The Intimate Relationship between Adipose Tissue, Fertility, and Bone.

BackgroundIncreasing studies have suggested that bone closely interacts with bone marrow adipose tissue (BMAT) and abdominal adipose tissue. However, this relationship remains debated. This study aimed to explore the association among BMAT, abdominal adipose tissue, and lumbar volumetric bone mineral density (vBMD).MethodsA total of 306 Chinese adult living liver transplant donors were enrolled in this cross-sectional study. vBMD and abdominal adipose tissue in terms of total adipose tissue (TAT), visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), were derived using quantitative computed tomography (QCT). Chemical shift encoded magnetic resonance imaging (MRI) of the lumbar spine was performed, and proton density fat fraction (PDFF) maps were calculated. Correlation analysis and multiple linear regression were used to assess the associations among BMAT, abdominal adipose tissue distribution, and vBMD.ResultsThe mean age of the participants was 38.1 ± 9.5 years (range: 19–66 years). The vBMD was significantly negatively associated with age (r = −0.508, p < 0.001), VAT (r = −0.235, p < 0.001), TAT (r = −0.127, p = 0.03), and BMAT measured by PDFF (r = −0.642, p < 0.001). After adjusting for age, gender, and BMI, multiple linear regression analysis showed BMAT (β = −0.523, p < 0.001), SAT (β = 0.116, p = 0.045) and VAT (β = −0.108, p = 0.037) to be independent factors influencing vBMD.ConclusionOur results indicated a negative association between BMAT and BMD. The association between abdominal adipose tissue distribution and BMD was dual; there was a positive association between SAT and BMD and a negative association between VAT and BMD. These findings suggest that the distribution of abdominal adipose tissue, particularly visceral adipose tissue accumulation, should be prioritized over total body weight in considerations of bone health.

Non-ambulatory children with severe cerebral palsy (CP) have a high degree of adipose tissue (AT) infiltration which could play a role in the development of insulin resistance and fractures. The objective of this study was to determine the degree of AT infiltration within the bone marrow cavity of the middle tibia and within the surrounding muscle in ambulatory children with mild spastic CP (5-11 y) compared to typically developing controls matched for age and sex (n = 8/group). The concentration of AT in the bone marrow and muscle, and the intermuscular, subfascial and subcutaneous AT volume, muscle volume, cortical bone volume and bone strength (i.e., section modulus, Z and polar moment of inertia, J) were estimated using magnetic resonance imaging. Children with CP vs. controls had a higher (P < 0.05) concentration of AT in the bone marrow (83 ± 2 % vs. 81 ± 2 %) and muscle (27 ± 7 % vs. 18 ± 5 %). Children with CP vs. controls also had higher (P < 0.05) subfascial AT (357 %), and lower muscle volume (40%), cortical bone volume (26 %), Z (31 %) and J (38 %). Although not statistically significant (P = 0.07), children with CP vs. controls also had higher intermuscular AT (391 %). Whether the high concentration of AT in bone marrow and muscle during childhood are early indicators of insulin resistance and future fracture requires further investigation. Supported by the NIH(Grant HD071397-01).

Vertebrae but not femur marrow fat transiently decreases in response to body weight loss in an 18-month randomized control trial.

PurposeThis study aimed to investigate the increase in bone marrow adipose tissue (BMAT) in overweight and obese women with polycystic ovary syndrome (PCOS) and its relationship with hyperandrogenism, obesity, and metabolic disorders.MethodsThe study included 87 overweight or obese women with PCOS (mean age 29 ± 4 years), as well as 87 age-matched controls recruited from a separate population study. All PCOS patients were measured for anthropometric features, abdominal adipose tissue areas, BMAT, biochemistry, and sex hormones. BMAT was compared between the PCOS patients and controls. In PCOS patients, subgroup comparisons of BMAT and its associations with body adiposity indices, biochemistry, and sex hormones were analyzed. The odds ratios (ORs) of elevated BMAT (defined as BMAT ≥ 38%) were calculated.ResultsOn average BMAT was increased by 5.6% ( ± 11.3%) in PCOS patients compared to controls. BMAT were significantly higher in the upper tertiles of total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). BMAT was not correlated with abdominal adiposity indices or biochemistry except for LDL-C (r = 0.253—0.263, p = 0.014—0.018). LDL-C was not significantly different between the normal and abnormal androgen PCOS subgroups (p = 0.10-0.887). LDL-C, follicle stimulating hormone (FSH), and total testosterone (TT) were risk factors for elevated BMAT, with ORs of 1.899 (p = 0.038-0.040), 1.369 (p = 0.030-0.042), and 1.002 (p = 0.040-0.044) for each unit increase, respectively.ConclusionBMAT was increased in overweight and obese PCOS patients, but the increase in BMAT was not associated with the hyperandrogenism related obesity or metabolic disorders.

