Vitamin D, osteocalcin, and risk for adiposity as comorbidities in middle school children

Nonclassic actions of vitamin D include potential regulation of immune function and glucose homeostasis. The bone-metabolism loop has recently been expanded to include osteocalcin, which appears to play a more direct role in pancreatic beta cell function and energy metabolism. We hypothesized that both vitamin D and osteocalcin would correlate negatively with indices of adiposity-related comorbidity risk in periadolescents, varying by ethnic group. We analyzed anthropometric, metabolic, and inflammatory markers from a multiethnic population of 106 school children 11 to 14 years of age studied as part of the Reduce Obesity and Diabetes (ROAD) consortium. As expected, 25-hydroxyvitamin D (25-OH vitamin D) was inversely correlated with intact parathyroid hormone (iPTH); total osteocalcin (OCN) and uncarboxylated osteocalcin (uOCN) were directly correlated with each other. OCN and uOCN concentrations correlated inversely with age. Vitamin D deficiency was most prevalent among East Asians (EA) and African Americans (AA). The highest lipid risk scores and homeostatic model for assessment of insulin resistance (HOMA-IR) values were seen in the South Asian (SA) group. Overall, adiposity measures were inversely correlated with OCN and iPTH, whereas such relationships were not observed for vitamin D. Acute insulin response to glucose challenge correlated negatively with uOCN in all subjects; however, lipid risk score correlated negatively with uOCN only in whites. The relationships between markers of calcium metabolism and body composition, glucose homeostasis, lipids, and inflammation all showed racial and ethnic differences. No consistent relationship was found between vitamin D and adiposity or vitamin D and glucose metabolism; instead vitamin D levels varied by race and ethnicity in this school-based group. These findings are consistent with the hypothesis that markers of calcium and bone metabolism may reflect risk for adiposity-related comorbidities in children.     

Marrow fat and preadipocyte factor-1 levels decrease with recovery in women with anorexia nervosa

Women with anorexia nervosa (AN) have elevated marrow fat mass despite low visceral and subcutaneous fat depots, which is inversely associated with bone mineral density (BMD). Whether marrow fat mass remains persistently elevated or decreases with recovery from AN is currently unknown. In this study, we investigated changes in marrow fat in women who have recovered from AN (AN-R). We also studied the relationship between preadipocyte factor (Pref)-1—a member of the EGF-like family of proteins and regulator of adipocyte and osteoblast differentiation—and fat depots and BMD in AN-R compared with women with AN and healthy controls (HC). We studied 29 women: 14 with active or recovered AN (30.7 + 2.2 years [mean ± SEM]) and 15 normal-weight controls (27.8 ± 1.2 years). We measured marrow adipose tissue (MAT) of the L4 vertebra and femur by ¹H-magnetic resonance spectroscopy; BMD of the spine, hip, and total body by DXA; and serum Pref-1 and leptin levels. We found that MAT of the L4 vertebra was significantly lower in AN-R compared with AN (p = 0.03) and was comparable to levels in HC. Pref-1 levels were also significantly lower in AN-R compared with AN (p = 0.02) and comparable to levels in healthy controls. Although Pref-1 was positively associated with MAT of the L4 vertebra in AN (R = 0.94; p = 0.002), we found that it was inversely associated with MAT of the L4 vertebra in HC (R = −0.71; p = 0.004). Therefore, we have shown that MAT and Pref-1 levels decrease with recovery from AN. Our data suggest that Pref-1 may have differential effects in states of nutritional deprivation compared with nutritional sufficiency. © 2012 American Society for Bone and Mineral Research.     

