BAT shows a clear sexual dimor- highlighted the presence of multilocular, brown-like adipo- phism [39, 40] that seems to also apply to BMAT. We have cytes that were positive for UCP1. Taken together, these found that female mice tend to have a higher volume of data suggest the presence of functional brown adipocytes rBMAT in the proximal tibial diaphysis [41], whereas in in vertebral BM of mammals. The authors suggest that the humans BM fat is higher in males than in females, at least in presence of brown adipocytes in the BM seems plausible younger adults [42]. To further explore such sex differences, given that Myf5-positive cells emerge at the juxtaspinal, Lecka-Czernik et al. investgiated the impact of sex steroids on prospectively paravertebral, regions within somites [30, BMAT [24]. While no sexual divergence in the volume and 31], and it has been well documented that BAT is derived transcriptional profile of distal BMAT was observed, ovariec- from Myf5-positive myoblastic cells [32]. tomy led to increased BMAT, increased Adipoq (adiponectin) A recent study provided further evidence for a mixed BAT/ and decreased beige fat gene markers. Orchidectomy in males WAT phenotype of BMAT both in vitro and in vivo. The also tended to increase BMAT, consistent with previous ob- authors showed that treatment of BM mesenchymal stromal servations that testosterone can decrease BMAT in female rats cells or stromal ST2 cells with triiodothyronine or a thyroid [43]. However, unlike ovariectomy, orchidectomy did not hormone receptor beta-specific agonist (GC-1) significantly change expression of Adipoq or beige fat gene markers [24]. increased expression of brown and beige fat markers. Thus, males and females may differ in how their sex steroid Furthermore, administration of GC-1 in vivo in thyroid deficiency affects BMAT formation and endocrine function −/− hormone-deficient (Tshr ) mice showed a 149-fold increase [24]. in Ucp1 expression in skeletal tissue (femoral and tibial epiph- In humans, the impact of testosterone on BMAT remains to yses). Whether this translates into detectable UCP1 protein be established, but the effects of oestrogen are similar to those expression remains to be confirmed; however, these data sug- observed in rodent studies. For example, Limonard et al. used gest not only that thyroid hormone induces the expression of MRI to measure vertebral BM fat in postmenopausal women BAT genes in mouse BMAT but, importantly, that like WAT, before, during, and following a two-week treatment with 17-β BMAT has the potential to beige [33]. estradiol. Even in such a short timescale, this treatment was Murine tracer models are crucial in search of the origin of found to rapidly decrease the BM fat fraction [44]. Consistent BMAT. In contrast with the above data, recent research has with this, in younger adults vertebral BM fat tends to be higher shown that the origin of BMAT is likely to be distinct to that of in males than in females, whereas, post-menopause, females − − WAT and BAT. WAT is derived from Myf5 /Pax7 progeni- have greater vertebral BM fat content [42]. Thus, oestrogen + + tors, while BAT is derived from Myf5 /Pax7 progenitors clearly has a profound ability to suppress BMAT formation, [14�� , 32, 34]. Strikingly, BM adipocytes are also derived which likely contributes to the sex differences in BMAT con- from progenitors that express Osterix. Once thought to be tent across the lifecourse. More recent studies suggest that osteoblast-specific, Osterix is a transcription factor that acts BMAT is also regulated by follicle-stimulating hormone downstream of Runx2/Cbfa1 and is required for osteoblast (FSH). Specifically, mice that underwent ovariectomy and differentiation [35]. Lineage tracing studies using Prx1- were then given an FSH antibody had decreased BMAT vol- Cre:mT/mG and Osx1-Cre:mT/mG showed that tibial and ume coupled with decreased fat mass and the production of UCP1-positive adipose tissue [45]. Thus, beyond oestrogen femoral BM adipocytes were traced in Prx1-Cre:mT/mG mice 44 Curr Mol Bio Rep (2018) 4:41–49 and testosterone, it will be important to determine if other sex in cases of failed bone regeneration, such as non-union frac- hormones can also regulate BMAT formation and function in ture, it remains unclear if BMAT has a positive or negative humans. impact on bone healing [57]. Most recently, Ambrosi et al. elegantly showed that BMAT exerts direct negative effects Adiponectin on bone healing and haematopoiesis in mouse models, with BM adipocytes secreting dipeptidyl peptidase-4 (DPP4) to BMAT is known to increase in caloric restriction (CR), con- inhibit fracture repair [58]. Given that DPP4 is a target of tributing to increases in circulating adiponectin [46, 47]. anti-diabetic therapies, this finding raises the intriguing possi- Adiponectin is the most abundant adipokine in the circulation bility that BMAT-derived DPP4 might impact not only skele- and can be used as a clinical biomarker for early detection of tal remodelling, but also systemic insulin resistance. conditions such as type 2 diabetes, cardiovascular diseases, Osteoarthritis (OA) is a heterogeneous disease that leads to and certain cancers. Although we have recently reviewed this the progressive loss of normal joint function and related elsewhere [47], many questions remain regarding adiponectin subchondral bone changes. OA is the most common form of secretion from BMAT and how this is altered by disease. For