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Bone Marrow Adipose Tissue Is a Unique Adipose Subtype with Distinct Roles in Systemic Glucose Homeostasis Running Title bioRxiv preprint doi: https://doi.org/10.1101/673129; this version posted June 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 1 Bone marrow adipose tissue is a unique adipose subtype with distinct roles in 2 systemic glucose homeostasis 3 4 Running Title: Marrow adipose tissue is a distinct, major subtype of adipose tissue 5 6 Karla J. Suchacki1, Adriana A.S. Tavares1, Domenico Mattiucci1,2, Erica L. Scheller3, 7 Giorgos Papanastasiou4, Calum Gray4, Matthew C. Sinton1, Lynne E. Ramage1, Wendy A. 8 McDougald1, Andrea Lovdel1, Richard J. Sulston1, Benjamin J. Thomas1, Bonnie M. 9 Nicholson1, Amanda J. Drake1, Carlos J. Alcaide-Corral1, Diana Said1, Antonella Poloni2, 10 Saverio Cinti2,5, Gavin J. MacPherson6, Marc R. Dweck1, Jack P.M. Andrews1, Michelle C. 11 Williams1, Robert J. Wallace7, Edwin J.R. van Beek4, Ormond A. MacDougald8, Nicholas M. 12 Morton1, Roland H. Stimson1 and William P. Cawthorn1*. 13 14 1University/BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's 15 Medical Research Institute, Edinburgh BioQuarter, 47 Little France Crescent, Edinburgh, 16 EH16 4TJ, Scotland, UK. 2Dipartimento di Scienze Cliniche e Molecolari, Clinica di 17 Ematologia, Università Politecnica delle Marche, Ancona, Italy. 3Division of Bone and 18 Mineral Diseases, Department of Medicine, Washington University, St. Louis, MO, USA. 19 4Edinburgh Imaging, University of Edinburgh, UK. 5Dipartimento di Medicina Sperimentale 20 e Clinica, Center of Obesity, Università Politecnica delle Marche, Ancona, Italy. 6Department 21 of Orthopaedic Surgery, Royal Infirmary Edinburgh, UK. 7Department of Orthopaedics, The 22 University of Edinburgh, UK. 8Department of Molecular & Integrative Physiology, University 23 of Michigan, Ann Arbor, MI, USA. 24 25 26 *Correspondence to: William Cawthorn, University/BHF Centre for Cardiovascular 27 Science, The Queen’s Medical Research Institute, Edinburgh BioQuarter, 47 Little France 28 Crescent, Edinburgh, EH16 4TJ. [email protected] 29 30 31 32 Keywords: 33 Bone marrow adipose tissue, bone marrow adipocytes, white adipose tissue, brown adipose 34 tissue, beige adipose tissue, PET/CT, glucose homeostasis, insulin, cold exposure, bone 1 bioRxiv preprint doi: https://doi.org/10.1101/673129; this version posted June 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 35 HIGHLIGHTS 36 37 • Bone marrow adipose tissue (BMAT) is molecularly distinct to other adipose 38 subtypes. 39 • BMAT is less insulin responsive than WAT and, unlike BAT, is not cold-responsive. 40 • Human BMAT has greater basal glucose uptake than axial bone or subcutaneous 41 WAT. 42 • We establish a PET/CT method for BMAT localisation and functional analysis in vivo. 2 bioRxiv preprint doi: https://doi.org/10.1101/673129; this version posted June 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 43 SUMMARY 44 45 Bone marrow adipose tissue (BMAT) represents >10% of total adipose mass, yet unlike 46 white or brown adipose tissues (WAT or BAT), its role in systemic metabolism remains 47 unclear. Using transcriptomics, we reveal that BMAT is molecularly distinct to WAT but is 48 not enriched for brown or beige adipocyte markers. Instead, pathway analysis indicated 49 altered glucose metabolism and decreased insulin responsiveness in BMAT. We therefore 50 tested these functions in mice and humans using positron emission tomography–computed 51 tomography (PET/CT) with 18F-fluorodeoxyglucose, including establishing a new method for 52 BMAT identification from clinical CT scans. This revealed that BMAT resists insulin- and 53 cold-stimulated glucose uptake and is thus functionally distinct to WAT and BAT. However, 54 BMAT displayed greater basal glucose uptake than axial bones or subcutaneous WAT, 55 underscoring its potential to influence systemic glucose homeostasis. These PET/CT 56 studies are the first to characterise BMAT function in vivo and identify BMAT as a distinct, 57 major subtype of adipose tissue. 3 bioRxiv preprint doi: https://doi.org/10.1101/673129; this version posted June 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 58 INTRODUCTION 59 60 Adipose tissue plays a fundamental role in systemic energy homeostasis. In mammals it is 61 typically classified into two major subtypes: white adipose tissue (WAT), which stores and 62 releases energy and has diverse endocrine functions; and brown adipose tissue (BAT), 63 which mediates adaptive thermogenesis (Cinti, 2018). Cold exposure and other stimuli also 64 cause the emergence of brown-like adipocytes within WAT, typically referred to as “beige” 65 adipocytes (Cinti, 2018). White, brown and beige adipocytes have attracted extensive 66 research interest, owing largely to their roles and potential as therapeutic targets in 67 metabolic diseases. 