Purpose of Review
To highlight recent basic, translational, and clinical works demonstrating exercise and diet regulation of marrow adipose tissue (MAT) and bone and how this informs current understanding of the relationship between marrow adiposity and musculoskeletal health.
Marrow adipocytes accumulate in the bone in the setting of not only hypercaloric intake (calorie excess; e.g., diet-induced obesity) but also with hypocaloric intake (calorie restriction; e.g., anorexia), despite the fact that these states affect bone differently. With hypercaloric intake, bone quantity is largely unaffected, whereas with hypocaloric intake, bone quantity and quality are greatly diminished. Voluntary running exercise in rodents was found to lower MAT and promote bone in eucaloric and hypercaloric states, while degrading bone in hypocaloric states, suggesting differential modulation of MAT and bone, dependent upon whole-body energy status. Energy status alters bone metabolism and bioenergetics via substrate availability or excess, which plays a key role in the response of bone and MAT to mechanical stimuli.
Marrow adipose tissue (MAT) is a fat depot with a potential role in—as well as responsivity to—whole-body energy metabolism. Understanding the localized function of this depot in bone cell bioenergetics and substrate storage, principally in the exercised state, will aid to uncover putative therapeutic targets for skeletal fragility.
An Inverse Relationship Between Adipocytes and Other Cells in the Bone Marrow Niche Led to Initial Scientific Investigations
Marrow adipose tissue (MAT), a depot that rises in states of skeletal fragility like osteoporosis, associates with reduced bone quantity and increased fracture risk [1,2,3,4]. As a responsive component of the marrow microenvironment, MAT and its physiologic function have garnered increased interest. Distinct from white and brown adipose depots, adipocytes anatomically join hematopoietic and mesenchymal precursors and related cells within the marrow niche and may play a key role in hematopoietic function [5,6,7]. MAT’s locus within bone, as well as a limited ability to access and isolate it from other bone marrow components, led to a knowledge gap in the scientific community’s understanding of MAT physiology vis-à-vis that of other fat depots.
Initial studies noted that marrow adiposity might serve as a filler tissue—i.e., a depot that occupies space and lacks physiologic purpose. In the 1930s, MAT’s rise with aging was referred to as a conversion from “red” to “yellow” marrow, suggesting that as hematopoietic cells diminish with aging, adipose tissue take up space as a “cushion” . An early report from 1971 by Meunier and colleagues posed, “is the decline in bone volume occurring in parallel with changes in the volume of marrow cell populations?” . In the 1980s, “yellow” marrow or marrow adipocytes were shown to be the product of terminal differentiation of mesenchymal stem cell (MSC) progenitors within bone [10, 11]. In sum, the field was initially focused on understanding the connection between MAT and hematopoietic cells and, in this setting, the inverse relationship of marrow adipocytes and bone began to be investigated.
The earliest quantitative analyses of marrow adipocytes in the late 1980s, at the University of Barcelona, noted the very problem facing researchers today, as they attempted to extrapolate two dimensional histologic data into the three-dimensional plane using geometry and statistical techniques to calculate marrow adipocyte number and diameter per cubic millimeter [12, 13]. These early quantitative analyses of marrow adipocytes emerged more than a decade after similar inquiry had been published in adipocytes in muscle , highlighting the uniqueness of this depot. It would be many years later that osmium staining combined with μCT was applied to visualize fat in rodent bones, facilitating region-of-interest quantification , and eventually a volumetric whole-bone, advanced medical image analysis workflow [16, 17] that can also be harnessed to analyze MAT via high-resolution MR imaging [18, 19]. As we solve methodologic challenges in the field, work begins to quantify and phenotype MAT which may uncover its physiologic function.
The initial discovery of the relationship between MAT and bone in osteoporosis sparked further interest in the link between bone, lean mass, body weight, and MAT [20, 21]. In recent years, our knowledge about bone in the setting of aging and disease has expanded via experiments that apply dietary and exercise interventions to ask fundamental questions about this depot’s functional purpose. A PubMed search using common MeSH terms for MAT yields 5041 results, of which 77% were published in the last 20 years, demonstrating a steep rise in interest in this field. Early studies demonstrating an inverse relationship between MAT and bone raised questions about the purpose of the MSC-derived adipocytes, prompting cell culture, translational, and clinical investigations which begin to shed light on mechanisms and targets for osteoporosis.
