Bone Marrow Adipose Tissue Research Articles

Loss of Adipogenic Dickkopf-1 prevents the expansion of bone marrow adipose tissue and tends to ameliorate bone loss under High-Fat Diet in Male Mice

Loss of Adipogenic Dickkopf-1 prevents the expansion of bone marrow adipose tissue and tends to ameliorate bone loss under High-Fat Diet in Male Mice

Gender- and Age-Associated Differences in Bone Marrow Adipose Tissue and Bone Marrow Fat Unsaturation Throughout the Skeleton, Quantified Using Chemical Shift Encoding-Based Water-Fat MRI.

Bone marrow adipose tissue (BMAT) is a dynamic tissue which is associated with osteoporosis, bone metastasis, and primary bone tumors. The aim of this study is to determine region-specific variations and age- and gender-specific differences in BMAT and BMAT composition in healthy subjects. In this cross-sectional study, we included 40 healthy subjects (26 male: mean age 49 years, range 22–75 years; 14 female: mean age 50 years, range 29–71) and determined the bone marrow signal fat fraction and bone marrow unsaturation in the spine (C3-L5), pelvis, femora, and tibiae using chemical shift encoding-based water–fat imaging (WFI) with multiple gradient echoes (mGRE). Regions of interest covered the individual vertebral bodies, pelvis and proximal epimetaphysis, diaphysis, and distal epimetaphysis of the femur and tibia. The spinal fat fraction increased from cervical to lumbar vertebral bodies (mean fat fraction ( ± SD or (IQR): cervical spine 0.37 ± 0.1; thoracic spine 0.41 ± 0.08. lumbar spine 0.46 ± 0.01; p < 0.001). The femoral fat fraction increased from proximal to distal (proximal 0.78 ± 0.09; diaphysis 0.86 (0.15); distal 0.93 ± 0.02; p < 0.001), while within the tibia the fat fraction decreased from proximal to distal (proximal 0.92 ± 0.01; diaphysis 0.91 (0.02); distal 0.90 ± 0.01; p < 0.001). In female subjects, age was associated with fat fraction in the spine, pelvis, and proximal femur (ρ = 0.88 p < 0.001; ρ = 0.87 p < 0.001; ρ = 0.63 p = 0.02; ρ = 0.74 p = 0.002, respectively), while in male subjects age was only associated with spinal fat fraction (ρ = 0.40 p = 0.04). Fat fraction and unsaturation were negatively associated within the spine (r = -0.40 p = 0.01), while in the extremities fat fraction and unsaturation were positively associated (distal femur: r = 0.42 p = 0.01; proximal tibia: r = 0.47, p = 0.002; distal tibia: r = 0.35 p = 0.03), both independent of age and gender. In conclusion, we confirm the distinct, age- and gender-dependent, distribution of BMAT throughout the human skeleton and we show that, contradicting previous animal studies, bone marrow unsaturation in human subjects is highest within the axial skeleton compared to the appendicular skeleton. Furthermore, we show that BMAT unsaturation was negatively correlated with BMAT within the spine, while in the appendicular skeleton, BMAT and BMAT unsaturation were positively associated.

Toward Marrow Adipocytes: Adipogenic Trajectory of the Bone Marrow Stromal Cell Lineage.

Bone marrow contains precursor cells for osteoblasts and adipocytes in the stromal compartment. Bone marrow adipose tissue (BMAT) is an important constituent of the bone marrow that is particularly abundant in adults. BMAT is composed of the proximal “regulated” BMAT containing individual adipocytes interspersed within actively hematopoietic marrow, and the distal “constitutive” BMAT containing large adipocytes in the area of low hematopoiesis. Historically, bone marrow adipocytes were regarded as one of the terminal states of skeletal stem cells, which stand at the pinnacle of the lineage and possess trilineage differentiation potential into osteoblasts, chondrocytes and adipocytes. Recent single-cell RNA-sequencing studies uncover a discrete group of preadipocyte-like cells among bone marrow stromal cells (BMSCs), and recent mouse genetic lineage-tracing studies reveal that these adipocyte precursor cells possess diverse functions in homeostasis and regeneration. These adipogenic subsets of BMSCs are abundant in the central marrow space and can directly convert not only into lipid-laden adipocytes but also into skeletal stem cell-like cells and osteoblasts under regenerative conditions. It remains determined whether there are distinct adipocyte precursor cell types contributing to two types of BMATs. In this short review, we discuss the functions of the recently identified subsets of BMSCs and their trajectory toward marrow adipocytes, which is influenced by multiple modes of cell-autonomous and non-cell autonomous regulations.

