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Structure and Function of Bone Marrow Adipocytes

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ABSTRACT

Adipocytes are heterogeneous cells strongly linked to energy storage and disposal. In parallel, adipocytes are endowed with an extensive portfolio of endocrine molecules, whose secretion varies depending on nutritional status. Marrow adipose tissue (MAT) has specific characteristics that are not shared by white (WAT) or brown (BAT) adipose tissue. First, marrow adipocytes and osteoblasts are terminally differentiated cells that originate from the same bone marrow mesenchymal stromal cell. Differently from WAT adipocytes, marrow adipocytes expand under conditions of energy restriction and seem to be not influenced by energy surplus, at least in humans. Over the last few years, several lines of evidence have suggested that bone cells and MAT are mutually connected regarding the modulation of both energy metabolism and bone remodeling. Adipokines (e.g., adiponectin, leptin, and chemerin), incretins (GLP1 and GIP), and several classical hormones (e.g., GH and insulin) are biochemical components involved in the modulation of bone remodeling, marrow adipogenesis, and energy metabolism. As expected, metabolic and nutritional diseases such as diabetes mellitus and anorexia nervosa (AN) greatly affect MAT quantity and quality as well as bone strength. Although the interest in MAT started recently, the rapid advances in current technology have expedited unprecedented growth of knowledge in this area. The present review intends to give to the reader an up‐to‐date perspective about MAT structure and physiology as well as its involvement in metabolic and nutritional diseases such as diabetes mellitus and ano‐rexia. © 2018 American Physiological Society. Compr Physiol 8:315‐349, 2018.