Marrow Adipose Tissue Accrues in Well-Perfused Trabecular Sites and Is Responsive to Exercise, Aging, and Caloric Intake
Histological assessment of marrow adipocytes (Fig. 1) identifies cellular “ghosts,” typically via staining of paraffin-embedded specimens. As noted above, recent advances in the quantification of MAT include imaging techniques, like osmium staining combined with μCT, as well as 9.4T MRI with advanced volumetric image analysis [16, 17, 19, 22]. In-depth characterization at the cellular level has been performed via 3D electron microscopy of marrow adipocytes at the proximal tibial metaphysis, revealing polarized deposits with a dense mitochondrial network—Robles et al. describe these cells as having the hallmarks of metabolically active cells . Interestingly, analysis at the caudal vertebra was limited due to the extremely high density of adipocytes at that site. These findings lend credence to recent detection of regional variance in marrow adipocytes, which associates with presence or absence of hematopoietic cells . We and others have evaluated MAT at hematopoietic sites adjacent to joints that experience a high degree of mechanical loading, like the femoral and tibial metaphyses and vertebrae [24, 25].
MAT expansion typically occurs with aging and is exacerbated by high fat feeding and obesity [25, 26]. MAT content is maximal at the growth plate, and the accumulation of MAT occurs progressively outwards from the metaphysis towards the diaphysis. Importantly, the addition of one average size adipocyte (~ 5.5 × 104 μm3) to the bone marrow niche displaces ~ 30 hematopoietic cells in mice . In fact, a 20% increase in MAT can displace ~ 50,000 hematopoietic cells, though the full extent of how MAT accumulation impacts hematopoiesis, both at a cellular level and clinically, has not yet been elucidated .
Marrow Adipocyte Locularity Resembles White Adipocytes, yet Function Remains to Be Elucidated
Marrow adipocytes physically resemble white adipose tissue, exhibiting a unilocular morphology akin to that seen in white fat depots and contrasting with the multilocular morphology of brown fat depots. MAT gene expression may overlap with beige/brown adipose (Table 1), though differing reports exist, which may depend on animal models applied . Recent analyses suggest that marrow fat might not be enriched in brown/beige-like genes and may be metabolically unique based on experiments in rabbits and humans .
In brown adipose tissue, and other cell types with a high energy demand (e.g., skeletal muscle), tethering of lipid droplets to mitochondria occurs via Perilipin (PLIN) 1 [34, 35]. Mitochondrial tethering to lipid droplets is hypothesized to serve as an efficient way to drive lipid-dependent ATP production . Tethered lipid droplets may display fundamental differences in metabolism than non-tethered counterparts . Increased PLIN5 induces lipid droplet-mitochondrial tethering, though mitochondrial binding partner of PLIN5 has not been identified . Tethering is reduced with cold exposure–induced brown adipogenesis, while starvation increases tethering [36, 37]. Marrow adipocytes, like brown adipocytes, exhibit a dense mitochondrial network , yet little is known about tethering in MAT. PLIN1 and PLIN5 are not only expressed by marrow adipocytes, but both PLIN1 and PLIN5 are increased in whole tibia in hypercaloric settings, suggesting that the tethering of lipid droplets to mitochondria may occur in MAT [19, 28]. The full extent of the physiologic role mitochondrial tethering plays in the regulation of metabolism in adipose depots, and its role specifically in MAT, remains to be elucidated.
Marrow adipocytes exhibit relatively high expression of genes involved in early adipocyte differentiation (e.g., C/ebpβ) and inflammatory cytokines (e.g., TNFα, IL6) and relatively low expression of adipocyte specific genes (e.g., Pparg, Fabp4) . MAT is composed predominantly of triglycerides, like WAT, and few have noted a difference in terms of lipid saturation in the marrow [33, 38]. Bone marrow has also been noted to demonstrate evidence of de novo lipogenesis ; however, this was post-irradiation in mice and thus it is unknown if this is physiologically relevant in the non-irradiated state. If de novo lipogenesis is ongoing in bone marrow, glucose uptake might serve this purpose as well. Questions remain about the metabolic function of adipocytes in the marrow and the purpose they might serve in normal as well as osteoporotic states.
Metabolic Functionality of Marrow Adipose Tissue: a Potential Mediator of Fracture Risk?
MAT is known to increase not only in states of skeletal fragility, like anorexia and calorie restriction, but also in states like obesity, where there is an association with greater bone mass, rather than skeletal fragility. It remains unknown how the mechanisms through which MAT accumulates and contributes to bone remodeling differ across disease states. Recent image analysis techniques in humans (e.g. 1H-MRS) have put forth marrow lipid unsaturation index as a correlate with skeletal integrity , with a lower unsaturation index linked to osteoporosis and fragility fractures [30, 39]. In fact, unsaturation of marrow adipocytes may be a by-product of marrow adipose tissue dysfunction, which induces declines in metabolic function [40,41,42]. Fat metabolism may be a key mediator in the crosstalk between fat and bone, particularly in the case of impaired fat metabolism seen in obesity . While improved metabolic and adipose tissue function are correlated with improved bone quality , little research has been performed to understand marrow adipose tissue dysfunction and its contribution to bone loss and fracture risk. Pharmacologic therapies (i.e., bisphosphonates, denosumab) reduce MAT while increasing bone density in patients with bone fragility, like osteoporosis [45,46,47,48]. MAT, found in patients with increased risk of fracture [1,2,3,4], is likely distinct from MAT in other states such as obesity. Much remains unknown about the causal relationship governing MAT’s association with fracture risk despite this being a central question in studies of marrow adipocytes.