The precise role of bone marrow adipose tissue (BMAT) in the marrow remains unknown. The purpose of the present study was therefore to describe a novel method for studying BMAT using 3-D collagen gel culture of BMAT fragments, immunohistochemistry, ELISA and real-time reverse transcription-polymerase chain reaction. Mature adipocytes and CD45+ leukocytes were retained for >3 weeks. Bone marrow stromal cells (BMSC) including a small number of lipid-laden preadipocytes and CD44+/CD105+ mesenchymal stem cell (MSC)-like cells, developed from BMAT. Dexamethasone (10 micromol/L), but not insulin (20 mU/mL), significantly increased the number of preadipocytes. Dexamethasone and insulin also promoted leptin production and gene expression in BMAT. Adiponectin production by BMAT was <0.8 ng/mL under all culture conditions. Dexamethasone promoted adiponectin gene expression, while insulin inhibited it. This finding suggests that dexamethasone, but not insulin, may serve as a powerful adipogenic factor for BMAT, in which adiponectin protein secretion is normally very low, and that BMAT may exhibit a different phenotype from that of the visceral and subcutaneous adipose tissues. BMAT-osteoblast interactions were also examined, and it was found that osteoblasts inhibited the development of BMSC and reduced leptin production, while BMAT inhibited the growth and differentiation of osteoblasts. The present novel method proved to be useful for the study of BMAT biology.

We have studied the effect of epinephrine and isoproterenol on free fatty acid (FFA) mobilization from bone marrow adipose tissue in dog tibia after constant-flow autoperfusion of the nutrient artery by ipsilateral femoral arterial blood. The perfusions of epinephrine (0.025 microgram/min) or isoproterenol (0.005 microgram/min) significantly increased the FFA level in the nutrient vein of the tibia. Moreover, our data demonstrate that in vitro the bone marrow adipose tissue was less responsive to catecholamines than omental adipose tissue. It can be concluded that bone marrow adipose tissue is able to release FFA after administration of catecholamines but to a lesser extent than in other adipose tissue (omental adipose tissue). These results support the hypothesis that the bone marrow adipose tissue is involved in local nutrition rather than in the total energy supply of the animal.

Anorexia nervosa, a psychiatric disorder predominantly affecting women, is characterized by self-induced starvation, low body weight, low subcutaneous and visceral fat depots, and low bone mass. More than 85% of women with anorexia nervosa have bone mineral density (BMD) values more than one standard deviation below the mean of women of comparable age. Although there is a significantly increased risk of fracture in women with anorexia nervosa, low BMD has not been shown to consistently predict the increased fracture rate in this population. Despite low subcutaneous and visceral adipose tissue stores, women with anorexia nervosa have increased bone marrow adiposity, which is inversely associated with BMD. We hypothesized that increased bone marrow adipose tissue would be associated with the increased fracture rate in women with anorexia nervosa. We studied sixty-two women: 34 with anorexia nervosa (mean age + SEM: 28.3 + 0.9 years) and 28 normal-weight controls of similar age (28.3 + 1.1 years; p=0.72). We examined associations between lifetime self-reported fracture history and 1) BMD of the lumbar spine (L1-L4), lateral spine (L2-L4), total hip, and femoral neck measured by dual energy X-ray absorptiometry and 2) bone marrow adipose tissue at the spine (L4 vertebra) and hip (femoral metaphysis, diaphysis and epiphysis) measured by 1H-magnetic resonance spectroscopy. Women with anorexia nervosa had significantly lower BMD at the spine and hip (p<0.0001 at all sites) and significantly higher bone marrow adipose tissue at the L4 vertebra (p<0.0001) and femoral metaphysis (p=0.001) as compared to normal-weight controls. Forty-seven percent (n=16) of women with anorexia nervosa versus 39% (n=11) of normal-weight controls reported a lifetime history of fracture (p=0.54). In women with anorexia nervosa, there was no significant association between fracture history and BMD at the spine or hip (p=0.27-0.98). In the group as a whole, bone marrow adipose tissue was greater in the L4 vertebra in individuals with a history of fracture compared to those without a fracture history (p=0.02). In subjects with anorexia nervosa, those with a history of fracture had greater bone marrow adipose tissue at the L4 vertebra (p=0.01) and femoral diaphysis (p=0.01) compared to those without a history of fracture; these differences in bone marrow adipose tissue remained significant after controlling for BMI (p=0.01-0.03) and also after controlling for BMD (p<0.01 for both). Higher bone marrow adipose tissue is associated with increased fracture prevalence and may be a better predictor of fracture risk than BMD in women with anorexia nervosa. Future prospective studies will be necessary to better understand the association between bone marrow adiposity and fracture risk in this population.

