Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues
Open accessAbstract
Marrow adipose tissue (MAT) accumulates in diverse clinical conditions but remains poorly understood. Here we show region-specific variation in MAT adipocyte development, regulation, size, lipid composition, gene expression and genetic determinants. Early MAT formation in mice is conserved, whereas later development is strain dependent. Proximal, but not distal tibial, MAT is lost with 21-day cold exposure. Rat MAT adipocytes from distal sites have an increased proportion of monounsaturated fatty acids and expression of Scd1/Scd2, Cebpa and Cebpb. Humans also have increased distal marrow fat unsaturation. We define proximal ‘regulated’ MAT (rMAT) as single adipocytes interspersed with active haematopoiesis, whereas distal ‘constitutive’ MAT (cMAT) has low haematopoiesis, contains larger adipocytes, develops earlier and remains preserved upon systemic challenges. Loss of rMAT occurs in mice with congenital generalized lipodystrophy type 4, whereas both rMAT and cMAT are preserved in mice with congenital generalized lipodystrophy type 3. Consideration of these MAT subpopulations may be important for future studies linking MAT to bone biology, haematopoiesis and whole-body metabolism.
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rBMAds and cBMAds have developmental and regulatory differences as well as distinct roles in hematopoiesis and bone remodeling.
“Given the developmental and regulatory differences between rBMAds and cBMAds as well as their distinct roles in hematopoiesis and bone remodeling61, it would be valuable to further investigate whether cBMAds in other locations, such as tail vertebrae, exhibit a similar age-related phenotype.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [61]
The Results (Strain-specific MAT development in mice) and Discussion describe distinct developmental patterns and regulatory responses for rMAT and cMAT. But the Discussion says their functions must be clarified; it proposes that rMAT is better positioned to influence haematopoiesis or skeletal remodelling, rather than establishing distinct roles for both populations. (LLM, conf=0.88)
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Bone marrow adipocytes support hematopoietic stem cell survival
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“Interestingly, in 1976 Tavassoli (1976) noted that different features are found in BM-A depending on their location within BM; Scheller et al. (2015) have recently validated his findings by describing region-specific variation in the properties of skeletal adipocytes and hypothesizing the existence…”
BackgroundQuantification and three-dimensional microanatomical organization of the bone marrow
Nombela‐Arrieta, C., & Manz, M. G. (2017) · Blood Advances · doi:10.1182/bloodadvances.2016003194 · Cited by 121 · see citing works
Bone Marrow Adiposity: Basic and Clinical Implications.
Sebo, Z. L., Rendina-Ruedy, E., Ables, G., Lindskog, D., Rodeheffer, M. S., Fazeli, P. K., & Horowitz, M. (2019) · Endocrine reviews · doi:10.1210/er.2018-00138 · Cited by 114 · see citing works
Self-citationChanges in Skeletal Integrity and Marrow Adiposity during High-Fat Diet and after Weight Loss
Scheller, E. L., Khoury, B. M., Moller, K. L., Wee, N. K. Y., Khandaker, S., Kozloff, K. M., Abrishami, S., Zamarron, B. F., & Singer, K. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00102 · Cited by 131 · see citing works
“Quantification of Marrow adipose Tissue Marrow adipose tissue volume within the tibia was assessed as described previously (37, 40).”
MethodSelf-citationHuman Bone Marrow Is Comprised of Adipocytes with Specific Lipid Metabolism
Attané, C., Estève, D., Chaoui, K., Iacovoni, J. S., Corre, J., Moutahir, M., Valet, P., Burlet‐Schiltz, O., Reina, N., & Muller, C. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.12.089 · Cited by 137 · see citing works
“Two types of murine BM-Ads have been described: regulatory and constitutive BM-Ads (rBM-Ads and cBM-Ads, respectively; Scheller et al., 2015). cBM-Ads are present in tail vertebrae and the medullary canal from the tibia-fibula junction of the malleolus.”
BackgroundInfluentialLong-Lived Plasma Cells in Mice and Men
Brynjolfsson, S. F., Berg, L. P., Ekerhult, T. O., Rimkutė, I., Wick, M. J., Mårtensson, I., & Grimsholm, O. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02673 · Cited by 118 · see citing works
“The distinction between these two adipose tissues is thus based on spatiotemporal distribution (13, 14).”