Next Generation Bone Marrow Adiposity Researchers: Report From the 1st BMAS Summer School 2021.

The first International Summer School on Bone Marrow Adiposity was organized by members of Bone Marrow Adiposity Society and held virtually on September 6-8 2021. The goal of this meeting was to bring together young scientists interested in learning about bone marrow adipose tissue biology and pathology. Fifty-two researchers from different backgrounds and fields, ranging from bone physiopathology to adipose tissue biology and hematology, participated in the summer school. The meeting featured three keynote lectures on the fundamentals of bone marrow adiposity, three scientific workshops on technical considerations in studying bone marrow adiposity, and six motivational and career development lectures, spanning from scientific writing to academic career progression. Moreover, twenty-one participants presented their work in the form of posters. In this report we highlight key moments and lessons learned from the event.

Exercise may impact on lumbar vertebrae marrow adipose tissue: Randomised controlled trial.

Animal and human cross-sectional data suggest that bone marrow adipose tissue (MAT) may respond to mechanical loads and exercise. We conducted the first randomised controlled trial of exercise on MAT modulations in humans. Forty patients with chronic non-specific low back pain (NSCLBP) were enrolled in a six-month single-blinded randomised controlled trial (ACTRN12615001270505). Twenty patients loaded their spines via progressive upright aerobic and resistance exercises targeting major muscle groups (Exercise). Twenty patients performed non-weightbearing motor control training and manual therapy (Control). Testing occurred at baseline, 3-months (3mo) and 6-months (6mo). Lumbar vertebral fat fraction (VFF) was measured using magnetic resonance imaging axial mDixon sequences. When compared to baseline (percent change), lumbar vertebral fat fraction (VFF; measured using magnetic resonance imaging axial mDixon sequences) was lower in Exercise at 3mo at L2 (-3.7[6.8]%, p=0.033) and L4 (-2.6[4.1]%, p=0.015), but not in Control. There were no between-group effects. The effects of Exercise on VFF were sex-specific, with VFF lower in men at L2, L3, L4 at 3mo and at L1, L2, L3 and L4 at 6mo (p all≤0.05), but not in women. Leg and trunk lean mass were increased at 3mo in Exercise. Changes in VFF correlated significantly with changes in total fat (ρ=0.40) and lean (ρ=-0.41) masses, but not with lumbar BMD (ρ=-0.10) or visceral adipose tissue volume (ρ=0.23). This trial provided first prospective evidence in humans that a moderate exercise intervention may modulate lumbar VFF as a surrogate measure of MAT at 3mo, yet not 6mo. The effect of exercise on MAT may be more prominent in males than females.

The Implications of Bone Marrow Adipose Tissue on Inflammaging.

Once considered an inert filler of the bone cavity, bone marrow adipose tissue (BMAT) is now regarded as a metabolically active organ that plays versatile roles in endocrine function, hematopoiesis, bone homeostasis and metabolism, and, potentially, energy conservation. While the regulation of BMAT is inadequately understood, it is recognized as a unique and dynamic fat depot that is distinct from peripheral fat. As we age, bone marrow adipocytes (BMAds) accumulate throughout the bone marrow (BM) milieu to influence the microenvironment. This process is conceivably signaled by the secretion of adipocyte-derived factors including pro-inflammatory cytokines and adipokines. Adipokines participate in the development of a chronic state of low-grade systemic inflammation (inflammaging), which trigger changes in the immune system that are characterized by declining fidelity and efficiency and cause an imbalance between pro-inflammatory and anti-inflammatory networks. In this review, we discuss the local effects of BMAT on bone homeostasis and the hematopoietic niche, age-related inflammatory changes associated with BMAT accrual, and the downstream effect on endocrine function, energy expenditure, and metabolism. Furthermore, we address therapeutic strategies to prevent BMAT accumulation and associated dysfunction during aging. In sum, BMAT is emerging as a critical player in aging and its explicit characterization still requires further research.