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Figure 1. Figure 1. Bone‐derived hormones involved in the modulation of energy and osteomineral metabolism. Osteocalcin (OCN) originated in osteoblasts, after posttranslational modification acquires the capacity to modulate glucose metabolism. The synthesis of undercarboxylated Glu17‐OCN (ucOCN) requires the intermediation of osteoclasts that generate an acidic environment necessary to break the γ‐carboxylation on the first Glu residue. After released in blood circulation ucOCN acts on insulin sensitive tissues (adipose, liver, and muscle) improving insulin sensitivity (). In addition, ucOCN promotes insulin secretion and β‐cell proliferaion. Osteocyte, the predominant cell in bone has relevant endocrine and paracrine function: (a) FGF‐23 as a major regulator of phosphate and of the synthesis of 1,25(OH)2D. Actually, FGF‐23 is produced not only by osteocytes but also by osteoblast. FGF‐23 increases fractional phosphate excretion, reduce serum phosphate levels, and reduces 1α‐hydroxylase activity, which decreases 1,25(OH)2D3 synthesis (). Sclerostin binds Wnt coreceptors LRP5/6 to inhibit Wnt signaling to decrease bone formation ().
Figure 2. Figure 2. Regulated and constitutive marrow adipose tissue (MAT) in the mouse. Proposed distribution of regulated MAT (rMAT) and constitutive MAT (cMAT) in the mouse skeleton when marrow is present. Regulated MAT is found in the more proximal regions including the mid‐ to proximal‐tibia, femur, and lumbar vertebrae. Constitutive MAT is found in the most distal portion of the tibia and tail vertebrae. Representative histology of rMAT and cMAT adipocytes within the bone marrow. Figure adapted, with permission, from Scheller et al. (2016) ().
Figure 3. Figure 3. Age‐related increase in marrow adipose tissue in a group of healthy controls, 53 individuals (28 females and 25 males); age (female: 38.8 ± 13.2 and male: 39.7 ± 15.6 years); weight (female: 60.4 ± 6.4 and male: 66.0 ± 8.0); height (female: 1.65 ± 0.08 and male: 1.71 ± 0.06 m); and IMC (female: 22.1 ± 1.8 and male: 22.3 ± 1.9 kg/m2). MAT was assessed by 1.5 T 1H magnetic resonance spectroscopy of the lumbar spine (L3) (Philips Achieva, Philips Medical Systems, Best, The Netherlands).
Figure 4. Figure 4. Age‐related decrease in bone mineral density in a group of healthy controls, 53 individuals (28 females and 25 males); age (female: 38.8 ± 13.2 and male: 39.7 ± 15.6 years); weight (female: 60.4 ± 6.4 and male: 66.0 ± 8.0); height (female: 1.65 ± 0.08 and male: 1.71 ± 0.06 m) and IMC (female: 22.1 ± 1.8 and male: 22.3 ± 1.9 kg/m2). BMD was measured by dual‐energy X‐ray absorptiometry of the lumbar spine (L1‐L4) (Hologic Discovery Wi QDR series, Waltham, MA).
Figure 5. Figure 5. These results depict the negative relationship between bone mass and MAT in a group of healthy controls, 53 individuals (28 females and 25 males); age (female: 38.8 ± 13.2 and male: 39.7 ± 15.6 years); weight (female: 60.4 ± 6.4 and male: 66.0 ± 8.0); height (female: 1.65 ± 0.08 and male: 1.71 ± 0.06 m); and IMC (female: 22.1 ± 1.8 and male: 22.3 ± 1.9 kg/m2).
Figure 6. Figure 6. The mesenchymal stromal cell differentiation to osteoblast needs activation of key factors such as runt‐related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2), transforming growth factor‐beta (TGFβ), and transcription factor Sp7 (osterix). In contraposition, the differentiation toward adipocyte requires groups of critical factors already present in mesenchymal stromal cells that need to be activated: CCAAT/enhancer binding proteins (C/EBP) family: C/EBPα, C/EBPβ, C/EBPγ, and C/EBPδ, and peroxisome proliferative activated receptors α, γ2, and δ. Molecules produced in adipocytes (PREF1 and chemerin) as well incretin (GLP1) affect BMMSC differentiation. PREF1 affects negatively both adipogenesis and osteoblastogenesis; chemerin exerts a positive stimulus to adipogenesis whereas it inhibits osteoblastogenesis. Conversely, GLP1 stimulates osteoblast differentiation and inhibits adipogenesis.
Figure 7. Figure 7. Vertebral body 1H MRS data were acquired using a point resolve 40/60/80 ms, repetition time (TR) = 2000 ms, eight averages, without fat suppression. Spectroscopy (PRESS) sequence with the following parameters: echo time (TE) = 1 min duration. A customized fitting algorithm for bone marrow analysis provided estimates for four lipid peaks: olefinic protons at 5.3 ppm (CHCH) were used to estimate unsaturated lipids (UL); methylene protons at 1.3 ppm [(CH2)n] provided estimates of saturated lipids (SL); residual lipids (RL) were estimated by allylic methylene protons at 2.3 ppm (CHCHCH2) and methyl protons at 0.9 ppm (CH3). Water (W) estimates were determined by a peak at 4.7 ppm.
Figure 8. Figure 8. 1H magnetic resonance spectroscopy allows the estimation of lipids composition in MAT. Recent studies called attention for the clinical relevance of this parameter, such as the association of saturated lipids with fracture in diabetic individuals. The above figure exhibits differences in unsaturated fat between male and female (female > male).
Figure 9. Figure 9. Leptin receptor in hypothalamic ventromedial neurons is not necessary for triggering leptin action. Leptin regulates bone mass accrual and appetite by inhibiting serotonin synthesis and release by the raphe nuclei neurons of the brainstem. Leptin acts through its binding to its receptor ObRb in the serotonergic neurons of the raphe nuclei. Figure adapted, with permission, from Karsenty and Oury (2010) ().
Figure 10. Figure 10. Model representing the GLP1R Role on promoting BMMSCs osteoblast differentiation and suppressing their differentiation into adipocytes through crosstalk with β‐catenin signaling pathway. GLP1 agonist, GLP1, or Ex4 bound to GLP1R activates the adenylyl cyclase with a consequent production of cyclic AMP and subsequent activation of PKA. GLP1‐mediated activation of PKA results in β‐catenin phosphorylation on Ser675, leading to its nuclear translocation and initiation of the osteogenic gene expression. The activated PKA also phosphorylates PI3K, leading to the activation of AKT. Phosphorylated PKA subsequently phosphorylates GSK3β, resulting in the inhibition of GSK3β activity. β‐Catenin degradation mediated by GSK3β is thus inhibited and nuclear accumulation of β‐catenin is potentiated. Finally, BMMSC osteoblast differentiation takes place and anabolic bone formation is promoted. Figure adapted, with permission, from Meng et al. (2016) ().
Figure 11. Figure 11. Calorie restriction deeply affects the GH/IGF1 axis. Usually, there is increased levels of GH secretion combined with low levels of IGF1. The mechanisms involved are not completely delineated but there are studies indicating reduction in GH receptor as well as postreceptor defects.
Figure 12. Figure 12. Bone marrow adipose tissue is paradoxically elevated in anorexia nervosa despite reduced total body fat. Elevated levels of preadipocyte factor 1 (PREF1), which are an important regulator of mesenchymal stromal cell differentiation, might be one of the mechanisms underlying the increase in bone marrow adipose tissue. Overall, a decrease in osteoblast differentiation, proliferation, and activity with a concomitant increase in osteoblast apoptosis is seen, in addition to an increase in osteoclast differentiation, proliferation, and activity with a concomitant decrease in osteoclast apoptosis. Growth hormone (GH) and insulin‐like growth factor 1 (IGF1) stimulate osteoblast differentiation while inhibiting osteoclast differentiation, and GH independently stimulates osteoblast proliferation. By contrast, cortisol decreases bone formation and increases bone resorption. Alterations in adipokines, such as leptin, and appetite‐regulating hormones, such as peptide YY (PYY), might also contribute to impaired bone microarchitecture in anorexia nervosa but are not well understood. *Hormone effect for which there are limited data. +, positive effect; −, negative effect. Figure adapted, with permission, from Schorr and Miller (2017) ().
Figure 13. Figure 13. The complex relationship between BMI, BMD, and fracture risk is illustrated in the schematic. Compared with an underweight individual, an overweight individual experiencing a fall from the same height would generate a proportionately greater load on a limb (ground reaction force). However, the presence of greater amount of soft tissue in the heavier individual should attenuate more of the load and distribute the remaining load over a larger bone surface, reducing peak strain such that the effective load could be greater in the lighter individual. Assuming equivalent bone quality, the higher BMD typical in the heavier individual would be a further advantage in reducing strain below that required for a fracture. However, based on epidemiological studies, further increases in weight may provide a diminishing return because the reductions in load during a fall related to soft tissue and higher BMD may not fully compensate for increased weight. Type 2 diabetes mellitus adds ingredients that impair bone quality and increase fracture risk. Figure adapted, with permission, from Iwaniec and Turner (2016) ().