BackgroundBone marrow adipocytes resist lipolysis and remodeling in response to β-adrenergic stimulation
Scheller, E., Khandaker, S., Learman, B. S., Cawthorn, W., Anderson, L., Pham, H. A., Robles, H., Wang, Z.-H., Li, Z.-R., Parlee, S., et al. (2018) · Bone · doi:10.1016/j.bone.2018.01.016 · Cited by 105 · see citing works
“This work supports the notion that cells within the proximal, hematopoietic-rich skeletal regions (“rBMAs”) are more susceptible to remodeling and lipolysis (1).”
InfluentialSelf-citationBone Marrow Fat and Hematopoiesis
Wang, H., Leng, Y., & Gong, Y. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00694 · Cited by 115 · see citing works
“In contrast, rMAT is composed of interspersed single adipocytes, and is more closely situated in areas of high bone turnover and is better positioned to actively influence hematopoiesis and/or skeletal remodeling (18).”
BackgroundLipids in the Bone Marrow: An Evolving Perspective
Rendina-Ruedy, E., & Rosen, C. J. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.015 · Cited by 107 · see citing works
Self-citationDrilling for Oil: Tumor-Surrounding Adipocytes Fueling Cancer
Attané, C., & Muller, C. (2020) · Trends in Cancer · doi:10.1016/j.trecan.2020.03.001 · Cited by 97 · see citing works
Bagchi, D. P., Nishii, A., Li, Z., DelProposto, J. B., Corsa, C. A. S., Mori, H., Hardij, J., Learman, B. S., Lumeng, C. N.-K., & MacDougald, O. A. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101078 · Cited by 105 · see citing works
“Fatty acids within extracted lipids were derivatized into their methyl esters by trans-esteri fi cation with boron tri fl uoride-methanol as previously described [46].”
Self-citationMarrow adipose tissue composition in adults with morbid obesity
Yu, E. W., Greenblatt, L. B., Eajazi, A., Torriani, M., & Bredella, M. (2016) · Bone · doi:10.1016/j.bone.2016.12.018 · Cited by 96 · see citing works
“MAT is distinct from white or brown adipose tissue with unique gene expression and the ability to respond to nutritional status [25, 35].”
Self-citationMR-Based Assessment of Bone Marrow Fat in Osteoporosis, Diabetes, and Obesity
Cordes, C., Baum, T., Dieckmeyer, M., Ruschke, S., Diefenbach, M., Hauner, H., Kirschke, J., & Karampinos, D. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00074 · Cited by 96 · see citing works
“Furthermore, new research questions are evolving on the role of bone marrow adipocytes in bone remodeling, hematopoietic stem cell differentiation, and whole body homeostasis (73, 74), on novel non-invasive MR biomarkers specific to the distribution, composition, microstructure, and function of bone marrow adipocytes…”
BackgroundAging adipose: Depot location dictates age-associated expansion and dysfunction
Bank, H. C. V., Kirsh, C., & Simcox, J. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101259 · Cited by 100 · see citing works
“Throughout life, regulated MAT (rMAT) begin to occupy red bone marrow [117, 118].”
BackgroundLi, Z.-R., Bowers, E., Zhu, J., Yu, H., Hardij, J., Bagchi, D. P., Mori, H., Lewis, K. T., Granger, K., Schill, R. L., et al. (2022) · bioRxiv · doi:10.7554/elife.78496 · Cited by 92 · see citing works
Self-citationThe Unique Metabolic Characteristics of Bone Marrow Adipose Tissue
Li, Y.-J., Meng, Y., & Yu, X.-J. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00069 · Cited by 92 · see citing works
“Nevertheless, there is possibility that both regulated and constitutive MAT adipocytes exist in the same position (26).”
BackgroundMethodInfluentialCharacterization of the bone marrow adipocyte niche with three-dimensional electron microscopy
Robles, H., Park, S., Joens, M. S., Fitzpatrick, J. A. J., Craft, C. S., & Scheller, E. L. (2018) · Bone · doi:10.1016/j.bone.2018.01.020 · Cited by 95 · see citing works
Self-citationAblation of Fat Cells in Adult Mice Induces Massive Bone Gain
Zou, W., Rohatgi, N., Brestoff, J., Li, Y.-J., Barve, R., Tycksen, E., Kim, Y., Silva, M. J., & Teitelbaum, S. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.09.011 · Cited by 90 · see citing works
“Marrow Fat osmium staining and μCT—marrow fat osmium was stained with osmium tetroxide according to previously described (Scheller et al., 2015).”