Cellular Bioenergetics in the Marrow Niche
Metabolic pathways provide fuel in the form of adenosine triphosphate (ATP) to active, growing, and differentiating cells. Tremendous energy is required for musculoskeletal anabolism with recent work focused on understanding the metabolic capacity of cells in the bone marrow niche as well as their preferred metabolic pathways, thus enabling an improved understanding of marrow adipocytes and their relationship with bone and hematopoietic cells. Oxidative phosphorylation, occurring primarily in the mitochondria, provides ATP more efficiently than other pathways, such as anaerobic glycolysis , though glycolysis may impart other advantages, like lower levels of oxidative stress . Understanding the metabolic requirements of cells housed in bone will facilitate our ability to promote these anabolic pathways, particularly in disease states. Here we discuss bioenergetic pathways of key cells in the bone marrow niche and the clinical implications of these processes to bone health (Table 2).
Mesenchymal Lineage Cells Exhibit Metabolic Switching in Quiescent Versus Active State
Mesenchymal stem cells (MSC) were noted in cell culture to rely on glycolysis during quiescence and active—i.e., proliferating or differentiating—states . In fact, glucose-free media added to cultured MSC lead to rapid cell death . However, glycolysis is not solely used by MSC; when active, MSC upregulate oxidative phosphorylation while maintaining similar level of glycolysis in vitro . Further, mitochondria within MSC change in morphology from disparate organelles to a connected network during differentiation, consistent with activation of oxidative phosphorylation . Undifferentiated MSC possess high levels of hypoxia-inducible transcription factor 1α (HIF-1α), a known inhibitor of oxidative phosphorylation , which is downregulated when MSC become active . Hypoxia signaling pathways in MSC and other stem cell populations, including hematopoietic stem cells (HSC), are integral to facilitate metabolic switching between glycolytic and oxidative metabolism .
Osteoblasts rely on both glucose as well as fatty acids for energy needs [49,50,51, 70]. In mice, glucose uptake is mediated in osteoblasts predominantly by glucose transporter 1 (GLUT1) [49,50,51], as the deletion of GLUT1 suppresses osteoblast differentiation in vitro and in vivo . Regulation of substrate utilization (e.g., glucose, amino acids, fatty acids) by osteoblasts occurs via Wnt signaling. Substrate usage activation via Wnt appears to be dependent upon the stage of osteoblast development, with Wnt signaling promoting glycolysis and glutaminolysis via mTORC in osteoblast progenitor and bone lining cells [50, 52, 53]. In mature osteoblasts, oxidative phosphorylation is promoted via Wnt-Lrp5 co-activation, which induces downstream accumulation of β-catenin and ultimately activates gene expression required for oxidation of long-chain fatty acids [54, 70]; mature osteoblasts also exhibit significantly greater mitochondrial density than both progenitors and bone lining cells [55, 71]. Loss and gain of function in Lrp5 co-receptors in osteoblasts confirm the reliance of mature osteoblasts on oxidative phosphorylation , as do work in mutated carnitine palmitoyltransferase 2, an enzyme integral for fatty acid oxidation, in osteoblasts and osteocytes . In exercising mice, bone formation is upregulated alongside genes associated with oxidative phosphorylation, such as PLIN3, and MAT is reduced, further suggesting osteoblasts utilize fat as a substrate [19, 70, 72]. The metabolism of osteocytes, terminally differentiated osteoblasts embedded in bone matrix, has, to date, not been investigated. Given their origin, it is likely that osteocytes exhibit a similar metabolic profile to osteoblasts, though the unique confines of the osteocytic environment may outweigh their origin. Recent methodological advances, such as the development of cell culture models like the stem cell–derived osteocyte model, will allow for future research into osteocyte metabolism .
Marrow adipocyte transcriptional control is thought to be unique and to favor oxidative phosphorylation over glucose metabolism, though the exact balance is not known on a “whole-organism” level due to complexity in isolating this depot from surrounding tissues [29, 32, 57, 73]. In addition to MAT’s function in energy storage, it may also be a source of circulating factors, like Kit ligand, mediating metabolism of HSC [7, 74]. Selective deletion of Kit ligand from marrow adipocytes impairs hematopoietic function, providing evidence for MAT as a potential regulator of hematopoiesis [7••].