Figure 1. Bone‐derived hormones involved in the modulation of energy and osteomineral metabolism. Osteocalcin (OCN) originated in osteoblasts, after posttranslational modification acquires the capacity to modulate glucose metabolism. The synthesis of undercarboxylated Glu17‐OCN (ucOCN) requires the intermediation of osteoclasts that generate an acidic environment necessary to break the γ‐carboxylation on the first Glu residue. After released in blood circulation ucOCN acts on insulin sensitive tissues (adipose, liver, and muscle) improving insulin sensitivity (). In addition, ucOCN promotes insulin secretion and β‐cell proliferaion. Osteocyte, the predominant cell in bone has relevant endocrine and paracrine function: (a) FGF‐23 as a major regulator of phosphate and of the synthesis of 1,25(OH)2D. Actually, FGF‐23 is produced not only by osteocytes but also by osteoblast. FGF‐23 increases fractional phosphate excretion, reduce serum phosphate levels, and reduces 1α‐hydroxylase activity, which decreases 1,25(OH)2D3 synthesis (). Sclerostin binds Wnt coreceptors LRP5/6 to inhibit Wnt signaling to decrease bone formation ().


Figure 2. Regulated and constitutive marrow adipose tissue (MAT) in the mouse. Proposed distribution of regulated MAT (rMAT) and constitutive MAT (cMAT) in the mouse skeleton when marrow is present. Regulated MAT is found in the more proximal regions including the mid‐ to proximal‐tibia, femur, and lumbar vertebrae. Constitutive MAT is found in the most distal portion of the tibia and tail vertebrae. Representative histology of rMAT and cMAT adipocytes within the bone marrow. Figure adapted, with permission, from Scheller et al. (2016) ().


Figure 3. Age‐related increase in marrow adipose tissue in a group of healthy controls, 53 individuals (28 females and 25 males); age (female: 38.8 ± 13.2 and male: 39.7 ± 15.6 years); weight (female: 60.4 ± 6.4 and male: 66.0 ± 8.0); height (female: 1.65 ± 0.08 and male: 1.71 ± 0.06 m); and IMC (female: 22.1 ± 1.8 and male: 22.3 ± 1.9 kg/m2). MAT was assessed by 1.5 T 1H magnetic resonance spectroscopy of the lumbar spine (L3) (Philips Achieva, Philips Medical Systems, Best, The Netherlands).