Methodde Bournonville, S., Vangrunderbeeck, S., & Kerckhofs, G. (2019) · Contrast Media & Molecular Imaging · doi:10.1155/2019/8617406 · Cited by 84
“Notwithstanding the widespread use of OsO4 as a staining dye for unsaturated lipids, it is highly toxic and has a limited tissue penetration capability [12].”
BackgroundMethodInfluentialTratwal, J., Labella, R., Bravenboer, N., Kerckhofs, G., Douni, E., Scheller, E., Badr, S., Karampinos, D., Beck-Cormier, S., Palmisano, B., et al. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00065 · Cited by 82 · see citing works
“In mice, smaller BMAds (31–33μm cell diameter) are interspersed between hematopoietic cells in the femur, the proximal portion of the tibia, and almost all skeletal segments that contain hematopoietic BM, while larger BMAds (38–39 um) are localized in the distal portion of the tibiae and phalanx [(12); Figure 1].”
BackgroundSelf-citationBone health in diabetes and prediabetes
Costantini, S., & Conte, C. (2019) · World Journal of Diabetes · doi:10.4239/wjd.v10.i8.421 · Cited by 84 · see citing works
Kerckhofs, G., Stegen, S., van Gastel, N., Sap, A., Falgayrac, G., Penel, G., Durand, M., Luyten, F., Geris, L., Vandamme, K., et al. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2017.12.016 · Cited by 80
Macrophages in epididymal adipose tissue secrete osteopontin to regulate bone homeostasis
Dai, B., Xu, J., Li, X., Huang, L., Hopkins, C., Wang, H., Yao, H., Mi, J., Zheng, L., Wang, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-021-27683-w · Cited by 87 · see citing works
Inside out: Bone marrow adipose tissue as a source of circulating adiponectin
Scheller, E. L., Burr, A. A., MacDougald, O. A., & Cawthorn, W. P. (2016) · Adipocyte · doi:10.1080/21623945.2016.1149269 · Cited by 79 · see citing works
“For example, several papers report that CR does increase adiponectin mRNA and/or protein expression in WAT (Table 1), suggesting that WAT does contribute to hyperadiponectinemia under these conditions of CR. Surprisingly, one of these studies also finds that CR leads to increased adiponectin expression in skeletal mus…”
BackgroundResultInfluentialSelf-citationFerland-McCollough, D., Maselli, D., Spinetti, G., Sambataro, M., Sullivan, N., Blom, A., & Madeddu, P. (2018) · Diabetes · doi:10.2337/db18-0044 · Cited by 75 · see citing works
“Investigation of BM-AD content by osmium tetroxide and micro computed tomography imaging may allow a more direct approach to visualize global changes of adiposity throughout the bone (48).”
BackgroundPanaroni, C., Yee, A. J., & Raje, N. S. (2017) · Current Osteoporosis Reports · doi:10.1007/s11914-017-0397-5 · Cited by 81 · see citing works
Marrow Adipocytes: Origin, Structure, and Function
de Paula, F. J. A., & Rosen, C. J. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034513 · Cited by 79 · see citing works
“However, in animal models, regulated marrow adipocytes are more responsive to adrenergic drive than constitutive marrow adipocytes (43, 44).”
BackgroundSelf-citationBone marrow adipose tissue: formation, function and regulation
Suchacki, K. J., Cawthorn, W. P., & Rosen, C. J. (2016) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2016.03.001 · Cited by 78 · see citing works
Self-citationBone marrow adipose tissue as an endocrine organ: close to the bone?
Sulston, R. J., & Cawthorn, W. (2016) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2016-0012 · Cited by 71 · see citing works
Self-citationBone marrow fat changes after gastric bypass surgery are associated with loss of bone mass
Kim, T. Y., Schwartz, A., Li, X.-J., Xu, K.-P., Black, D. M., Petrenko, D., Stewart, L., Rogers, S. J., Posselt, A., Carter, J. T., et al. (2017) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3212 · Cited by 67 · see citing works
“Although marrow adipocyte characteristics differ in the spine compared with the femur,((42)) and our study involved vertebral marrow fat evaluation only, others have demonstrated moderate correlations between the two sites.”
