Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues

Abstract

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, while later development is strain dependent. Proximal, but not distal, 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 hematopoiesis, whereas distal ‘constitutive’ MAT (cMAT) has low hematopoiesis, 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, hematopoiesis and whole-body metabolism.

Expansion of Bone Marrow Adipose Tissue During Caloric Restriction Is Associated With Increased Circulating Glucocorticoids and Not With Hypoleptinemia

“…This is consistent with an early study of starvation in rabbits, which shows that BM adiposity decreases more in proximal bones (eg, humeri and femurs) than in distal regions (eg, tibiae, radii, and ulnae) (63). This is also consistent with our recent research that identifies regionally distinct MAT subtypes with different characteristics: cMAT exists at distal sites and is relatively refractory to external stimuli, whereas rMAT is interspersed within RM at proximal skeletal sites and is more responsive to external stimuli, such as cold exposure (43). Our present analyses confirm and extend these observations by revealing that CR-associated MAT expansion predominantly occurs within rMAT, whereas increases in cMAT are far less pronounced ( Figure 5, A and B).…”

“…As expected, in both sexes CR was associated with decreased body mass (Supplemental Figure 4, A and B), hyperadiponectinemia (Supplemental Figure 4, C and F), and significant MAT expansion, as assessed by analysis of osmium tetroxide-stained tibiae ( Figure 5, A and B). MAT expansion occurred predominantly in the proximal tibia, from the growth plate to tibia-fibula junction, consistent with this region containing "regulated" MAT (rMAT) that is more responsive to external stimuli than the "constitutive" MAT (cMAT) in the distal tibia (43). However, other effects of CR differed between males and females.…”

“…MAT volume in distinct tibial regions was then quantified and is presented relative to total tibial marrow volume, as described previously (43). Osmium tetroxide staining could not be used for quantitation of MAT volume in rabbit bones, because the osmium tetroxide is unable to stain beyond the periphery of these large tissues, especially those that are densely packed with fat (E. L. Scheller, unpublished observations).…”

Quantification and three-dimensional microanatomical organization of the bone marrow

“…Of note, multiple studies suggest that marrow adipose tissue is heterogeneous in terms of adipocytic and lipid content, regional distribution, and regulatory function. 59,60 Finally, stromal cell networks are built around the proteic acellular backbone created by fibers of extracellular matrix (ECM). Studies in BM and other lymphoid organs indicate that highly plastic ECM networks could play vital roles in steady state as well as pathological hematopoiesis.…”

SnapShot: Niche Determines Adipocyte Character I

“…Marrow adipose tissue, contained within bone, can be classified in rodents as constitutive (distal tibia and caudal vertebrae) or regulated (mid-to-proximal tibia, femur, and lumbar vertebrae) (Scheller et al, 2015). Understudied depots that are likely to have important local roles include intramuscular adipocytes interspersed between fibers of skeletal muscles; periarticular adipocytes (e.g., infrapatellar) surrounding or within joints; paracardial and epicardial depots that surround the heart; and retro-orbital, which lies behind the eye.…”