Constant light induces alterations in melatonin levels,food intake,feed efficiency,visceral adiposity,and circadian rhythms in rats

Abstract

Melatonin levels, metabolic parameters, circadian rhythm activity patterns, and behavior were observed in rats subjected to a 12-h/12-h light/dark cycle (LD) compared to animals exposed to continuous dark (DD) or continuous light (LL). LD and DD animals were similar in melatonin levels, food intake, relative food intake, feed efficiency, water intake, circadian activity levels, and behavior. LL animals had lower melatonin levels in the subjective dark compared to LD and DD animals. Food intake, relative food intake, and water intake values were lower and feed efficiency was more positive in LL animals compared to LD and DD animals. In addition, LL animals exhibited greater visceral adiposity than the other two groups. The circadian rhythmicity of activity became free-running in LL animals and there was a decrease in overall activity. Notable behavioral changes in LL animals were an increase in irritability and excitability. Results indicate that a decrease in melatonin levels and concomitant changes in metabolism, circadian rhythms, and behavior are consequences of exposure to constant light.     

Adverse Fat Depots and Marrow Adiposity Are Associated With Skeletal Deficits and Insulin Resistance in Long‐Term Survivors of Pediatric Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem‐cell transplantation (alloHSCT) survivors treated with total body irradiation (TBI) exhibit bone deficits and excess adiposity, potentially related to altered mesenchymal stem cell differentiation into osteoblasts or adipocytes. We examined associations among fat distribution, bone microarchitecture, and insulin resistance in alloHSCT survivors after TBI. This was a cross‐sectional observational study of 25 alloHSCT survivors (aged 12 to 25 years) a median of 9.7 (4.3 to 19.3) years after alloHSCT compared to 25 age‐, race‐, and sex‐matched healthy controls. Vertebral MR spectroscopic imaging and tibia micro‐MRI were used to quantify marrow adipose tissue (MAT) and trabecular microarchitecture. Additional measures included DXA whole‐body fat mass (WB‐FM), leg lean mass (Leg‐LM), trunk visceral adipose tissue (VAT), and CT calf muscle density. Insulin resistance in alloHSCT survivors was estimated by HOMA‐IR. AlloHSCT survivors had lower Leg‐LM (p < 0.001) and greater VAT (p < 0.01), MAT (p < 0.001), and fat infiltration of muscle (p = 0.04) independent of WB‐FM, versus matched controls; BMI did not differ. Survivors had lower bone volume fraction and abnormal microarchitecture including greater erosion and more rod‐like structure versus controls (all p = 0.04); 14 had vertebral deformities and two had compression fractures. Greater WB‐FM, VAT, MAT, and muscle fat infiltration were associated with abnormal trabecular microarchitecture (p < 0.04 for all). AlloHSCT HOMA‐IR was elevated, associated with younger age at transplantation (p < 0.01), and positively correlated with WB‐FM and VAT (both p < 0.01). In conclusion, the markedly increased marrow adiposity, abnormal bone microarchitecture, and abnormal fat distribution highlight the risks of long‐term treatment‐related morbidity and mortality in alloHSCT recipients after TBI. Trabecular deterioration was associated with marrow and visceral adiposity. Furthermore, long‐term survivors demonstrated sarcopenic obesity, insulin resistance, and vertebral deformities. Future studies are needed to identify strategies to prevent and treat metabolic and skeletal complications in this growing population of childhood alloHSCT survivors. © 2015 American Society for Bone and Mineral Research.     

Relationship between Single Nucleotide Polymorphisms in Leptin, IL6 and Adiponectin Genes and their Circulating Product in Morbidly Obese Subjects before and after Gastric Banding Surgery