BackgroundRegulation of Glucose Handling by the Skeleton: Insights From Mouse and Human Studies
Liu, J.-M., Rosen, C., Ducy, P., Kousteni, S., & Karsenty, G. (2016) · Diabetes · doi:10.2337/db16-0053 · Cited by 67 · see citing works
“Sympathetic activation by b-adrenergic agents or cold induction reduces marrow adiposity but without any browning of marrow adipocytes (28).”
BackgroundResultInfluentialSelf-citationInflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis
Zioni, N., Bercovich, A. A., Chapal-Ilani, N., Bacharach, T., Rappoport, N., Solomon, A., Avraham, R., Kopitman, E., Porat, Z., Sacma, M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36906-1 · Cited by 67 · see citing works
Human bone marrow adipocytes display distinct immune regulatory properties
Miggitsch, C., Meryk, A., Naismith, E., Pangrazzi, L., Ejaz, A., Jenewein, B., Wagner, S., Nägele, F., Fenkart, G., Trieb, K., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.07.023 · Cited by 71 · see citing works
“The role of adipose tissue in the BMmicroenvironment is largely unknown, and contrary to classical tsWAT depots, its morphology and functionality is insufficiently described [20,21].”
BackgroundMyeloma Cells Down-Regulate Adiponectin in Bone Marrow Adipocytes Via TNF-Alpha
Morris, E. V., Suchacki, K. J., Hocking, J., Cartwright, R., Sowman, A., Gámez, B., Lea, R., Drake, M. T., Cawthorn, W. P., & Edwards, C. M. (2019) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3951 · Cited by 68 · see citing works
“Indeed, KaLwRij mice are a sister strain of the B6 mouse, which have low levels of regulated fat until later in life.((29)) At younger ages, as in our mice, regulated BMAds are dispersed among hematopoietic cells, whereas constitutive BMAds are clustered together resembling the tightly packed structure of adipocytes i…”
BackgroundSelf-citationThe Differentiation Balance of Bone Marrow Mesenchymal Stem Cells Is Crucial to Hematopoiesis
Wu, J., Zhang, W., Ran, Q., Xiang, Y., Zhong, J. F., Li, S. C., & Li, Z. (2018) · Stem Cells International · doi:10.1155/2018/1540148 · Cited by 66 · see citing works
“They can be divided into rMAT (regulated marrow adipose tissues) and cMAT (constitutive marrow adipose tissues) based on their characteristics [100].”
BackgroundInfluentialIdentification and Dissection of Diverse Mouse Adipose Depots
Bagchi, D. P., & MacDougald, O. (2019) · Journal of Visualized Experiments · doi:10.3791/59499 · Cited by 63 · see citing works
Self-citationBone marrow adipose tissue-derived stem cell factor mediates metabolic regulation of hematopoiesis
Zhang, Z., Huang, Z., Ong, B., Sahu, C., Zeng, H., & Ruan, H. (2019) · Haematologica · doi:10.3324/haematol.2018.205856 · Cited by 78 · see citing works
“However, a minimal amount of MAT is present at the age of one week in mice and MAT rapidly expands afterwards.(52) We argue that the hematopoietic defects observed in adult Adipoq-Cre;Kitlmice were largely due to SCF excision during adulthood.”
BackgroundGusky, H. C., Diedrich, J. D., MacDougald, O., & Podgorski, I. (2016) · Obesity Reviews · doi:10.1111/obr.12450 · Cited by 63 · see citing works
“However, the possibility that different postnatal lineages for adipocytes and osteoblasts exist may explain the lack of correlation between increasedMATand decreased bone density in various strains of mice (22,101) and in fatty bones induced by high-fat diet (102).”
BackgroundInfluentialSelf-citationConstitutive bone marrow adipocytes suppress local bone formation
Li, Z.-R., Bagchi, D. P., Zhu, J., Bowers, E., Yu, H., Hardij, J., Mori, H., Granger, K., Skjaerlund, J., Mandair, G., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.160915 · Cited by 62 · see citing works
“Previous studies have profiled the differences in size, fatty acid composition (2, 39), and lipolysis (40) between rBMAT and cBMAT; however, functional differences between these subpopulations were not well delineated.”