Hematopoietic Lineage Cells Differentially Utilize Glycolytic and Oxidative Metabolism
Hematopoiesis, bone cells, and MAT are highly interconnected components of the marrow niche, with bone and MAT thought to be integral for HSC function [5, 7, 74]; similarly, HSC-derived osteoclasts are integral for bone metabolism. HSC rely predominantly on glycolysis during quiescent periods. Glycolysis results in low levels of reactive oxygen species and low oxidative stress is essential for survival of quiescent HSC . HSC may rely on FOXO3, a key regulator of oxidative stress, for this coupling of mitochondrial metabolism and HSC homeostasis , though HSC metabolism is also regulated via HIF-1α, as a potent inducer of anaerobic metabolism. Similar to MSC, HSC exhibit metabolic switching to oxidative phosphorylation when active via downregulation of HIF-1α [58, 75]. Erythrocyte progenitors, responsible for production of the most abundant blood cell and terminally differentiated HSC lineage cell, rely predominantly on glucose via the pentose phosphate pathway, glutamine, and iron metabolism to produce ~ 2.4 million erythrocytes per second [59, 60].
Osteoclasts, like HSC and MSC, have been shown to exhibit metabolic switching of substrate utilization, dependent upon the stage of differentiation and maturation [61, 76]. Osteoclastogenesis strongly relies on mitochondrial oxidative phosphorylation, consistent with the dense mitochondrial network observed in mature osteoclasts [77, 78]. In vitro work has documented significant reductions in cellular proliferation of osteoclasts in high glucose media (e.g., 20–100 mM) . The inhibition of oxidative phosphorylation in vitro drastically reduced osteoclast differentiation, while the absence of glucose did not , suggesting that osteoclast differentiation can occur without glucose as a substrate, but not without oxidative phosphorylation. Interestingly, bone resorption requires both glucose and glutamine as substrates, in addition to oxidative phosphorylation, though evidence for this has only been demonstrated in vitro [77, 78]. Metabolically, both osteoblasts and osteoclasts utilize oxidative phosphorylation, yet osteoblast activity is not routinely promoted simply with an abundance of fuel; and in the setting of aging, it is osteoclastic resorption that exceeds formation. Recent work by Weivoda et al. investigated energy metabolism, bone formation, and bone resorption utilizing denosumab to biologically ablate osteoclasts in post-menopausal women to identify secreted factors coupling bone resorption and formation . These significant experiments applying RNA-seq of centrifuged bone biopsies—in the setting of denosumab therapy—identified genes involved in osteoblast to osteoclast coupling. Specifically, osteoclast-derived dipeptidyl peptidase IV (DPP4), a serine exopeptidase and known target for diabetes therapy, was noted to be significantly downregulated by denosumab and thus might be an important link between RANKL signaling and energy metabolism.
Whole-Body Energy Balance Emerges as Integral in Regulation of Bone and Marrow Adipose Tissue
In a hypercaloric state, the accumulation of MAT correlates well with accumulation of white fat depots in obese humans, suggesting a shared mechanism to accommodate higher caloric intake and energy storage . It was previously expected that excess lipid in bone would be harmful to bone health; however, exercise-induced bone formation is promoted, even to a larger extent, in obese rodents, suggesting that MAT might be beneficial to the skeleton in this setting [19, 80]. Conversely, exercise provides a stimulus for bone growth that when combined with high fat feeding appears to promote bone quantity while limiting MAT via potential utilization of marrow adipocyte as a fuel source .
Intriguingly in a hypocaloric state, like anorexia and calorie restriction (CR), MAT increases while other adipose stores decline [18, 79, 81]. Modest CR leads to significant accumulation of MAT and degradation of bone alongside significant increases in CD36, a key regulator of metabolic flexibility and promotor of fatty acid uptake [18••]. Exercise during CR further exacerbates CR-induced bone loss, alongside decreased MAT [18••]. With hypocaloric intake, mechanical loading/exercise appears unable to stimulate bone formation which might be due to the quality of the marrow adipocyte depot in this state. As bone formation requires a great deal of energy, it might be advantageous, in the setting of CR, to resorb rather than form bone.