Postnatal deletion of β-catenin in preosteoblasts regulates global energy metabolism through increasing bone resorption and adipose tissue fibrosis.

Many studies revealed bone can regulate global energy metabolism and our previous study also showed that Wnt/β-catenin pathway is involved in this process. To better understand the participation of canonical Wnt pathway in energy metabolism, we examined the β-catenin knock-out (β-cat KO) mice by crossing the osterix-cre transgenic mice with β-cateninflox/flox mice. First, we identified that postnatal deletion of β-catenin in preosteoblasts led to decreased fat mass and increased energy expenditure in mice. Osteoprotegerin administration largely rescued the decreased fat mass and partly normalized the energy expenditure accompanied by the inhibition of bone resorption. Anti-resorption with alendronate or RANKL-antibody could also partly rescued the decreased bone mass, decreased fat mass and increased energy expenditure in β-cat KO mice. We further found that the adipose cells in the inguinal fat tissue were smaller and the extracellular matrix components around adipocytes accumulated more in β-cat KO mice than their controls by histomorphology. Gene analysis by RT-PCR showed that the expression of collagen VI is 4.8 folds in adipose tissue of the β-cat KO mice compared with the control mice. We further detected the expression of cytokines which were related to fibrosis and the data showed that the level of TGF-beta1 was elevated in both of bone marrow serum and adipose tissue derived from the β-cat KO mice. After administration of TGF-beta1 neutralizing antibody, the impaired energy metabolism was partly rescued in β-cat KO mice. Besides, anti-resorption treatment and TGF-beta1 antibody could partly suppress the increased expression of genes related to fat tissue fibrosis. These results indicate that the abnormal global energy metabolism in β-cat KO mice may be attributed to increasing bone resorption and adipose tissue fibrosis.

DAPK1 Interacts with the p38 Isoform MAPK14, Preventing Its Nuclear Translocation and Stimulation of Bone Marrow Adipogenesis.

Bone marrow (BM) adipose tissue (BMAT), a unique adipose depot, plays an important role in diseases such as osteoporosis and bone metastasis. Precise control of mesenchymal stem cell (MSC) differentiation is critical for BMAT formation and regeneration. Here, we show that death associated protein kinase 1 (DAPK1) negatively regulates BM adipogenesis in vitro and in vivo. Prx1creDapk1loxp/loxp mice showed more adipocytes in the femur than Dapk1loxp/loxp mice. Further mechanistic analyses revealed that DAPK1 inhibits p38 mitogen-activated protein kinase (MAPK) signaling in the nucleus by binding the p38 isoform MAPK14, decreasing p38 nuclear activity, which subsequently inhibits BM adipogenesis. The inhibitory effect of DAPK1 against MAPK14 was independent of its kinase activity. In addition, the decreased DAPK1 was observed in the BM-MSCs of ageing mice. Our results reveal a previously undescribed function for DAPK1 in the regulation of adipogenesis and may also reveal the underlying mechanism of BMAT formation in ageing.

골수지방조직의 건강과 질병에서의 역할

골수지방조직의 건강과 질병에서의 역할

Exercise Increases Bone in SEIPIN Deficient Lipodystrophy, Despite Low Marrow Adiposity.