Figure 4. Age‐related decrease in bone mineral density in a group of healthy controls, 53 individuals (28 females and 25 males); age (female: 38.8 ± 13.2 and male: 39.7 ± 15.6 years); weight (female: 60.4 ± 6.4 and male: 66.0 ± 8.0); height (female: 1.65 ± 0.08 and male: 1.71 ± 0.06 m) and IMC (female: 22.1 ± 1.8 and male: 22.3 ± 1.9 kg/m2). BMD was measured by dual‐energy X‐ray absorptiometry of the lumbar spine (L1‐L4) (Hologic Discovery Wi QDR series, Waltham, MA).


Figure 5. These results depict the negative relationship between bone mass and MAT in a group of healthy controls, 53 individuals (28 females and 25 males); age (female: 38.8 ± 13.2 and male: 39.7 ± 15.6 years); weight (female: 60.4 ± 6.4 and male: 66.0 ± 8.0); height (female: 1.65 ± 0.08 and male: 1.71 ± 0.06 m); and IMC (female: 22.1 ± 1.8 and male: 22.3 ± 1.9 kg/m2).


Figure 6. The mesenchymal stromal cell differentiation to osteoblast needs activation of key factors such as runt‐related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2), transforming growth factor‐beta (TGFβ), and transcription factor Sp7 (osterix). In contraposition, the differentiation toward adipocyte requires groups of critical factors already present in mesenchymal stromal cells that need to be activated: CCAAT/enhancer binding proteins (C/EBP) family: C/EBPα, C/EBPβ, C/EBPγ, and C/EBPδ, and peroxisome proliferative activated receptors α, γ2, and δ. Molecules produced in adipocytes (PREF1 and chemerin) as well incretin (GLP1) affect BMMSC differentiation. PREF1 affects negatively both adipogenesis and osteoblastogenesis; chemerin exerts a positive stimulus to adipogenesis whereas it inhibits osteoblastogenesis. Conversely, GLP1 stimulates osteoblast differentiation and inhibits adipogenesis.


Figure 7. Vertebral body 1H MRS data were acquired using a point resolve 40/60/80 ms, repetition time (TR) = 2000 ms, eight averages, without fat suppression. Spectroscopy (PRESS) sequence with the following parameters: echo time (TE) = 1 min duration. A customized fitting algorithm for bone marrow analysis provided estimates for four lipid peaks: olefinic protons at 5.3 ppm (CHCH) were used to estimate unsaturated lipids (UL); methylene protons at 1.3 ppm [(CH2)n] provided estimates of saturated lipids (SL); residual lipids (RL) were estimated by allylic methylene protons at 2.3 ppm (CHCHCH2) and methyl protons at 0.9 ppm (CH3). Water (W) estimates were determined by a peak at 4.7 ppm.


Figure 8. 1H magnetic resonance spectroscopy allows the estimation of lipids composition in MAT. Recent studies called attention for the clinical relevance of this parameter, such as the association of saturated lipids with fracture in diabetic individuals. The above figure exhibits differences in unsaturated fat between male and female (female > male).


Figure 9. Leptin receptor in hypothalamic ventromedial neurons is not necessary for triggering leptin action. Leptin regulates bone mass accrual and appetite by inhibiting serotonin synthesis and release by the raphe nuclei neurons of the brainstem. Leptin acts through its binding to its receptor ObRb in the serotonergic neurons of the raphe nuclei. Figure adapted, with permission, from Karsenty and Oury (2010) ().


Figure 10. Model representing the GLP1R Role on promoting BMMSCs osteoblast differentiation and suppressing their differentiation into adipocytes through crosstalk with β‐catenin signaling pathway. GLP1 agonist, GLP1, or Ex4 bound to GLP1R activates the adenylyl cyclase with a consequent production of cyclic AMP and subsequent activation of PKA. GLP1‐mediated activation of PKA results in β‐catenin phosphorylation on Ser675, leading to its nuclear translocation and initiation of the osteogenic gene expression. The activated PKA also phosphorylates PI3K, leading to the activation of AKT. Phosphorylated PKA subsequently phosphorylates GSK3β, resulting in the inhibition of GSK3β activity. β‐Catenin degradation mediated by GSK3β is thus inhibited and nuclear accumulation of β‐catenin is potentiated. Finally, BMMSC osteoblast differentiation takes place and anabolic bone formation is promoted. Figure adapted, with permission, from Meng et al. (2016) ().