InfluentialSelf-citationDistinct skeletal stem cell types orchestrate long bone skeletogenesis
Ambrosi, T. H., Sinha, R., Steininger, H. M., Hoover, M. Y., Murphy, M. P., Koepke, L. S., Wang, Y., Lu, W.-J., Morri, M., Neff, N. F., et al. (2021) · eLife · doi:10.7554/elife.66063 · Cited by 70 · see citing works
“In agreement with the original reports, we found that ocSSCs/BCSPs are enriched in micro-dissected non-marrow fractions of femurs while pvSSCs and the committed APCs are more evenly distributed but accumulate at the ends of long bones where coincidentally BMAT first appears (Figure 2A and Figure 2—figure supplement 1A…”
ResultAdipokines, adiposity, and bone marrow adipocytes: Dangerous accomplices in multiple myeloma
Morris, E., & Edwards, C. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26884 · Cited by 60 · see citing works
“However, the lipid content is thought to differ with rBMAT preferentially storing saturated fats and cBMAT unsaturated fats (Scheller et al., 2015), this could suggest that they have distinct functions that may influence the adipokines they secrete.”
BackgroundHawkes, C., & Mostoufi-Moab, S. (2018) · Bone · doi:10.1016/j.bone.2018.03.012 · Cited by 60 · see citing works
“[80] Iliac bone biopsies in osteoporotic individuals demonstrate increased MAT volume and decreased trabecular bone volume compared with age-matched controls, suggesting increased fracture risk in individuals with increased MAT.”
BackgroundInfluentialSimilarities Between Disuse and Age-Induced Bone Loss
Buettmann, E. G., Goldscheitter, G., Hoppock, G. A., Friedman, M. A., Suva, L. J., & Donahue, H. J. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4643 · Cited by 59 · see citing works
“For example, both C57BL/6J and C3H/HeJ mice show an age-related increase in bMAT in the distal and proximal tibia, albeit to differing extents, that occurs between skeletal maturity and 1 year of age.((187)) In humans, from skeletal maturity to middle age, marrow fat increases by 5%–10% per decade in both sexes before…”
BackgroundLorenz, M. R., Brazill, J. M., Beeve, A. T., Shen, I. R., & Scheller, E. L. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4273 · Cited by 61 · see citing works
“1G), also consistent with prior comparisons at this region and age.((34)) Trabecular bone was largely absent in the tibial diaphysis of both B6 and C3H mice (L2 to L4).”
ResultSelf-citationBone Marrow Adipocytes: The Enigmatic Components of the Hematopoietic Stem Cell Niche
Cuminetti, V., & Arranz, L. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8050707 · Cited by 58 · see citing works
“For example, C57BL/6J mice accumulate rBMAT in proximal tibia later than C3H/HeJ mice [13].”
BackgroundInfluentialQiang, G., Kong, H. W., Xu, S., Pham, H. A., Parlee, S. D., Burr, A. A., Gil, V., Pang, J., Hughes, A., Gu, X., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.05.005 · Cited by 51 · see citing works
“In the distal tibia, which has been previously characterized as constitutive MAT [28], ablation of the IR significantly decreased total volume of MAT compared to WT controls (Figure 3A).”
MethodResultSelf-citationRobinson, M. J., Webster, R. H., & Tarlinton, D. M. (2020) · Immunological Reviews · doi:10.1111/imr.12895 · Cited by 58 · see citing works
Cahu, X., Calvo, J., Poglio, S., Prade, N., Colsch, B., Arcangeli, M., Leblanc, T., Petit, A., Baleydier, F., Baruchel, A., et al. (2017) · Blood Advances · doi:10.1182/bloodadvances.2017004960 · Cited by 55 · see citing works
“The adipocyte-rich BM appears around birth and develops during the first weeks of life in the distal skeleton including hands, feet, and distal tibia in humans and tail vertebrae in rodents, giving rise to constitutive marrow adipose tissue.(14) Later, during childhood and early adulthood, BM adipocytes develop at the…”
BackgroundInfluentialMarrow Adipose Tissue: Skeletal Location, Sexual Dimorphism, and Response to Sex Steroid Deficiency
Lecka-Czernik, B., Stechschulte, L. A., Czernik, P., Sherman, S. B., Huang, S.-L., & Krings, A. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00188 · Cited by 55 · see citing works
“On the other hand, caloric restriction increases MAT volume predominantly in proximal but not in distal location (7).”