Exercise, typically beneficial for skeletal health, has not yet been studied in lipodystrophy, a condition characterized by paucity of white adipose tissue, with eventual diabetes, and steatosis. We applied a mouse model of global deficiency of Bscl2 (SEIPIN), required for lipid droplet formation. Male twelve-week-old B6 knockouts (KO) and wild type (WT) littermates were assigned six-weeks of voluntary, running exercise (E) versus non-exercise (N=5-8). KO weighed 14% less than WT (p=0.01) and exhibited an absence of epididymal adipose tissue; KO liver Plin1 via qPCR was 9-fold that of WT (p=0.04), consistent with steatosis. Bone marrow adipose tissue (BMAT), unlike white adipose, was measurable, although 40.5% lower in KO vs WT (p=0.0003) via 9.4T MRI/advanced image analysis. SEIPIN ablation’s most notable effect marrow adiposity was in the proximal femoral diaphysis (-56% KO vs WT, p=0.005), with relative preservation in KO-distal-femur. Bone via μCT was preserved in SEIPIN KO, though some quality parameters were attenuated. Running distance, speed, and time were comparable in KO and WT. Exercise reduced weight (-24% WT-E vs WT p<0.001) but not in KO. Notably, exercise increased trabecular BV/TV in both (+31%, KO-E vs KO, p=0.004; +14%, WT-E vs WT, p=0.006). The presence and distribution of BMAT in SEIPIN KO, though lower than WT, is unexpected and points to a uniqueness of this depot. That trabecular bone increases were achievable in both KO and WT, despite a difference in BMAT quantity/distribution, points to potential metabolic flexibility during exercise-induced skeletal anabolism.

Aging of Skeletal Stem Cells.

The skeletal system is generated and maintained by its progenitors, skeletal stem cells (SSCs), across the duration of life. Gradual changes associated with aging result in significant differences in functionality of SSCs. Declines in bone and cartilage production, increase of bone marrow adipose tissue, compositional changes of cellular microenvironments, and subsequent deterioration of external and internal structures culminate in the aged and weakened skeleton. The features and mechanisms of skeletal aging, and of its stem and progenitor cells in particular, are topics of recent investigation. The discovery of functionally homogeneous SSC populations with a defined cell surface phenotype has allowed for closer inspection of aging in terms of its effects on transcriptional regulation, cell function, and identity. Here, we review the aspects of SSC aging on both micro- and macroscopic levels. Up-to-date knowledge of SSC biology and aging is presented, and directions for future research and potential therapies are discussed. The realm of SSC-mediated bone aging remains an important component of global health and a necessary facet in our understanding of human aging.

Fatty Acid Composition of Proximal Femur Bone Marrow Adipose Tissue in Subjects With Systemic Lupus Erythematous Using 3T Magnetic Resonance Spectroscopy.

Systemic lupus erythematosus (SLE) is a chronic, inflammatory disease with common musculoskeletal manifestations, notably reductions in bone quality. Bone marrow adipose tissue composition and quantity has been previously linked to bone quality and may play a role in SLE pathophysiology but has not been thoroughly studied. To use magnetic resonance spectroscopy (MRS) to investigate bone marrow adipose tissue quantity and composition in proximal femur subregions of untreated SLE patients compared to controls and treated patients. Prospective. A total of 64 female subjects: 28 SLE, 15 glucocorticoid (GC)-treated SLE and 21 matched controls. Stimulated echo acquisition mode (STEAM) sequence at 3 T. MRS was performed at multiple echo times in the femoral neck and trochanter regions and fatty acids (FA) composition was computed. Intergroup comparisons were carried out using ANOVA. A P value < 0.05 was considered statistically significant. SLE patients had significantly higher saturated FA compared to controls in both the femoral neck (+0.12) and trochanter (+0.11), significantly lower monounsaturated FA in the trochanter compared to controls (-0.05), and significantly lower polyunsaturated FA in the femoral neck compared to both controls (-0.07) and SLE patients on GC therapy (-0.05). SLE patients have altered proximal femur marrow fat metabolism, which may reflect a manifestation of, or play a role in, the altered inflammatory response of these patients. 2 TECHNICAL EFFICACY: Stage 2.

Gut Microbiota and Serum Metabolic Signatures of High-Fat-Induced Bone Loss in Mice.