arthritis and represents the world’s leading cause of physical example, recent human data suggest that adiponectin may disability in adults. At a time when the population is ageing regulate the relationship between BMAT and insulin sensitiv- and the prevalence of obesity is increasing, there has never ity in obese and non-obese premenopausal women [48]. It been a greater need for the prevention of OA. Currently, OA is remains unclear if adiponectin secretion from BMAT directly routinely managed therapeutically and patients are offered influences cardiac function or the risk of cardiovascular dis- physiotherapy [59]. Traditionally, OA was considered to be a ease. Studies in rats showed that bone marrow and adipose disease of the cartilage, but more recently has been shown to mesenchymal stem cells attenuated cardiac fibrosis [49]. affect the entire joint, including the bone, synovium, tendons, However, far more research effort is required to understand and muscles [60]. The location of BMAT suggests that BM if BMAT directly impacts cardiac function or impacts other adipocytes may play a role in the pathology of OA. A recent tissues, such as the liver and pancreas, that are known to be study found increased BMAT in postmenopausal women with targeted by adiponectin [50]. both OA and osteoporosis (OP), and the authors suggested that a subgroup of OA subjects with elevated BMAT may Bone Trauma and Pathology have a high risk of developing OP [61]. Given the close proximity of BMAT to the bone, researchers Interaction of BMAT with Bone Cells have suggested that BMAT directly regulates bone metabo- lism. In the last decade, bone has emerged as a highly meta- BMAT has recently been shown to be responsive to parathy- bolic organ that contributes to the regulation of whole-body roid hormone and to secrete receptor activator of nuclear fac- metabolism [51]. Indeed, bone has the capability to regenerate tor kappa-Β ligand (RANKL), a key regulator of osteoclast without scar formation following mechanical and structural differentiation and activation [26]. This suggests that BMAT failure. This occurs typically by secondary endochondral exhibits unique osteo-resorptive characteristics. Furthermore, healing, which consists of both endochondral and murine models with decreased sclerostin (SOST) have signif- intramembranous ossification. The process of secondary en- icantly decreased BMAT [62], suggesting that BMAT forma- dochondral healing begins with haematoma formation; then tion is governed directly by osteocytes, which secrete SOST. an acute inflammatory response with pro-inflammatory sig- Currently, there is much interest in anti-SOST therapy for nalling; primary callus formation (soft callus), which un- treatment of OP. This is driving a greater consideration of dergoes revascularisation and calcification to form the hard the clinicalimplications ofBMAT, which shouldhelptofur- callus; and finally bone remodelling [52]. This process of ther our knowledge of this complex adipose depot [62, 63]. In fracture healing is highly metabolically demanding and re- murine models and human patients with low bone mineral quires the cooperation between different cell types, as recently density (BMD) and bone formation, BMAT has been shown reviewed elsewhere [53]. BM adipocytes secrete adipokines to be elevated (reviewed [64�� , 65]). Mice with a loss of func- (e.g. adiponectin), cytokines (e.g. RANKL), and free fatty tion mutation in the Dock7 gene, which results in low BMD acids that act to promote bone resorption, haematopoietic re- and reduced bone formation, have very few osteoblasts but covery and supply energy. Indeed, BMAT has been reported BMAT is increased 3.5-fold compared to wild-type controls. to be increased in subjects with prevalent vertebral fracture However, it is important to highlight that other studies have [54, 55] and prevalent vertebral deformities [56]. Despite re- not found an inverse relationship between BMD and BMAT. cent efforts, it remains unclear why BMAT increases in frac- For example, BMAT was significantly increased following ture and, specifically, why there is an intricate relationship 12 weeks of high-fat diet feeding in mice, while BMD was between bone and BMAT during bone pathology. Moreover, unchanged [66]. Furthermore, C3H/HeJ mice have increased Curr Mol Bio Rep (2018) 4:41–49 45 bone mass and BMAT compared to C57BL/6 mice [67], and worth highlighting the developments in BMAT imaging that we have shown that during CR in rabbits, bone loss can occur are particularly relevant to its metabolic characteristics and independently of BMAT expansion [41]. functions. For example, ex vivo high-resolution magic angle spinning (HRMAS) proton nuclear magnetic resonance ( H Metastasis, Myeloma and BMAT NMR) spectroscopy has recently been used in humans to de- termine the (un)saturation level of fatty acids in BMAT [75]. The interplay between tumour cells, osteoclasts and osteo- A novel, dual-energy computed tomography (DECT) method blasts is well documented, but despite occupying 50 to has also been described to assess both BMAT and marrow- 70% of the total BM volume, the relationship between corrected volumetric BMD (mcvBMD) [76]. Hopefully, these BMAT, multiple myeloma, and metastasis of breast and developments in new clinical techniques will allow re- prostate has only just begun to be understood. While be- searchers to more accurately assess BMAT’s lipid composi- yond the scope of this