Bone marrow adipose tissue is a unique adipose subtype with distinct roles in systemic glucose homeostasis

Abstract

Bone marrow adipose tissue, bone marrow adipocytes, white adipose tissue, brown adipose 33 tissue, beige adipose tissue, PET/CT, glucose homeostasis, insulin, cold exposure, bone 34 1 HIGHLIGHTS 35 36 • Bone marrow adipose tissue (BMAT) is molecularly distinct to other adipose 37 subtypes. 38 • BMAT is less insulin responsive than WAT and, unlike BAT, is not cold-responsive. 39 • Human BMAT has greater basal glucose uptake than axial bone or subcutaneous 40 WAT. 41• We establish a PET/CT method for BMAT localisation and functional analysis in vivo. 42 2 SUMMARY 43 44Bone marrow adipose tissue (BMAT) represents >10% of total adipose mass, yet unlike 45 white or brown adipose tissues (WAT or BAT), its role in systemic metabolism remains 46 unclear. Using transcriptomics, we reveal that BMAT is molecularly distinct to WAT but is 47 58 59Adipose tissue plays a fundamental role in systemic energy homeostasis. In mammals it is 60 typically classified into two major subtypes: white adipose tissue (WAT), which stores and 61 releases energy and has diverse endocrine functions; and brown adipose tissue (BAT), 62 which mediates adaptive thermogenesis (Cinti, 2018). Cold exposure and other stimuli also 63 cause the emergence of brown-like adipocytes within WAT, typically referred to as "beige" 64 adipocytes (Cinti, 2018). White, brown and beige adipocytes have attracted extensive 65 research interest, owing largely to their roles and potential as therapeutic targets in 66 metabolic diseases. 67 68 Adipocytes are also a major cell type within the bone marrow (BM), accounting for up to 69 70% of BM volume. Indeed, this BM adipose tissue (BMAT) can represent over 10% of total 70 adipose tissue mass in healthy adults (Cawthorn et al., 2014). BMAT further accumulates in 71 diverse physiological and clinical conditions, including aging, obesity, type 2 diabetes and 72 osteoporosis, as well as therapeutic contexts such as radiotherapy or glucocorticoid 73 treatment. Strikingly, BMAT also increases in states of caloric restriction (Scheller et al., 74 2016). These observations suggest that BMAT is distinct to WAT and BAT and might impact 75 the pathogenesis of diverse diseases. However, unlike WAT and BAT, the role of BMAT in 76 systemic energy homeostasis remains poorly understood. 77 78 The metabolic importance of WAT is highlighted in situations of both WAT excess (obesity) 79 and deficiency (lipodystrophy), each of which leads to systemic metabolic dysfunction (Cinti, 80 2018). This largely reflects the key role of WAT as an insulin target tissue. Adipocyte-specific 81 ablation of the insulin receptor in mice causes insulin resistance, glucose intolerance and 82 dyslipidaemia (Qiang et al., 2016; Sakaguchi et al., 2017). Similar effects result from 83 adipocytic deletion of Slc2a4 (Glut4), the insulin-sensitive glucose transporter (Abel et al., 84 2001). Conversely, adipocyte-specific overexpression of Slc2a4 reverses insulin resistance 85 and diabetes in mice predisposed to diabetes (Carvalho et al., 2005). Thus...

Standardised Nomenclature, Abbreviations, and Units for the Study of Bone Marrow Adiposity: Report of the Nomenclature Working Group of the International Bone Marrow Adiposity Society

“…do not undergo cold-induced glucose uptake (108). However, multilocular BMAds do exist and account for around 5% of all BMAds in the long bones of mice (107).…”

“…SECT-based measurements of BM density, expressed in Hounsfield Units, correlate inversely with BMA; however, these measurements include the density of yellow and red marrow as well as trabecular bone, and therefore do not allow for direct quantification of BMA (142). Nevertheless, several recent studies have used SECT to estimate relative adipose volume within the BM based on HU thresholds indicative of adipose tissue (108,143). In contrast to SECT, DECT is able to separate BMA from the other tissue components, allowing true quantification of BMA.…”

Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow

“…It is well-accepted that bone marrow adipocytes (BMAds) originate from BMSCs which also give rise to osteoblasts and osteocytes 3 . Marrow adipose tissue (MAT) accounts for approximately 10% of the total fat mass and about 70% of the whole bone marrow volume in healthy adult humans 4 . However, ectopic BMAds accumulation often occurs in diverse clinical conditions including obesity, diabetes, anorexia nervosa, glucocorticoid treatment, radiotherapy, menopause and ageing, most of which are concomitant with bone deterioration 5 .…”