Dietary Interventions Serve to Advance Understanding of the Relationship Between MAT and Bone
Marrow Adipose Tissue Is Not Inherently Pathological in a Hypercaloric State
The relationship between bone, MAT, and caloric excess/obesity was recently elegantly reviewed in Pagnotti et al. . In contrast to osteoporotic conditions, MAT volume can increase in states where bone is preserved or increased; this is well exemplified during the rapid growth of puberty, where MAT expansion and bone acquisition both increase in eucaloric and hypercaloric settings . Further, MAT and bone quantity both increase in high-fat diet (HFD) feeding and obesity in humans and rodents [43, 83, 84]. We previously showed 6 weeks of HFD feeding increases MAT without decreasing bone quantity in female mice, suggesting that marrow adipocytes might function similarly to white adipocytes, converting fat calories into new and larger adipocytes [16, 85, 86]. Diet-induced obesity increases MAT expression of Fsp27, a gene involved in determining lipid storage capacity and required for efficient energy storage and for formation of unilocular lipid droplets . Hence, MAT and bone quantity are not necessarily inversely proportional . This suggests that MAT and its relationship with bone health are complex and may not be solely regulated by preferential biasing of MSC.
Hypocaloric States Promote Marrow Adipose Accumulation and Degradation of Bone
Modest calorie restriction (CR) is associated with increased longevity in aged mice; however, CR exerts a detrimental impact on bone health, particularly in young, growing animals. While total body fat stores are reduced with CR, MAT paradoxically accumulates. Twelve weeks of 30% CR in young male mice diminished bone mass and structure, suppressed bone turnover via reduced bone formation and enhanced bone resorption, and induced MAT accumulation . In female mice, exercise combined with 30% CR further degraded bone despite reducing MAT stores [18••]. Additional energy expenditure via running exercise combined with a hypocaloric state likely negates the mechanical stimulus for bone formation and enhances bone resorption, based on Pontzer’s constrained energy expenditure model, further impairing bone health [89, 90]. CR in obese humans reduces visceral and subcutaneous depots but does not impact vertebral MAT . In contrast, anorexic women exhibit greater MAT in lumbar vertebra and femora compared with normal weight controls . Interestingly, 8% CR in obese mice yielded similar detrimental effects to those documented by McGrath and colleagues [18••]; however, simultaneous exercise and CR in mice mitigated both weight-loss induced deterioration of bone and accumulation MAT . Taken together, these data suggest a differential modulation of bone and MAT with exercise in CR dependent upon whole-body energy status.
MAT Accumulation and Bone Loss in a Eucaloric State
With whole-body energy homeostasis, or a eucaloric state, bone loss can occur and, while linked to mechanical loading/unloading and energy status, bone fragility can be additionally mediated by a multitude of factors including: aging, genetic, hormonal, or nutritional status. In such states, mechanisms of bone loss are diverse and beyond the scope of this review. Control diet and sedentary groups in experimental manipulation of caloric intake and expenditure (e.g., exercise) provide insights for mechanisms of bone loss in a eucaloric state. Conclusions made from such experiments, however, may not be generalizable to other states of skeletal fragility. Exercise in the eucaloric state promotes trabecular and cortical bone formation alongside reductions in MAT volume, suggesting utilization of MAT to fuel bone formation [16, 19, 94].
Vitamin and Mineral Intake May Impact Bone and MAT Independently of Whole-Body Energy Status
Vitamins and minerals influence bone health independent of energy status and can alter the effects of dietary and activity interventions. For example, dietary phosphate restriction significantly impairs bone mass and enhances MAT accumulation via suppression of osteogenic genes and activation of adipogenic genes . Similarly, vitamin D, calcium, and potassium deficiencies, as well as trace minerals like magnesium, negatively impact bone mass and mineralization [96,97,98], though impacts on MAT have not been well characterized.
Mechanical Loading and Unloading Interventions to Understand Exercise Regulation of MAT and Bone
While metabolic factors play a central role in maintaining healthy tissue, especially those compromised by poor diet and sedentary lifestyles, one of the principal and universal components derived from physical exertion in general, and various exercise modalities, is the mechanical loading environment. Whether high-magnitude (e.g., weight-lifting, running) or low-magnitude (e.g., balance, vibration), mechanical loading has the unique ability to suppress adiposity while providing regulatory cues of musculoskeletal anabolism and/or homeostatic regulation of bone and muscle [99,100,101,102,103]. In contrast, without mechanical input, cells will default to a state of energy conservation (i.e., adipogenic over osteogenic) rather than utilization. This discrepancy in MSC lineage outcome highlights the interdependency of the mechanical loading environment and bone homeostasis. Further, mechanical loading highlights crosstalk within the musculoskeletal system, whereby muscle and bone signaling is integral for proper function of both tissues. While beyond the scope of this review, the intersection of muscle, muscle-bone crosstalk, and fat metabolism is an integral component of exercise regulation of the musculoskeletal system (reviewed in ).