BackgroundAccumulating evidence indicates that high-fat diet (HFD) is a controllable risk factor for osteoporosis, but the underlying mechanism remains to be elucidated. As a primary biological barrier for nutrient entry into the human body, the composition and function of gut microbiota (GM) can be altered rapidly by HFD, which may trigger abnormal bone metabolism. In the current study, we analyzed the signatures of GM and serum metabolomics in HFD-induced bone loss and explored the potential correlations of GM and serum metabolites on HFD-related bone loss.MethodsWe conducted a mouse model with HFD-induced bone loss through a 12-week diet intervention. Micro-CT, Osmium-μCT, and histological analyses were used to observe bone microstructure and bone marrow adipose tissue. Quantitative Real-Time PCR was applied to analyze gene expression related to osteogenesis, adipogenesis, and osteoclastogenesis. Enzyme-linked immunosorbent assay was used to measure the biochemical markers of bone turnover. 16s rDNA sequencing was employed to analyze the abundance of GM, and UHPLC-MS/MS was used to identify serum metabolites. Correlation analysis was performed to explore the relationships among bone phenotypes, GM, and the metabolome.ResultsHFD induced bone loss accompanied by bone marrow adipose tissue expansion and bone formation inhibition. In the HFD group, the relative abundance of Firmicutes was increased significantly, while Bacteroidetes, Actinobacteria, Epsilonbacteraeota, and Patescibacteria were decreased compared with the ND group. Association analysis showed that thirty-two bacterial genera were significantly related to bone volume per tissue volume (BV/TV). One hundred and forty-five serum metabolites were identified as differential metabolites associated with HFD intervention, which were significantly enriched in five pathways, such as purine metabolism, regulation of lipolysis in adipocyte and cGMP-PKG signaling pathway. Sixty-four diffiential metabolites were matched to the MS2 spectra; and ten of them were positively correlated with BV/TV and five were negatively correlated with BV/TV.ConclusionsThese findings indicated that the alternations of GM and serum metabolites were related to HFD-induced bone loss, which might provide new insights into explain the occurrence and development of HFD-related osteoporosis. The regulatory effects of GM and metabolites associated with HFD on bone homeostasis required further exploration.

Osteal Macrophages and Megakaryocytes Increase Adipogenesis

Bone marrow adipose tissue (MAT) increases with aging and contributes to low bone density and skeletal fractures. However, the cells and factors within the bone marrow (BM) that regulate adipogenesis remain poorly understood. In the current study, we examined the role of osteal macrophages (OMs) and megakaryocytes (MKs) on the regulation of adipogenesis. We cultured murine osteoblasts/osteoblast progenitors (OBs from hereon) derived from neonatal calvarial cells (CCs, a combination of OBs and OMs) or OBs isolated by fluorescence activated cell sorting (FACS) in the presence or absence of fetal liver derived murine MK. The cells underwent induced adipogenesis for 5-7 days by supplementation of media with insulin, indomethacin, and dexamethasone, and then the number of adipocytes was quantified. We found that co-culturing MKs and OMs with OBs results in up to a 7.8-fold and 11.7-fold increase in adipocytes, respectively. We also elucidated that thrombopoietin (TPO), the major growth factor for MKs, inhibits adipogenesis in both OBs and CCs by approximately 60%. Similarly, we found that CCs and OBs derived from mice deficient in the TPO receptor, Mpl, had approximately 30% more adipocytes than their wild-type (WT) counterparts. Finally, in vitro findings were corroborated in vivo through quantification of MKs and adipocytes in mice in which MK number was elevated or reduced. Mice with significantly higher numbers of BM-residing MKs also had significantly higher numbers of BM-residing adipocytes. Because there is typically an inverse relationship between adipogenesis and osteogenesis, understanding ways to inhibit adipogenesis could lead to an increase in OB number and bone formation, which in turn could lead to new treatments for bone loss diseases such as osteoporosis.

Bone marrow adiposity during pathologic bone loss: molecular mechanisms underlying the cellular events.