review, others have recently provid- tion and relationship with skeletal parameters. ed elegant overviews of the growing evidence linking Finally, imaging studies are beginning to shed light on the BMAT to tumour growth and the development of associat- metabolic functions of BMAT. Positron emission tomogra- ed bone disease [68–71]. phy–computed tomography (PETCT) is a non-invasive tech- nique allowing the visualisation of biological processes. Most simply, compounds are radiolabelled with positron-emitting 11 15 18 Technological Advances to Assess BMAT radioisotopes (e.g. C, O, and F). These radiolabelled Quantity and Metabolic Function compounds emit positrons which annihilate with electrons and produce two annihilation photons that travel in opposite As reviewed elsewhere in this issue, techniques for BMAT directions and are detected by the PET scanner. Upon detec- imaging are improving and expanding. Standard histological tion, the PETCT scanner uses various algorithms and attenu- approaches, such as haematoxylin and eosin staining of ation correction factors to hybridise the PET data with the CT paraffin-embedded sections, have been used routinely to de- images, allowing the user to visualise and analyse the anatom- tect adipocytes within BM. More recently, osmium tetroxide ical locations of the tracer. PET imaging can be conducted staining followed by micro-computed tomography (μCT) has either dynamically or statically. Clinically, static imaging is been used to visualise and quantify BMAT in situ [72]. New most common as dynamic analysis requires kinetic modelling, μCT contrast agents are currently being developed to assess which is complex and time consuming [77]. The most com- 18 18 BMAT, vasculature and nerves without the requirement for monly used radiotracer is F-fluorodeoxyglucoe ( F-FDG), time-consuming decalcification. The most recent of these a glucose analogue that is actively transported into the cell by stains, for use in contrast-enhanced microfocus computed to- glucose transporters. After import, F-FDG can be phosphor- mography (CE-CT), is a Hafnium-based Wells-Dawson ylated by hexokinase to form 2-deoxyglucose-6-phosphate; polyoxometalate (Hf-POM) [73, 74]. Hf-POM has been vali- however, unlike endogenous glucose, once phosphorylated dated in murine long bones and provides the researcher with a F-FDG is unable to continue along the glycolytic pathway and 3D representation of the mineralised bone, vasculature and instead accumulates in the cell as F-labelled 2- BMAT. These developments in contrast agents allow novel deoxyglucose-6-phosphate. This intracellular accumulation of insights into the interaction between the bone, vasculature F allows the user to calculate the standardised uptake value and BMAT. However, as for osmium μCT, specialist high- (SUV, the concentration of radioactivity in a specific anatomic resolution CT scanners are required. region, normalised to body weight and the injected dose of the One relatively simple technique has been developed by the radiotracer), which allows for the quantification of glucose Horowitz laboratory, allowing BMAT to be visualised ex vivo utilisation, commonly in sites of inflammation, tissue repair by confocal microscopy (described in [14�� ]). Briefly, the and cancer [78]. One study in humans assessed F-FDG up- BMAT is extracted from long bones by using a needle to take into femoral and vertebral BM during a punch through the length of the diaphysis. This BMAT plug hyperinsulinaemic-euglycaemic clamp, the gold-standard in is then gently ejected onto a slide, immersed in Fluoromount- assessing insulin sensitivity [15]. This revealed that insulin G (eBioscience), cover-slipped and then visualised. This sensitivity in femoral BM, but not in vertebral BM, correlates method does not affect intrinsic fluorescence (e.g. mT/mG with whole-body insulin sensitivity and is improved by exer- reporter mice) and allows staining of neutral lipids within cise. However, it is unclear if this reflects insulin action in the BM adipocytes. BMAT or in other BM components. Indeed, in another study Studies in human subjects routinely use CT and magnetic this group used F-FDG PET/CT, combined with MRI anal- resonance spectroscopy (MRS) and imaging (MRI) methods ysis of BMAT, to further characterise BMAT metabolic func- to measure BMAT. A comprehensive review of these tech- tions. They found that vertebral BM uptake was inversely niques can be found elsewhere in this issue; however, it is associated with BMAT content in both diabetic and healthy 46 Curr Mol Bio Rep (2018) 4:41–49 Open Access This article is distributed under the terms of the Creative pigs [79]. This suggests that BMAT itself may not be highly Commons Attribution 4.0 International License (http:// insulin responsive. In addition to F-FDG, other tracers that creativecommons.org/licenses/by/4.0/), which permits unrestricted use, target, for example, translocator protein 18 kDa (TSPO) may distribution, and reproduction in any medium, provided you give appro- be useful in dissecting BMAT function. TSPO is an outer priate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. mitochondrial membrane transporter that is downregulated in both WAT and BAT during obesity [80] and can be used to image human BAT mass under thermoneutral conditions [81]. Therefore, TSPO may be useful to further understand References the phenotypic WAT/BAT properties of BMAT. 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