BackgroundMethodSkeletal energy homeostasis: a paradigm of endocrine discovery
Suchacki, K. J., Roberts, F. L., Lovdel, A., Farquharson, C., Morton, N. M., MacRae, V. E., & Cawthorn, W. P. (2017) · Journal of Endocrinology · doi:10.1530/joe-17-0147 · Cited by 47 · see citing works
“MAT consists of two subtypes: constitutive MAT (cMAT) and regulated MAT (rMAT). cMAT is found predominantly in the distal skeleton, giving the bone marrow a yellow appearance (Scheller et al .”
Self-citationRole of adipose tissues in osteoarthritis
Zapata-Linares, N., Eymard, F., Berenbaum, F., & Houard, X. (2021) · Current Opinion in Rheumatology · doi:10.1097/bor.0000000000000763 · Cited by 54 · see citing works
“Both of them differ by the time of their development, their localization in the skeleton, their gene expression pattern and their content in saturated/unsatured lipids [86].”
BackgroundBone Marrow Adipocyte: An Intimate Partner With Tumor Cells in Bone Metastasis
Luo, G., He, Y.-D., & Yu, X.-J. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00339 · Cited by 54 · see citing works
“BMAs were well preserved in Cav1 knockout mice; however, Ptrf knockout resulted in a significant reduction of rBMAs (proximal tibial) instead of cBMAs (distal tibia) (9).”
BackgroundInfluentialTan, Z., Kong, M., Wen, S., Tsang, K. Y., Niu, B., Hartmann, C., Chan, D., Hui, C.-C., & Cheah, K. S. E. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.4132 · Cited by 52 · see citing works
“This finding is consistent with the reported variation in adipocyte development between proximal and distal tibias.((50)) To investigate whether specific ablation of Irx3 and Irx5 would affect the fate determination of HC-derived cells, we double-labeled cells with HC lineage marker and adipocyte marker Perilipin at t…”
ResultTratwal, J., Rojas‐Sutterlin, S., Bataclan, C., Blum, S., & Naveiras, O. (2021) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2021.101564 · Cited by 61 · see citing works
“Meanwhile Ptrf-/- mice, a model of congenital generalized lipodystrophy 4, selectively inhibits the formation of rBMAds; however the effect on hematopoiesis has not yet been reported [110].”
BackgroundInfluentialAdipocytes in hematopoiesis and acute leukemia: friends, enemies, or innocent bystanders?
Zinngrebe, J., Debatin, K., & Fischer‐Posovszky, P. (2020) · Leukemia · doi:10.1038/s41375-020-0886-x · Cited by 54 · see citing works
“proposing the concept of regulated MAT (rMAT) and constitutive MAT (cMAT) [41].”
BackgroundInfluentialHuman Bone Marrow Adipose Tissue is a Metabolically Active and Insulin-Sensitive Distinct Fat Depot
Pham, T., Ivaska, K., Hannukainen, J., Virtanen, K., Lidell, M. E., Enerbäck, S., Mäkelä, K., Parkkola, R., Piirola, S., Oikonen, V., et al. (2020) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/clinem/dgaa216 · Cited by 52 · see citing works
Molecular differences between subtypes of bone marrow adipocytes
Craft, C. S., Li, Z.-R., MacDougald, O., & Scheller, E. (2018) · Current Molecular Biology Reports · doi:10.1007/s40610-018-0087-9 · Cited by 52 · see citing works
Self-citationAdipose, Bone and Myeloma: Contributions from the Microenvironment
McDonald, M., Fairfield, H., Falank, C., & Reagan, M. (2016) · Calcified Tissue International · doi:10.1007/s00223-016-0162-2 · Cited by 52 · see citing works
Baroi, S., Czernik, P. J., Chougule, A., Griffin, P. R., & Lecka‐Czernik, B. (2021) · Bone · doi:10.1016/j.bone.2021.115913 · Cited by 56 · see citing works
Ruschke, S., Pokorney, A. L., Baum, T., Eggers, H., Miller, J. H., Hu, H., & Karampinos, D. (2017) · Magnetic Resonance Materials in Physics, Biology and Medicine · doi:10.1007/s10334-017-0617-0 · Cited by 51 · see citing works
Motyl, K. J., Guntur, A. R., Carvalho, A., & Rosen, C. J. (2017) · Toxicologic Pathology · doi:10.1177/0192623317737065 · Cited by 51 · see citing works
“Furthermore, stimulation of the SNS through cold exposure, or treatment with antipsychotic drugs, promotes marrow fat loss, suggesting fat is lipolyzed for fuel in these cases (Scheller et al. 2015; Motyl et al. 2015).”