Figure 11. Calorie restriction deeply affects the GH/IGF1 axis. Usually, there is increased levels of GH secretion combined with low levels of IGF1. The mechanisms involved are not completely delineated but there are studies indicating reduction in GH receptor as well as postreceptor defects.


Figure 12. Bone marrow adipose tissue is paradoxically elevated in anorexia nervosa despite reduced total body fat. Elevated levels of preadipocyte factor 1 (PREF1), which are an important regulator of mesenchymal stromal cell differentiation, might be one of the mechanisms underlying the increase in bone marrow adipose tissue. Overall, a decrease in osteoblast differentiation, proliferation, and activity with a concomitant increase in osteoblast apoptosis is seen, in addition to an increase in osteoclast differentiation, proliferation, and activity with a concomitant decrease in osteoclast apoptosis. Growth hormone (GH) and insulin‐like growth factor 1 (IGF1) stimulate osteoblast differentiation while inhibiting osteoclast differentiation, and GH independently stimulates osteoblast proliferation. By contrast, cortisol decreases bone formation and increases bone resorption. Alterations in adipokines, such as leptin, and appetite‐regulating hormones, such as peptide YY (PYY), might also contribute to impaired bone microarchitecture in anorexia nervosa but are not well understood. *Hormone effect for which there are limited data. +, positive effect; −, negative effect. Figure adapted, with permission, from Schorr and Miller (2017) ().


Figure 13. The complex relationship between BMI, BMD, and fracture risk is illustrated in the schematic. Compared with an underweight individual, an overweight individual experiencing a fall from the same height would generate a proportionately greater load on a limb (ground reaction force). However, the presence of greater amount of soft tissue in the heavier individual should attenuate more of the load and distribute the remaining load over a larger bone surface, reducing peak strain such that the effective load could be greater in the lighter individual. Assuming equivalent bone quality, the higher BMD typical in the heavier individual would be a further advantage in reducing strain below that required for a fracture. However, based on epidemiological studies, further increases in weight may provide a diminishing return because the reductions in load during a fall related to soft tissue and higher BMD may not fully compensate for increased weight. Type 2 diabetes mellitus adds ingredients that impair bone quality and increase fracture risk. Figure adapted, with permission, from Iwaniec and Turner (2016) ().
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Teaching Material

F. J. A. de Paula, C. J. Rosen. Structure and Function of Bone Marrow Adipocytes. Compr Physiol. 8: 2018, 315-349.

Didactic Synopsis

Major Teaching Points:

  • Several lines of evidence indicate that marrow adipose tissue (MAT) participates in the regulation of bone remodeling and energy metabolism, but the mechanisms involved are still to be delineated.
  • The recognition of morphological and physiological differences between two types of MAT led to its classification as constitutive (c) and regulated (r) MAT.
  • rMAT has exquisite sensitivity to calorie restriction, which is a positive stimulus of MAT expansion.
  • The role of adipokines such as PREF1 and chemerin may be a link between marrow adipocytes and osteoblasts for the control of bone remodeling.
  • In human beings, MAT seems not to be a niche for fuel storage under conditions of energy surplus.
  • In the presence of calorie restriction, MAT may be a relevant source of endocrine adiponectin.
  • Insulin resistance is not associated with MAT in obesity or type 2 diabetes mellitus.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Bone-derived hormones involved in the modulation of energy and osteomineral metabolism. Osteocalcin (OCN) originated in osteoblasts, after posttranslational modification acquires the capacity to modulate glucose metabolism. The synthesis of undercarboxylated Glu17-OCN (ucOCN) requires the intermediation of osteoclasts that generate an acidic environment necessary to break the γ-carboxylation on the first Glu residue. After released in blood circulation ucOCN acts on insulin sensitive tissues (adipose, liver, and muscle) improving insulin sensitivity (102, 179, 208, 342). In addition, ucOCN promotes insulin secretion and β-cell proliferaion. Osteocyte, the predominant cell in bone has relevant endocrine and paracrine function: (a) FGF-23 as a major regulator of phosphate and of the synthesis of 1,25(OH)2D. Actually, FGF-23 is produced not only by osteocytes but also by osteoblast. FGF-23 increases fractional phosphate excretion, reduce serum phosphate levels, and reduces 1α-hydroxylase activity, which decreases 1,25(OH)₂D₃ synthesis (54, 56). Sclerostin binds Wnt coreceptors LRP5/6 to inhibit Wnt signaling to decrease bone formation (19).