Mechanical Unloading of the Skeleton Induces Marrow Adipose Accumulation and Bone Loss
Severe loss of muscle and bone due to disuse or mechanical unloading, clinically termed osteo-sarcopenia, is correlated with high morbidity and mortality [45, 104]. Musculoskeletal tissue dependency on mechanical forces is well illustrated in circumstances where mechanical forces are absent, as exemplified by chronic bedrest, disuse, and through conditions of microgravity [105, 106]. Exposure to microgravity and resulting unloading-induced bone loss was first documented following astronaut missions in the late 1970s. Early studies using rodents flown in space were the first to demonstrate increased MAT at the humeral and femoral metaphases with just 18.5 days of weightlessness . Ground-based models of unloading, using tail suspension, induce reduction of femoral bone mass and volume and accumulation of MAT via suppression of dynamic markers of bone formation (marrow apposition rate, mineralizing surface, bone formation rate) and enhancement of relative osteoclast surface and number [108, 109]. Osteocyte apoptosis, assessed via the percentage of empty lacunae, resulting from tail suspension or targeted ablation of osteocytes, occurs alongside MAT accumulation and bone loss [110, 111]. Gene expression in the femora of unloaded mice reveals the downregulation of bone formation markers osteocalcin, type 1 collagen, and Cbfa1 and upregulation of adipocyte markers Pparg, Cebpα, and Cebpβ . Keune and colleagues document exacerbated loss of trabecular bone with 2 weeks of hindlimb unloading in MAT-deficient mice, achieved via loss of function in cKit receptor (KitW/W-v), though KitW/W-v mice have higher baseline bone volume and connective density of trabecular bone . Surprisingly, osteoblast perimeter, marrow apposition rate, and bone formation rate are elevated in unloaded MAT-deficient mice relative to genotype and loading controls, which contrasts with significant trabecular bone loss. It is worth noting that this study was conducted at thermoneutral temperature (32 °C), rather than room temperature (22 °C), which suppresses MAT accumulation, measured via adipocyte number, and BAT-like gene expression in rodents . Further, Kit ligand, also known as stem cell factor, has been recently elucidated as a mediator of metabolic regulation of HSC and loss of Kit ligand function significantly impairs hematopoietic function [7, 74].
As experienced by astronauts subjected to sustained microgravity and chronic bed-rest analogs, skeletal unloading results in significant, and potentially irreversible, bone loss, though the degree to which this is observed is highly variable between individuals [113, 114]. In addition to bone loss, skeletal unloading has been documented to directly correlate with increased MAT in aging, osteoporosis, and bed-rest models [115,116,117]. Healthy young women and men exposed to 60 days of bed rest experienced significant increases in MAT at the lumbar vertebrae at the expense of bone [115, 116]. Intriguingly, vertebral MAT accumulation after 60 days of bed rest in healthy young women was maintained 1 year later alongside reductions in hematopoietic markers, suggesting irreversible changes to the vertebral niche .
Mechanical Loading of the Skeleton Induces Differential Effects on Marrow Adipose Tissue and Bone Dependent upon Mode of Exercise
Voluntary wheel running, a frequently applied model of physical activity in rodents, improves trabecular and cortical bone mass and structure with concurrent reductions in marrow adiposity in states of hypercaloric or eucaloric intake [16, 17, 19, 118,119,120]; though this is not the case in hypocaloric states. Exercise benefits from wheel running are equally as evident in the setting of HF feeding; however, reductions in MAT occur here via reduced adipocyte size, rather than number [16, 17, 19]. HF feeding, in sedentary and exercising mice, is associated with greater Fsp27, a promoter of fat storage, and PLIN5, a promoter of beta-oxidation, while PLIN1, a promoter of fat utilization during starvation, is greater with exercise irrespective of diet . Metabolically, greater utilization of fat stores and upregulation of beta oxidation likely fuel bone formation in wheel running mice with MAT as a local fuel source [19, 70, 72]. In sum, voluntary wheel running consistently improves bone mass while reducing MAT in hyper- and eucaloric, but not hypocaloric, states.