BackgroundSelf-citationSulston, R. J., Learman, B. S., Zhang, B.-F., Scheller, E., Parlee, S., Simon, B., Mori, H., Bree, A. J., Wallace, R., Krishnan, V., et al. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00128 · Cited by 50 · see citing works
“These MAT subtypes also differ in their lipid composition and response to external stimuli (4).”
BackgroundSelf-citationThe dynamics of human bone marrow adipose tissue in response to feeding and fasting
Fazeli, P. K., Bredella, M., Pachón-Peña, G., Zhao, W.-X., Zhang, X., Faje, A., Resulaj, M., Polineni, S., Holmes, T. M., Lee, H., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.138636 · Cited by 49 · see citing works
“responsive to systemic challenges compared to proximal skeletal BMAT sites(21).”
BackgroundSelf-citationDo polyunsaturated fatty acids protect against bone loss in our aging and osteoporotic population?
Martyniak, K., Wei, F., Ballesteros, A., Meckmongkol, T. T., Calder, A. N., Gilbertson, T. A., Orlovskaya, N. A., & Coathup, M. J. (2020) · Bone · doi:10.1016/j.bone.2020.115736 · Cited by 49 · see citing works
Bravenboer, N., Bredella, M., Chauveau, C., Corsi, A., Douni, E., Ferris, W., Riminucci, M., Robey, P., Rojas-Sutterlin, S., Rosen, C., et al. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00923 · Cited by 47 · see citing works
“Thus, it was recommended to use BMAds to represent bone marrow adipocytes.”
BackgroundInfluentialSelf-citationQuantification of Bone Fatty Acid Metabolism and Its Regulation by Adipocyte Lipoprotein Lipase
Bartelt, A., Koehne, T., Tödter, K., Reimer, R., Müller, B., Behler-Janbeck, F., Heeren, J., Scheja, L., & Niemeier, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18061264 · Cited by 51 · see citing works
“Of note, region-specific differences in the responsiveness of BMAs to high-fat diet feeding [11] or caloric restriction [46] have also been described, in that they appear more plastic and regulated in the proximal tibiae and more constitutive, less reactive in the distal tibia.”
BackgroundA T Cell View of the Bone Marrow
Bonomo, A. C., Monteiro, A. C., Gonçalves-Silva, T., Cordeiro-Spinetti, E., Galvani, R. G. A., & Balduíno, A. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00184 · Cited by 53 · see citing works
“Recent data, however, indicate that the hypothesis of a direct impact of MAT accumulation on skeletal tissue balance disruption is controversial, as adipocytes in the BM may present distinctive phenotypes, resembling either brown or white adipocytes, with potential different interactions with the skeletal tissue (53,…”
BackgroundBusilacchi, E. M., Morsia, E., & Poloni, A. (2024) · Cells · doi:10.3390/cells13090724 · Cited by 60 · see citing works
“In mice, BMAT is located in the red marrow of the tibia proximal to the fibula junction, in the femur, and in the axial skeleton [6].”
BackgroundResultInfluentialZhang, X., Robles, H., Magee, K. L., Lorenz, M. R., Wang, Z.-H., Harris, C. A., Craft, C. S., & Scheller, E. (2021) · eLife · doi:10.7554/elife.66275 · Cited by 45 · see citing works
“The development and subsequent regulation of bone marrow adipocytes (BMAds) varies between skeletal sites (Scheller et al., 2019; Scheller et al., 2015; Craft et al., 2018; Scheller and Rosen, 2014a), and current work suggests that BMAds are functionally unique within the context of their niche (Robles et al.”
BackgroundInfluentialSelf-citationMcilroy, G., Suchacki, K., Roelofs, A., Yang, W., Fu, Y.-Y., Bai, B., Wallace, R., Bari, C. D., Cawthorn, W., Han, W., et al. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.01.019 · Cited by 45 · see citing works
“We next examined the MAT located in the caudal vertebrae of the tail, which has also been considered a region of cMAT [36].”