Bone marrow (BM) is a heterogeneous niche where bone marrow stromal cells (BMSCs), osteoblasts, osteoclasts, adipocytes, hematopoietic cells, and immune cells coexist. The cellular composition of BM changes with various pathophysiological states. A reduction in osteoblast number and a concomitant increase in adipocyte number in aging and pathological conditions put bone marrow adipose tissue (BMAT) into spotlight. Accumulating evidence strongly supports that an overwhelming production of BMAT is a major contributor to bone loss disorders. Therefore, BMAT-targeted therapy can be an efficient and feasible intervention for osteoporosis. However, compared to blocking bone-destroying molecules produced by BMAT, suppressing BMAT formation is theoretically a more effective and fundamental approach in treating osteoporotic bone diseases. Thus, a deep insight into the molecular basis underlying increased BM adiposity during pathologic bone loss is critical to formulate strategies for therapeutically manipulating BMAT. In this review, we comprehensively summarize the molecular mechanisms involved in adipocyte differentiation of BMSCs as well as the interaction between bone marrow adipocytes and osteoclasts. More importantly, we further discuss the potential clinical implications of therapeutically targeting the upstream of BMAT formation in bone loss diseases.

Multiple Myeloma Derived Mitochondrial Damps Induce Inflammation in the Bone Marrow Adipose Tissue Which Promotes Tumour Development

Multiple myeloma (MM) is a malignancy of the antibody secreting plasma cells, characterized by the localisation and accumulation of tumour cells in the bone marrow (BM) microenvironment. The mitochondrial DNA (mtDNA) belongs to a group of mitochondrial damage associated molecular patterns (mtDAMPs) and contains islands of unmethylated CpG nucleotide motifs, which have been shown to activate and promote memory B cell antibody secretion and proliferation. Studies have indicated that mitochondrial DNA (mtDNA) is elevated in the circulation of trauma and cancer patients, highlighting a need to explore the functional purpose of mtDNA in the BM microenvironment. Moreover, myeloma relies on the BM microenvironment for survival, proliferation and drug resistance. BM adipocytes are highly secretory cells that support myeloma cells through the release of various factors. It has been shown that myeloma cells induce a shift from osteoblast progenitors towards adipogenesis. Here, we hypothesise that MM cells release mtDAMPs that leads to the promotion of a state of chronic inflammation that supports multiple myeloma disease progression and expansion by inducing adipocyte inflammation.First, we engrafted immunocompromised NSG mice with human myeloma cell line MM1S, blood serum samples were taken and analysed by RT-qPCR to detect the presence of human mtDNA. We found elevated levels of human mtDNA in the serum of engrafted mice correlating to disease progression. Next, we showed that mtDNA was higher in serum patients with MM compared to healthy controls, moreover, we discovered that BM serum from MM patients had significantly higher levels of mtDNA than blood serum. Furthermore, this observation was recapitulated in myeloma engrafted NSG mice. Next, we examined the effect of mtDNA on various cell populations of the BM. We found that in vitro both BM derived macrophages and BM derived adipocytes had increased inflammatory signatures, including upregulation of IL-6, when treated with mtDNA from myeloma cells. MtDNA induced IL-6 expression was attenuated upon blocking of the TLR9 receptor with antagonist ODN 2088. To understand the role of BM adipocyte induced inflammation in MM, we treated adipocytes with mtDNA before culturing them with MM. We found that MM cells had enhanced proliferation on mtDNA activated adipocytes. We further show that MM cells cultured with mtDNA activated adipocytes have increased uptake of free fatty acids and seahorse analysis confirmed an increase in b-oxidation derived metabolism.Here we establish that MM releases mtDNA into the microenvironment promoting the disease progression via a pro-inflammatory BM. We also show that both BM macrophages and BM adipocytes play a supportive role in multiple myeloma expansion and contribute to the pro-inflammatory bone marrow microenvironment. DisclosuresNo relevant conflicts of interest to declare.

Genetically Determined Obesity and Adipose Distribution Impact Human Blood Trait Variation across Cell Lineages