68 69 Adipocytes are also a major cell type within the bone marrow (BM), accounting for up to 70 70% of BM volume. Indeed, this BM adipose tissue (BMAT) can represent over 10% of total 71 adipose tissue mass in healthy adults (Cawthorn et al., 2014). BMAT further accumulates in 72 diverse physiological and clinical conditions, including aging, obesity, type 2 diabetes and 73 osteoporosis, as well as therapeutic contexts such as radiotherapy or glucocorticoid 74 treatment. Strikingly, BMAT also increases in states of caloric restriction (Scheller et al., 75 2016). These observations suggest that BMAT is distinct to WAT and BAT and might impact 76 the pathogenesis of diverse diseases. However, unlike WAT and BAT, the role of BMAT in 77 systemic energy homeostasis remains poorly understood. 78 79 The metabolic importance of WAT is highlighted in situations of both WAT excess (obesity) 80 and deficiency (lipodystrophy), each of which leads to systemic metabolic dysfunction (Cinti, 81 2018). This largely reflects the key role of WAT as an insulin target tissue. Adipocyte-specific 82 ablation of the insulin receptor in mice causes insulin resistance, glucose intolerance and 83 dyslipidaemia (Qiang et al., 2016; Sakaguchi et al., 2017). Similar effects result from 84 adipocytic deletion of Slc2a4 (Glut4), the insulin-sensitive glucose transporter (Abel et al., 85 2001). Conversely, adipocyte-specific overexpression of Slc2a4 reverses insulin resistance 86 and diabetes in mice predisposed to diabetes (Carvalho et al., 2005). Thus, insulin- 87 stimulated glucose uptake is fundamental to WAT’s role in systemic metabolic homeostasis. 88 89 In contrast to WAT, the defining function of BAT is in mediating adaptive thermogenesis via 90 uncoupled respiration. This is driven by mitochondria expressing uncoupling protein-1 91 (UCP1), which are abundant in brown adipocytes. Cold exposure is the classical stimulator 92 of BAT activity: cold-induced glucose uptake is a hallmark of BAT activation and can be 93 quantified in vivo using positron emission tomography–computed tomography (PET/CT) 94 with 18F-fluorodeoxyglucose (18F-FDG) (Cinti, 2018; Ramage et al., 2016a). Cold exposure 95 or chronic sympathetic stimulation exert similar effects on beige adipocytes, and activation 96 of brown or beige adipocytes can enhance energy expenditure (Cinti, 2018). Consequently, 97 the past decade has seen extensive interest in activating BAT, or promoting beiging of WAT, 98 to treat metabolic disease (Cinti, 2018). 99 100 Compared to WAT and BAT, study of BMAT has been relatively limited. However, given its 101 abundance and clinical potential (Scheller et al., 2016), BMAT is now attracting increasing 102 attention, with several studies beginning to investigate its metabolic properties. BM 103 adipocytes (BMAds) have been proposed to exist in two broad subtypes: ‘constitutive’ 104 BMAds (cBMAds) appear as contiguous groups of adipocytes that predominate at distal 105 skeletal sites, whereas ‘regulated’ BMAds (rBMAds) occur interspersed with the 106 haematopoietic BM in the proximal and axial skeleton (Craft et al., 2018). Both subtypes are 107 morphologically similar to white adipocytes, with large unilocular lipid droplets; however, 108 their lipid content differs, with cBMAds having a greater proportion of unsaturated fatty acids 109 than rBMAds or white adipocytes (Scheller et al., 2016). Like white adipocytes, BMAds also 4 bioRxiv preprint doi: https://doi.org/10.1101/673129; this version posted June 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 110 produce adipokines such as leptin and adiponectin (Sulston and Cawthorn, 2016) and can 111 release free fatty acids in response to lipolytic stimuli, albeit to a lesser extent than WAT 112 (Scheller et al., 2018; Tran et al., 1981). This lipolysis resistance is more pronounced for 113 rBMAds, underscoring the functional differences in BMAd subtypes. 114 115 Despite these advances in understanding of BMAT lipid metabolism, its insulin 116 responsiveness and role in systemic glucose homeostasis is poorly understood. PET/CT 117 studies have demonstrated glucose uptake into whole bones or BM of animal models and 118 humans (Huovinen et al., 2016; Huovinen et al., 2014; Nishio et al., 2012; Zoch et al., 2016), 119 but uptake specifically into BMAT has not previously been examined. Whether BMAT is 120 BAT- or beige-like is also debated (Scheller et al., 2016).
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