Self-citationHigh Spatial Resolution MALDI Imaging Mass Spectrometry of Fresh-Frozen Bone
Good, C. J., Neumann, E. K., Butrico, C., Cassat, J., Caprioli, R., & Spraggins, J. M. (2022) · Analytical Chemistry · doi:10.1021/acs.analchem.1c04604 · Cited by 44 · see citing works
de Bournonville, S., Vangrunderbeeck, S., Ly, H. G. T., Geeroms, C., Borggraeve, W. D., Parac-Vogt, T., & Kerckhofs, G. (2020) · Acta Biomaterialia · doi:10.1016/j.actbio.2020.01.038 · Cited by 44
Burian, E., Subburaj, K., Mookiah, M., Rohrmeier, A., Hedderich, D., Dieckmeyer, M., Diefenbach, M., Ruschke, S., Rummeny, E., Zimmer, C., et al. (2019) · Osteoporosis International · doi:10.1007/s00198-019-04924-9 · Cited by 44
Daily leptin blunts marrow fat but does not impact bone mass in calorie restricted mice
Devlin, M. J., Brooks, D. J., Conlon, C., van Vliet, M., Louis, L., Rosen, C. J., & Bouxsein, M. (2016) · Journal of Endocrinology · doi:10.1530/joe-15-0473 · Cited by 44 · see citing works
Self-citationWee, N. K. Y., Lorenz, M. R., Bekirov, Y., Jacquin, M. F., & Scheller, E. L. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00668 · Cited by 39 · see citing works
“Relative to B6 mice, C3H mice are known to have a significant expansion of BMAT in the proximal tibia by 12-weeks of age (29).”
BackgroundInfluentialSelf-citationBone marrow adipose tissue in metabolic health
Pachón-Peña, G., & Bredella, M. A. (2022) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2022.03.003 · Cited by 52 · see citing works
Self-citationFat and bone: the multiperspective analysis of a close relationship
Gómez, M. P. A., Benavent, C. A., Simoni, P., Aparisi, F., Guglielmi, G., & Bazzocchi, A. (2020) · Quantitative Imaging in Medicine and Surgery · doi:10.21037/qims.2020.01.11 · Cited by 53 · see citing works
“Only a few years ago, two types of MAT were described in rodents (14).”
Background
- Authors
- 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.
- Affiliations
- University of Michigan (US)
- Maine Medical Center Research Institute (US)
- Boston University (US)
- Harvard University (US)
- Corresponding author
- Scheller, Erica L.
- MacDougald, Ormond A.
- ORCID
- Venue
- Nature Communications
- Published
- 2015-08-06
- Volume
- 6
- Issue
- 1
- Pages
- 13775-13775
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4530473
- OpenAlex
- W2155268144
- Cited by
- 433
- References
- 57
- Citations by year
- 2026: 25 · 2025: 36 · 2024: 36 · 2023: 40 · 2022: 36 · 2021: 39 · 2020: 63 · 2019: 49 · 2018: 49 · 2017: 31 · 2016: 25 · 2015: 2 · 2014: 1
- FWCI
- 26.01
- Type
- journal article
- Language
- en
- Update notices
- correction (2016-12-08)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Eli Lilly and Company
- University of Michigan (DK089503)
- Royal Commission for the Exhibition of 1851
- National Institutes of Health (5k99de024178-02, 1s10rr026336-01a1, AR44927, K99-DE024178, DK089503)
- National Institute of Diabetes and Digestive and Kidney Diseases (K23DK094820, R24DK092759, R01DK097708, P30DK020572, P30DK089503, P30DK040561)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 44927, R29AR044927, R56AR044927, R01AR044927)
- National Institute of Dental and Craniofacial Research (K99-DE024178, R00DE024178)
- National Center for Research Resources (S10-RR026336)
- Michigan Nutrition Obesity Research Center, Medical School, University of Michigan (P30-DK089503, DK089503)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- marrow adipose tissue, bone marrow fat, adipocyte development, cold exposure, monounsaturated fatty acids, CEBPA, CEBPB, hematopoiesis, lipid composition
- MeSH terms
- Animals, Bone Marrow, Bone Marrow Cells, Cold Temperature, Fatty Acids, Female, Humans, Male, Membrane Proteins, Mice, Inbred C3H, Mice, Inbred C57BL, Transcription Factors, RNA-Binding Proteins, Rats, Sprague-Dawley, Adipocytes, Mice, Knockout, Lipid Metabolism, Proton Magnetic Resonance Spectroscopy
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