Running in rodents additionally affects bone deferentially depending on whether it is voluntary (e.g., wheel running) or forced (e.g., treadmill running), graded (e.g., level, uphill, downhill), and short- or long-term, among other variables. Downhill treadmill running of 10° or more appears to be consistently detrimental to bone, while uphill running promotes large gains in bone mass, volume, and structure [121, 122]. In fact, ground reaction forces to the hindlimbs, measured in cats, are lesser with a downhill slope than level running, while an uphill slope results in larger ground reaction forces . Given the degree of mechanical input is the principal determinant of the stimulus for bone growth, this likely explains the differential effect of slope on bone outcomes. Level running, while less anabolic than uphill running, beneficially impacts bone [122, 124,125,126] and lessens MAT . Interestingly, Wallace and colleagues report that, despite greater peak strains engendered at the forelimbs during level treadmill running in young female rats, minimal changes are seen in microarchitecture and geometry of the humerus, radius, and ulna, while the tibia and femur undergo significant and widespread improvements to trabecular and cortical bone . The differential response of the forelimbs documented by Wallace et al. coincided with reduced MSC responsiveness in the forelimbs, suggesting that responsivity to loading may be more important for bone growth . Mechanical stimuli promote MSC lineage selection towards osteogenesis and suppress adipogenesis in vitro, and treadmill running may elicit a similar response in vivo. In fact, 4 and 8 weeks of treadmill running reduced MAT at the proximal tibial metaphysis relative to sedentary controls, though bone mass remained unchanged . Treadmill running exercise, whether level or uphill, across young to old rodent ages, consistently improves trabecular bone mass, volume, and structure of the hindlimbs in rodents.
Human studies have demonstrated a similar relationship to what is noted in rodents, between exercise and MAT. Human studies have largely focused on MAT at vertebral sites due to methodologic imaging restrictions. Bone marrow fat fraction at the lumbar vertebrae, but not the femur, was inversely associated with physical activity over a certain threshold (> 2 h/week) . Notably, long-distance runners (> 50 km/week), but not habitual joggers (20–40 km/week) or high-volume cyclists (> 150 km/week), demonstrated significantly reduced vertebral MAT compared with controls (< 150 min/week of moderate activity) . Long-distance running and high-volume cycling are regarded as comparable in terms of exertion, suggesting that mechanical loading of the spine, not aerobic exercise per se, suppresses adipogenesis in vertebrae.
Progressive resistance training exercise, typically conducted via ladder climbing, jump training, or squat training, widely promotes bone formation, trabecular bone volume, and bone strength and suppresses bone resorption in aging and osteoporosis models, as well as in young, growing rats [130,131,132,133]. Ladder climbing with progressive loading up to 75% of body weight significantly improved femoral BMD, cortical cross-sectional area, and mechanical properties via increased mRNA of Runx2, Osterix, Bmp2, Bsp, and Osteocalcin and decreased expression of Pparg and Osteoprotegerin . MAT has yet to be assessed in “resistance-trained” rodents, though the simulation of such exercise in an animal model poses experimental challenges which to date have not been resolved.
Exercise interventions which enable sufficient mechanical loading on the skeleton have demonstrably improved bone mass in young, old, osteoporotic, and obese humans [134,135,136]. Low bone mass older men and post-menopausal women undergoing high-intensity resistance and impact training for 8 months significantly improved lumbar spine and femoral neck BMD, as well as cortical thickness at the femoral neck [137••, 138]. These LIFTMOR exercise trials are of strong clinical and translational importance, as previously exercise programs were regarded as unsafe for older individuals with low bone mass or osteoporosis. The minimal frequency, intensity, and duration required to improve and maintain bone mass have yet to be delineated. Further, the response of MAT to resistance exercise interventions in healthy individuals and disorders of skeletal fragility remains largely unknown.
Despite the large body of evidence supporting the benefits of exercise in lessening MAT while improving bone, there are distinct patient populations, for reasons of bone fragility, muscle weakness, or general unwillingness, who are unable to participate in exercise regimens. The administration of lower magnitude forces in the form of whole-body-delivered low-intensity vibration (LIV) has been applied as a therapeutic surrogate to mechanical loading/exercise. Investigated as a measure to protect against ovariectomy-induced bone loss, LIV administration in rodents was found to mitigate ovariectomy-induced bone loss [139, 140]. Such studies document preservation of trabecular bone volume and microarchitecture, as well as suppression of MAT [139,140,141]. As with in vitro mechanical stimulation, rest days improved bone-related outcomes in high frequency, low magnitude (HFLM) whole-body vibration in ovariectomized female rats and healthy male rats [140, 142, 143]. Interestingly, the impact of HFLM on bone may differ in a sex-dependent manner [143, 144]. With LIV, applied frequency and signal amplitude are integral to stimulating bone formation; however, Zhang et al. utilized a higher frequency and noted negative impacts to bone; thus, there must exist a range of adequate signal parameters and differential sex-dependent responses to HFLM vibration exposure [144, 145].
In contrast to animal models, clinical trials utilizing whole-body vibration had equivocal effects in older adults with bone loss [146,147,148,149]. Younger women, though, demonstrated significant bone density improvements following vibration, highlighting the fact that age might play a role in the mechanical responsiveness of the skeleton . For example, a 12-month trial of 15–20-year-old women with low bone mass found 2–3% increases in trabecular bone at the lumbar vertebra and cortical bone at the femoral diaphysis , which has been similarly reported in young disabled children pre- and post-puberty . Further, children in cancer remission exhibited increased T-scores after 1 year of LIV . In sum, human studies point to vibration as a potential augmenter of bone in younger individuals, though there is much that remains unknown.