IntroductionGenome wide association studies (GWAS) have catalogued thousands of loci that influence blood traits, but genetic mechanisms and impacted cell types are often unknown. While some regulatory factors are blood cell-autonomous, other extrinsic regulatory factors respond to systemic physiology. Epidemiologic studies have correlated generalized obesity (increased body mass index, BMI) and high cholesterol with anemia, but cell types and mechanisms that mediate these effects are incompletely understood, and these studies do not provide evidence for causality. Thus, we wanted to use genetic effects of BMI and cholesterol on hemoglobin level (HGB) and other blood traits to infer causal relationships, identify relevant cell types, and propose genetic mechanisms.MethodsMendelian randomization (MR), akin to a “genetic randomized controlled trial”, uses variants linked to an exposure trait to estimate causal effects of that exposure on a given outcome. 1 Random variant allele allocation at meiosis enables this approach to address confounding and reverse causality that can otherwise preclude causal inference from epidemiologic and cohort studies. Further, effects of multiple factors can be parsed using multivariable MR and causal mediation analyses to help explain genetic associations. 2 Our study used gender- and age-adjusted GWAS summary statistics from European individuals.ResultsWe hypothesized that increased genetically determined BMI would decrease HGB. Using a MR framework, we found that a 5 kg/m 2 (1 standard deviation unit) increase in BMI decreased hemoglobin by 0.06±0.01 g/dL (p=1x10 -5, Fig). Increased BMI also decreased erythrocyte count, and unexpectedly also decreased platelet and white blood cell counts (all with p<5x10 -3). These data showed that obesity-related mechanisms extended beyond the erythroid lineage, perhaps impacting multipotent hematopoietic progenitor cells (HPCs).Similar to BMI, a 1 SD unit increase in total cholesterol decreased HGB (0.10±0.03 g/dL, p=2x10 -3, Fig). However, genetic effects of cholesterol were restricted to erythroid traits (HGB and hematocrit). Multivariable and mediation analyses confirmed that effects of BMI and cholesterol functioned through distinct genetic mechanisms.We speculated that multilineage effects from BMI could reflect a genetic predisposition to accumulate bone marrow adipose tissue, which can impact HPCs and hematopoiesis. 3 A tendency for ‘central’ adiposity increases one's waist-hip ratio (WHR), and increases cardiovascular disease risk concordant with BMI. Unexpectedly, we found that increased WHR, in contrast to BMI, increased HGB (0.08±0.02 g/dL, p=9x10 -6) as well as erythrocyte, platelet, and white blood cell counts (all with p<4x10 -3, Fig). In multivariable experiments, the effects of WHR were exacerbated after accounting for BMI at the individual or population level. Thus, obesity impacts blood traits through genetically determined adipose distribution.ConclusionsOur results confirm that BMI and cholesterol negatively impact HGB at a genetic level, consistent with clinical observations. The unexpected multilineage effects of genetically determined BMI most likely reflects a tendency to accumulate bone marrow adipose tissue, which in turn impacts HPCs and downstream blood cell production. Our findings suggest that adjustment for BMI and adiposity traits may be considered in blood trait GWAS analyses and illuminate opportunities to functionally dissect related genes and molecular pathways.

Bone marrow adipose tissue composition following high-caloric feeding and fasting.

Bone marrow adipose tissue (BMAT) plays a role in systemic energy metabolism and responds to nutritional changes. Chronic starvation as well as visceral adiposity are associated with BMAT accumulation. Two types of BMAT have been described which differ in anatomic location (proximal-regulated-rBMAT vs distal-constitutive-cBMAT) and composition (higher unsaturated lipids of cBMAT compared to rBMAT). To determine the response of BMAT composition to short-term high-caloric feeding and fasting. We hypothesized that high-feeding and caloric restriction would be associated with differences in BMAT composition according to the skeletal site. We examined 23 healthy subjects (13m, 10 f, mean age 33±7years, BMI 26±1.5kg/m2) who were admitted for a 10-day high-caloric stay (caloric intake with goal to achieve 7% weight gain) followed by discharge home for 13-18days to resume normal diet (stabilization period), followed by a 10-day fasting stay (no caloric intake). Subjects underwent single voxel proton MR spectroscopy (1H-MRS) at 3T of the lumbar spine (L4) (rBMAT), the femoral diaphysis and distal tibial metaphysis (cBMAT) to determine BMAT composition (unsaturation index, UI and saturation index, SI). Within group comparisons were performed by the Wilcoxon signed rank test. After the high-calorie visit, SI of L4 increased compared to baseline (0.62±0.27 to 0.70±0.28, p=0.02), and there was a trend of an increase in femoral SI and UI (p≥0.07), while there was no significant change in tibial BMAT (p≥0.13). During the stabilization period, SI of L4 decreased (0.70±0.28 to 0.57±0.21, p<0.0001) and SI of the femoral diaphysis decreased (5.37±2.27 to 5.09±2.43, p=0.03), while there was no significant change in UI or tibial BMAT (p≥0.14). During the fasting period, SI of L4 increased (0.57±0.21 to 0.63±0.30, p=0.03), while there was no change in UI (p=0.7). SI and UI of femoral diaphysis decreased (5.09±2.43 to 4.68±2.15, p=0.03, and 0.62±0.42 to 0.47±0.37, p=0.02, respectively) and UI of the tibial metaphysis decreased (1.48±0.49 to 1.24±0.57, p=0.04). 1H-MRS is able to quantify BMAT composition during short-term nutritional challenges, showing a significant increase in SI of rBMAT during high caloric feeding and a differential response to fasting with an increase in SI of rBMAT and a decrease in SI and UI of femoral cBMAT and decrease in UI of tibial cBMAT.