Background: Certain adipose-produced signals are secreted in proportion to body fat mass and are involved in regulation of the energy metabolism of the whole body. Leptin, IL6 and adiponectin can be considered as adiposity signals. Several Single Nucleotide Polymorphisms (SNPs) in genes encoding for these molecules are known to influence their concentration in situations of stable weight. We hypothesized that polymorphism effects could be better detected in a situation of negative energy balance and that modified concentrations of adiposity signal genes could change the dynamics of weight gain in obese subjects. Methods: 65 obese patients undergoing gastric banding surgery were genotyped for LEP+19A→G, LEP-2548G→C, IL6-174G→C, APM1-11377C→G and PM1-11391G→A common SNPs. BMI and concentrations of leptin, IL6 and adiponectin were measured before surgery and after 1 year. Results: All SNPs except IL6-174G→C SNP were associated with modifications of the circulating concentrations of signals produced by adipose tissue at baseline. During weight loss, variant genotype carriers of LEP -2548 and +19 SNPs were characterized by a trend towards less decrease in circulating leptin. Weight loss was associated with an increase in IL6 concentration (16.9%±12.2) in the IL6-174 C/C genotype carriers, whereas the C/G or G/G genotypes carriers showed a decrease in IL6 (19.9%±5.2, P=0.001). Conclusion: We observed that the SNPs studied could modulate the concentration of adiposity signals not only at baseline but also during weight loss. Such variations may be sensed by the homeostatic feedback system that controls energy balance and may in turn contribute to some disturbances in weight regulation.     

Visceral Adipose Tissue Is Associated With Bone Microarchitecture in the Framingham Osteoporosis Study

Obesity has been traditionally considered to protect the skeleton against osteoporosis and fracture. Recently, body fat, specifically visceral adipose tissue (VAT), has been associated with lower bone mineral density (BMD) and increased risk for some types of fractures. We studied VAT and bone microarchitecture in 710 participants (58% women, age 61.3 ± 7.7 years) from the Framingham Offspring cohort to determine whether cortical and trabecular BMD and microarchitecture differ according to the amount of VAT. VAT was measured from CT imaging of the abdomen. Cortical and trabecular BMD and microarchitecture were measured at the distal tibia and radius using high‐resolution peripheral quantitative computed tomography (HR‐pQCT). We focused on 10 bone parameters: cortical BMD (Ct.BMD), cortical tissue mineral density (Ct.TMD), cortical porosity (Ct.Po), cortical thickness (Ct.Th), cortical bone area fraction (Ct.A/Tt.A), trabecular density (Tb.BMD), trabecular number (Tb.N), trabecular thickness (Tb.Th), total area (Tt.Ar), and failure load (FL) from micro–finite element analysis. We assessed the association between sex‐specific quartiles of VAT and BMD, microarchitecture, and strength in all participants and stratified by sex. All analyses were adjusted for age, sex, and in women, menopausal status, then repeated adjusting for body mass index (BMI) or weight. At the radius and tibia, Ct.Th, Ct.A/Tt.A, Tb.BMD, Tb.N, and FL were positively associated with VAT (all p‐trend <0.05), but no other associations were statistically significant except for higher levels of cortical porosity with higher VAT in the radius. Most of these associations were only observed in women, and were no longer significant when adjusting for BMI or weight. Higher amounts of VAT are associated with greater BMD and better microstructure of the peripheral skeleton despite some suggestions of significant deleterious changes in cortical measures in the non–weight bearing radius. Associations were no longer significant after adjustment for BMI or weight, suggesting that the effects of VAT may not have a substantial effect on the skeleton independent of BMI or weight. © 2016 American Society for Bone and Mineral Research.     

Bone Marrow and Muscle Fat Infiltration Are Correlated among Postmenopausal Women With Osteoporosis: The AMBERS Cohort Study