Bone marrow adipose tissue: Role in bone remodeling and energy metabolism

Adipose tissue dysfunction is one of the features of Polycystic Ovary Syndrome (PCOS) with dysregulated adipogenesis, altered functional pathways and increased inflammation. It is increasingly clear that there are also male correlates of the hormonal and metabolic features of PCOS. We hypothesised that the effects of adipose tissue dysfunction are not sex-specific but rather fat depot-specific and independent of obesity. We used a clinically realistic ovine model of PCOS where pregnant sheep are injected with 100mg of testosterone propionate twice weekly from day 62 to day 102 of gestation. We studied control and prenatally androgenised (PA) female and male offspring during adolescence and weight-matched control and PA female sheep during adulthood. We examined subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and in adult female sheep bone marrow adipose tissue (BMAT). Adipogenesis related gene expression in SAT was similar in adolescent female and male controls and the reduction in adipogenesis related gene expression by PA in female adipose tissue was not observed in males. Differences in expression of genes associated with adipose tissue function in adolescence in SAT driven by PA were found in both sexes. In adulthood, the changes seen in adolescent females were absent or reversed but there was an increase in inflammatory markers that was weight independent. In addition, BMAT showed increased inflammatory markers. Adipose dysfunction evolves with time and is focussed on SAT rather than VAT and is generally sex-specific although there are also effects of prenatal androgenisation on male SAT. In female adults, the inflammation seen in SAT is also present in BMAT and the development of blood cells in an inflammatory environment may have systemic implications.

Global trends in the prevalence of overweight and obesity put the adipocyte in the focus of huge medical interest. This review highlights a new topic in adipose tissue biology, namely the emerging pathogenic role of fat accumulation in bone marrow (BM). Specifically, we summarize current knowledge about the origin and function of BM adipose tissue (BMAT), provide evidence for the association of excess BMAT with diabetes and related cardiovascular complications, and discuss potential therapeutic approaches to correct BMAT dysfunction. There is still a significant uncertainty about the origins and function of BMAT, although several subpopulations of stromal cells have been suggested to have an adipogenic propensity. BM adipocytes are higly plastic and have a distinctive capacity to secrete adipokines that exert local and endocrine functions. BM adiposity is abundant in elderly people and has therefore been interpreted as a component of the whole-body ageing process. BM senescence and BMAT accumulation has been also reported in patients and animal models with Type 2 diabetes, being more pronounced in those with ischaemic complications. Understanding the mechanisms responsible for excess and altered function of BMAT could lead to new treatments able to preserve whole-body homeostasis.