Adipose tissue: colors, depots and functions

Obesity is a chronic disease characterized by excessive accumulation of adipose tissue. The prevalence of obesity and associated diseases has prompted researchers to expand the study of the biology of adipose tissue. New technologies have significantly expanded the understanding of adipogenesis mechanisms, various aspects of lipid and glucose metabolism, as well as the paracrine and endocrine functions of adipose tissue. Adipose tissue is a complex, heterogeneous endocrine organ. The existence of several shades of adipocytes demonstrates their morphological and functional heterogeneity. The main function of white adipose tissue is to store energy. Brown and white adipocytes perform a predominantly thermogenic function. Bone marrow (yellow) adipose tissue regulates the processes of bone remodeling and hematopoiesis. Pink adipocytes are formed during pregnancy and satisfy the energy needs of the offspring. The study of the biology of adipose tissue is crucial to understanding the pathophysiology of obesity and determining its molecular relationships with type 2 diabetes as well as cardiovascular and oncological diseases. The review presents current literature data on the origin, adipogenesis, and functional properties of adipose tissue depending on its cellular composition and localization. It outlines the nature of changes in adipose tissue in obesity and the clinical significance and therapeutic potential of various adipose tissue depots.

Bone marrow adipose tissue content in Latino adolescents with prediabetes and obesity.

This study aimed to examine whether total, regional, and organ fat predicts bone marrow adipose tissue (BMAT) fat content and to explore whether BMAT fat content differs by sex among Latino youth. Latino youth (n = 86; age 13.6 [1.4] years, 62% male) with obesity (BMI percentile = 98.5% [1.2%]) underwent a dual-energy x-ray absorptiometry scan to assess body composition and a magnetic resonance imaging scan to determine abdominal adiposity, liver fat, and vertebral BMAT fat content in the thoracic (average of T8-T12) and lumbar (average of L1-L5) spine. Male youth exhibited significantly greater thoracic (male youth = 30.8% [1.4%] vs. female youth = 24.5% [2.1%], p = 0.027) and lumbar (male youth = 36.3% [1.5%] vs. female youth = 30.2% [2.2%], p = 0.038) BMAT fat content compared with female youth. Visceral adipose tissue was a significant predictor of thoracic (β = 0.434, t[86] = 3.016, p = 0.003) and lumbar (β = 0.389, t[86] = 2.677, p = 0.009) BMAT fat content, explaining 8.9% and 6.9% of the variance, respectively. Liver fat was a significant predictor of both thoracic (β = 0.487, t[86] = 4.334, p < 0.001) and lumbar (β = 0.436, t[86] = 3.793, p < 0.001) BMAT fat content, explaining 17.6% and 13.8% of the variance, respectively. Male youth had significantly greater thoracic and lumbar BMAT fat content than female youth. Greater BMAT fat content is associated with greater liver fat and visceral adipose tissue among youth with obesity. Further investigation of the mechanistic underpinnings of BMAT may help to differentiate its metabolic and bone-related functions.