Figure 2. Teaching points: Regulated and constitutive marrow adipose tissue (MAT) in the mouse. (A) Proposed distribution of regulated MAT (rMAT) and constitutive MAT (cMAT) in the mouse skeleton when marrow is present. Regulated MAT is found in the more proximal regions including the mid- to proximal-tibia, femur, and lumbar vertebrae. Constitutive MAT is found in the most distal portion of the tibia and tail vertebrae. (C) Representative histology of rMAT and cMAT adipocytes within the bone marrow. Figure adapted, with permission, from Scheller et al. (2016) (281).

Figure 3. Teaching points: Age-related increase in marrow adipose tissue in a group of healthy controls, 53 individuals (28 females and 25 males); age (female: 38.8 ± 13.2 and male: 39.7 ± 15.6 years); weight (female: 60.4 ± 6.4 and male: 66.0 ± 8.0); height (female: 1.65 ± 0.08 and male: 1.71 ± 0.06 m); and IMC (female: 22.1 ± 1.8 and male: 22.3 ± 1.9 kg/m2). MAT was assessed by 1.5 T 1H magnetic resonance spectroscopy of the lumbar spine (L3) (Philips Achieva, Philips Medical Systems, Best, The Netherlands).

Figure 4. Teaching points: Age-related decrease in bone mineral density in a group of healthy controls, 53 individuals (28 females and 25 males); age (female: 38.8 ± 13.2 and male: 39.7 ± 15.6 years); weight (female: 60.4 ± 6.4 and male: 66.0 ± 8.0); height (female: 1.65 ± 0.08 and male: 1.71 ± 0.06 m); and IMC (female: 22.1 ± 1.8 and male: 22.3 ± 1.9 kg/m2). BMD was measured by dual-energy X-ray absorptiometry of the lumbar spine (L1-L4) (Hologic Discovery Wi QDR series, Waltham, MA).

Figure 5. Teaching points: These results depict the negative relationship between bone mass and MAT in a group of healthy controls, 53 individuals (28 females and 25 males); age (female: 38.8 ± 13.2 and male: 39.7 ± 15.6 years); weight (female: 60.4 ± 6.4 and male: 66.0 ± 8.0); height (female: 1.65 ± 0.08 and male: 1.71 ± 0.06 m); and IMC (female: 22.1 ± 1.8 and male: 22.3 ± 1.9 kg/m2).

Figure 6. Teaching points: The mesenchymal stromal cell differentiation to osteoblast needs activation of key factors such as runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2), transforming growth factor-beta (TGFβ), and transcription factor Sp7 (osterix). In contraposition, the differentiation toward adipocyte requires groups of critical factors already present in mesenchymal stromal cells that need to be activated: CCAAT/enhancer binding proteins (C/EBP) family: C/EBPα, C/EBPβ, C/EBPγ, and C/EBPδ, and peroxisome proliferative activated receptors α, γ2, and δ. Molecules produced in adipocytes (PREF1 and chemerin) as well incretin (GLP1) affect BMMSC differentiation. PREF1 affects negatively both adipogenesis and osteoblastogenesis; chemerin exerts a positive stimulus to adipogenesis whereas it inhibits osteoblastogenesis. Conversely, GLP1 stimulates osteoblast differentiation and inhibits adipogenesis.

Figure 7. Teaching points: Vertebral body 1H MRS data were acquired using a Point Resolve 40/60/80 ms, repetition time (TR) = 2000 ms, eight averages, without fat suppression. Spectroscopy (PRESS) sequence with the following parameters: echo time (TE) = 1 min duration. A customized fitting algorithm for bone marrow analysis provided estimates for four lipid peaks: olefinic protons at 5.3 ppm (-CH = CH-) were used to estimate unsaturated lipids (UL); methylene protons at 1.3 ppm [(–CH2–)n] provided estimates of saturated lipids (SL); residual lipids (RL) were estimated by allylic methylene protons at 2.3 ppm (-CH = CHCH2) and methyl protons at 0.9 ppm (-CH3). Water (W) estimates were determined by a peak at 4.7 ppm.