In vitro Loading of Bone Cells Biases MSC Lineage Selection Towards Osteogenesis and Away from Adipogenesis
Applied at the level of the cell, the administration of biaxial strain or other mechanical loads to MSC largely downregulate adipogenesis [31, 153,154,155,156]. TGFβ1/Smad2 signaling, upregulated by strain, may also play a role in the mechanical repression of adipogenesis . β-catenin is required for mechanical strain–induced inhibition of adipogenesis , and recent work demonstrates that β-catenin promotes the stemness of MSC via the activation of EZH2, a key epigenetic enzyme that silences genes . Though most cell culture work has demonstrated mechanical input represses adipogenesis, some have also demonstrated correlative increase in osteogenesis with MSC undergoing cyclic stretch . Despite extensive in vitro work showing biasing away from the adipogenic lineage, it remains unclear if this translates in vivo and whether the mechanical diminution of MAT is driven by similar pathways that regulate lineage selection.
The Role of Endogenous Sex Hormones in Regulation of Bone and Marrow Adipose Tissue
While diet and physical activity attenuate MAT and bone, other circulating factors may elicit increases in marrow adiposity at the expense of bone. Endogenous sex hormones, such as estrogens and androgens, are known to independently impact musculoskeletal anabolism and fat metabolism in bone and muscle [158, 159]. Age or pharmacologically induced deprivation of estrogens and/or androgens stimulates bone loss in post-menopausal women and older men [160,161,162,163], and waning sex hormone synthesis is associated with fat accumulation in bone and muscle [164, 165]. Factors such as sclerostin, glucocorticoids, pref-1, adiponectin, and leptin have been investigated, and yet, causality in mediating MAT or MAT’s interaction with bone has not been firmly established [79, 166,167,168]. Hormones such as insulin, IGF-1, and IGF-binding proteins are central to metabolic processes discussed herein, and their significance to the musculoskeletal system has previously been well-reviewed [169,170,171,172]. The significance of these hormonal factors to MAT is unclear and deserves further investigation.
Aging-induced replacement of viable bone with MAT, linked to waning sex hormone synthesis, may be further linked to a higher incidence of breast and prostate cancer in these populations [160,161,162,163]. Pharmacologic modalities to suppress estrogens and androgens in these disorders highlight a molecular dependency for sex hormones in preventing bone loss and MAT accrual, as well as preventing degradations in bone quality and strength [164, 165]. Recent work suggests that MAT could play a role in metastatic homing of cancer cells to the bone, highlighting a great need to define and maintain a healthy marrow microenvironment [173,174,175]. In-depth assessment of these mechanisms is reviewed elsewhere in this topical collection on Bone Marrow and Adipose Tissue from Current Osteoporosis Reports [176, 177]. Ongoing efforts are underway to understand the relationship between MAT, bone, and cancer, though much remains to be elucidated.
Marrow adipocytes accumulate in bone in hypercaloric (calorie excess; e.g., diet-induced obesity) and hypocaloric (calorie restriction; e.g., anorexia) states, despite an opposing effect on bone (Fig. 2). Bone quantity remains largely unaffected with hypercaloric intake, whereas in the hypocaloric state, bone quantity and quality are greatly diminished. Endurance exercise prevents MAT accumulation and increases bone in eucaloric and hypercaloric states, while further diminishing bone in hypocaloric states, suggesting differential modulation of MAT and bone, dependent upon whole-body energy status. Energy status alters bone metabolism and bioenergetics via substrate availability or excess, playing a key role in the response of bone and MAT to exercise/mechanical stimuli.
In summary, MAT’s response to whole-body energy requirements in the setting of exercise may supply adjacent osteoblasts energy required for exercise-induced bone formation, though in the hypocaloric state, MAT’s function has yet to be illuminated. Investigations applying physiologic interventions such as diet and exercise provide critical mechanistic insights about poorly understood tissues, serving to identify potential targets for future therapies.
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This review was supported by funds from the NIH/NIAMS R01AR073264 and NIH/NCATS KL2TR002490.
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Little-Letsinger, S.E., Pagnotti, G.M., McGrath, C. et al. Exercise and Diet: Uncovering Prospective Mediators of Skeletal Fragility in Bone and Marrow Adipose Tissue. Curr Osteoporos Rep 18, 774–789 (2020). https://doi.org/10.1007/s11914-020-00634-y
- Mesenchymal stem cell (MSC)
- Marrow adipose tissue (MAT)
- Bone marrow cells
- Caloric restriction