Bone regeneration is a highly coordinated biological process that restores tissue integrity and function following traumatic fractures. However, 10–15% of patients experience impaired healing or non-union, placing a considerable burden on healthcare systems worldwide. During our investigations, we observed bone marrow adipose tissue (BMAT) at fracture sites, where it influences the local endocrine and inflammatory environment, suggesting an essential role in the bone healing process. While BMAT has historically been associated with poor bone health, recent studies present a more nuanced relationship between BMAT and bone (Ambrosi et al., Cell Stem Cell , 2017; Li et al., eLife , 2022). This study aims to investigate the role of BMAT and its secreted adipokines, such as adiponectin, in bone regeneration. We specifically seek to clarify how different BMAT types affect healing outcomes. We employed a murine osteotomy model to modulate BMAT under distinct conditions, such as obesity and adiponectin signaling activation, to explore its role in fracture healing. Bone healing progression, along with BMAT frequency and morphology, was assessed using µCT imaging and histological analysis. Complementary in vitro experiments were conducted with human mesenchymal stromal cells (hMSCs) differentiated into adipocytes and osteoblasts under various treatments to validate in vivo findings and uncover the underlying signaling pathways. Additionally, genomic and lipidomic analyses of osteotomized bones were performed to identify the molecular mechanisms through which BMAT influences bone healing. Our findings reveal that BMAT formation is a physiological response to trauma, particularly in areas distal to the fracture site with limited nutrient and oxygen supply. In obese mice fed a high-fat diet, the number of adipocytes at the fracture site significantly increased, correlating with impaired bone regeneration. This was evidenced by decreased bone volume and insufficient bone bridging. Conversely, activation of adiponectin signaling, whether through PPARγ agonist treatment or direct receptor activation, promoted BMAT formation while improving bone healing outcomes. This improvement was accompanied by morphological and molecular changes in BMAs, suggesting a shift toward a more supportive role in the healing process. Bone marrow adipocytes exhibit metabolic plasticity, exerting either beneficial or detrimental effects on bone regeneration depending on local and systemic metabolic conditions. These findings highlight the dual role of BMAT in bone health and underscore their potential as therapeutic targets for enhancing bone regeneration in patients with metabolic disorders.

Spatial and biochemical interactions between bone marrow adipose tissue and hematopoietic stem and progenitor cells in rhesus macaques.

Fat is the main component of an adult bone marrow and constitutes the so-called bone marrow adipose tissue (BMAT). Marrow adipocytes, which are the fat cells in the bone marrow, become more abundant with age, and may influence the whole-body metabolism. In osteoporotic patients, the amount of BMAT has an inverse correlation with the amount of bone mass. In people with anorexia nervosa that lose weight after the reduction of peripheral adipose tissues, BMAT expands. Although bone marrow adipocytes are increasingly recognized as a target for therapy, there is still much to learn about their role in skeletal homeostasis, metabolism, cancer, and regenerative treatments. The Bone Marrow Adiposity Society (BMAS), established in 2017, aims to enhance the understanding of how BMAT relates to bone health, cancer, and systemic metabolism. BMAS is committed to training young scientists and organized the second edition of the BMAS Summer School, held on September 4-6, 2023, as a virtual event.

Correction of QCT vBMD using MRI measurements of marrow adipose tissue.

Obesity, a growing pandemic, is a risk factor for many cancers and causes increased bone marrow adipose tissue (BMAT). in vitro studies and obese animal models suggest that BMAT contributes to cancer progression, but there is a lack of preclinical models to directly test BMAT's role in cancer. Overactivation of peroxisome-proliferator-activated receptor-γ (PPARγ) can skew bone formation and resorption rates, resulting in increased BMAT and trabecular bone loss. Thiazolidinediones (eg, rosiglitazone) are anti-diabetic therapies that promote adipogenesis through PPARγ activation. We investigated if rosiglitazone increases BMAT in an immunocompromised model, commonly used in cancer research, and if these effects could be reversed by co-administering a bone anabolic agent (sclerostin-neutralizing antibody [Scl-Ab]), which has been shown to inhibit adipogenesis, using DXA, μCT, OsO4 μCT, and dynamic histomorphometry. Four weeks of rosiglitazone in female SCID Beige mice (cohort 1) significantly decreased trabecular bone volume (BV/TV) by about one-half, through increased osteoclast and suppressed osteoblast activity, and significantly increased BMAT. In cohort 2, mice were administered rosiglitazone ± Scl-Ab for 4 weeks, and then rosiglitazone was discontinued and Scl-Ab or vehicle were continued for 6 weeks. Scl-Ab significantly increased bone parameters (eg, BV/TV, N.Ob/B.Pm, and MS/BS) in both groups. Scl-Ab also overcame many negative effects of rosiglitazone (eg, effects on trabecular bone parameters, increased mineralization lag time [MLT], and decreased bone formation rate [BFR]). Interestingly, Scl-Ab significantly decreased rosiglitazone-induced BMAT in the femur, mostly due to a reduction in adipocyte size, but had a much weaker effect on tibial BMAT. These data suggest targeting sclerostin can prevent rosiglitazone-induced bone loss and reduce BM adiposity, in some, but not all BMAT locations. Collectively, our data demonstrate that rosiglitazone increases BMAT in SCID Beige mice, but concomitant changes in bone may confound its use to specifically determine BMAT's role in tumor models. © 2020 American Society for Bone and Mineral Research (ASBMR).