Figure 8. Teaching points: 1H magnetic resonance spectroscopy allows the estimation of lipids composition in MAT. Recent studies called attention for the clinical relevance of this parameter, such as the association of saturated lipids with fracture in diabetic individuals. The above figure exhibits differences in unsaturated fat between male and female (female > male).

Figure 9. Teaching points: Leptin receptor in hypothalamic ventromedial neurons is not necessary for triggering leptin action. Leptin regulates bone mass accrual and appetite by inhibiting serotonin synthesis and release by the raphe nuclei neurons of the brainstem. Leptin acts through its binding to its receptor ObRb in the serotonergic neurons of the raphe nuclei. Figure adapted, with permission, from Karsenty and Oury (2010) (162).

Figure 10. Teaching points: Model representing the GLP1R role on promoting BMSCs osteoblast differentiation and suppressing their differentiation into adipocytes through crosstalk with β-catenin signaling pathway. GLP1 agonist, GLP1, or Ex4 bound to GLP1R activates the adenylyl cyclase with a consequent production of cyclic AMP and subsequent activation of PKA. GLP1-mediated activation of PKA results in β-catenin phosphorylation on Ser675, leading to its nuclear translocation and initiation of the osteogenic gene expression. The activated PKA also phosphorylates PI3K, leading to the activation of AKT. Phosphorylated PKA subsequently phosphorylates GSK3β, resulting in the inhibition of GSK3β activity. β-Catenin degradation mediated by GSK3β is thus inhibited and nuclear accumulation of β-catenin is potentiated. Finally, BMSC osteoblast differentiation takes place and anabolic bone formation is promoted. Figure adapted, with permission, from Meng et al. (2016) (207).

Figure 11. Teaching points: Calorie restriction deeply affects the GH/IGF1 axis. Usually, there is increased levels of GH secretion combined with low levels of IGF1. The mechanisms involved are not completely delineated but there are studies indicating reduction in GH receptor as well as postreceptor defects.

Figure 12. Teaching points: Bone marrow adipose tissue is paradoxically elevated in anorexia nervosa despite reduced total body fat. Elevated levels of preadipocyte factor 1 (PREF1), which are an important regulator of mesenchymal stromal cell differentiation, might be one of the mechanisms underlying the increase in bone marrow adipose tissue. Overall, a decrease in osteoblast differentiation, proliferation, and activity with a concomitant increase in osteoblast apoptosis is seen, in addition to an increase in osteoclast differentiation, proliferation, and activity with a concomitant decrease in osteoclast apoptosis. Growth hormone (GH) and insulin-like growth factor 1 (IGF1) stimulate osteoblast differentiation while inhibiting osteoclast differentiation, and GH independently stimulates osteoblast proliferation. By contrast, cortisol decreases bone formation and increases bone resorption. Alterations in adipokines, such as leptin, and appetite-regulating hormones, such as peptide YY (PYY), might also contribute to impaired bone microarchitecture in anorexia nervosa but are not well understood. *Hormone effect for which there are limited data. + , positive effect; − , negative effect. Figure adapted, with permission, from Schorr and Miller (2017) (286).

Figure 13. Teaching points: The complex relationship between BMI, BMD, and fracture risk is illustrated in the schematic. Compared with an underweight individual, an overweight individual experiencing a fall from the same height would generate a proportionately greater load on a limb (ground reaction force). However, the presence of greater amount of soft tissue in the heavier individual should attenuate more of the load and distribute the remaining load over a larger bone surface, reducing peak strain such that the effective load could be greater in the lighter individual. Assuming equivalent bone quality, the higher BMD typical in the heavier individual would be a further advantage in reducing strain below that required for a fracture. However, based on epidemiological studies, further increases in weight may provide a diminishing return because the reductions in load during a fall related to soft tissue and higher BMD may not fully compensate for increased weight. Type 2 diabetes mellitus adds ingredients that impair bone quality and increase fracture risk. Figure adapted, with permission, from Iwaniec and Turner (2016) (148).

 


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Francisco José Albuquerque de Paula, Clifford J. Rosen. Structure and Function of Bone Marrow Adipocytes. Compr Physiol 2017, 8: 315-349. doi: 10.1002/cphy.c170010