Bone and muscle have shown to interact, but little is known about fat within bone and muscle. Clinical studies have isolated fat within bone and muscle using MRI. In this cross-sectional study, we hypothesized that bone marrow adiposity and muscle adiposity are related and that this relationship is associated with osteoporosis. Postmenopausal women aged 60 to 85 years were recruited as part of the Appendicular Muscle and Bone Extension Research Study (AMBERS). Participants completed dual-energy X-ray absorptiometry (DXA) of the hip and spine to diagnose osteoporosis. Muscle adiposity was measured with MRI at the 66% site of the leg. Fat segmentation was achieved using a semi-automated iterative threshold-optimizing algorithm (error < 5%). Peripheral quantitative computed tomography measured marrow density of the 4% distal tibia (surrogate for marrow fat) by threshold-based, edge-detection segmentations and by examining residuals from trabecular bone density regressed on trabecular tissue mineral density. Muscle adiposity from MRI was regressed on marrow density using linear regression. Models were further examined with an interaction with osteoporosis status. Among 312 women (aged 75.4 ± 5.9 years, body mass index [BMI] 29.5 ± 5.7 kg/m²), a larger amount of muscle fat was associated with lower marrow density at the 66% mid-tibia (B = 84.08 [27.56], p = 0.002) and at the 4% distal tibia (B = 129.17 [55.96], p = 0.022) after accounting for age, height, weight, average daily energy expenditure, hypertension, and diabetes. Interactions of this relationship with osteoporosis status were also significant. Upon probing these interactions, the relationships were significant only in women with osteoporosis but not in those without osteoporosis. Fat from bone marrow and muscle may be related to one another through the same phenomenon, which is likely also responsible for osteoporosis, but independent of hypertension and diabetes. More research should focus on the potential abnormalities in muscle and bone fat metabolism and mesenchymal cell commitment to fat within patients with osteoporosis. © 2019 American Society for Bone and Mineral Research.     

Single‐Limb Irradiation Induces Local and Systemic Bone Loss in a Murine Model

Increased fracture risk is commonly reported in cancer patients receiving radiotherapy, particularly at sites within the field of treatment. The direct and systemic effects of ionizing radiation on bone at a therapeutic dose are not well‐characterized in clinically relevant animal models. Using 20‐week‐old male C57Bl/6 mice, effects of irradiation (right hindlimb; 2 Gy) on bone volume and microarchitecture were evaluated prospectively by microcomputed tomography and histomorphometry and compared to contralateral‐shielded bone (left hindlimb) and non‐irradiated control bone. One week postirradiation, trabecular bone volume declined in irradiated tibias (–22%; p < 0.0001) and femurs (–14%; p = 0.0586) and microarchitectural parameters were compromised. Trabecular bone volume declined in contralateral tibias (–17%; p = 0.003), and no loss was detected at the femur. Osteoclast number, apoptotic osteocyte number, and marrow adiposity were increased in irradiated bone relative to contralateral and non‐irradiated bone, whereas osteoblast number was unchanged. Despite no change in osteoblast number 1 week postirradiation, dynamic bone formation indices revealed a reduction in mineralized bone surface and a concomitant increase in unmineralized osteoid surface area in irradiated bone relative to contralateral and non‐irradiated control bone. Further, dose‐dependent and time‐dependent calvarial culture and in vitro assays confirmed that calvarial osteoblasts and osteoblast‐like MC3T3 cells were relatively radioresistant, whereas calvarial osteocyte and osteocyte‐like MLO‐Y4 cell apoptosis was induced as early as 48 hours postirradiation (4 Gy). In osteoclastogenesis assays, radiation exposure (8 Gy) stimulated murine macrophage RAW264.7 cell differentiation, and coculture of irradiated RAW264.7 cells with MLO‐Y4 or murine bone marrow cells enhanced this effect. These studies highlight the multifaceted nature of radiation‐induced bone loss by demonstrating direct and systemic effects on bone and its many cell types using clinically relevant doses; they have important implications for bone health in patients treated with radiation therapy. © 2015 American Society for Bone and Mineral Research.     

Deficits in Trabecular Bone Microarchitecture in Young Women With Type 1 Diabetes Mellitus

The pathophysiological mechanism of increased fractures in young adults with type 1 diabetes mellitus (T1DM) is unclear. We conducted a case‐control study of trabecular bone microarchitecture and vertebral marrow adiposity in young women with T1DM. Thirty women with T1DM with a median age (range) age of 22.0 years (16.9, 36.1) attending one outpatient clinic with a median age at diagnosis of 9.7 years (0.46, 14.8) were compared with 28 age‐matched healthy women who acted as controls. Measurements included MRI‐based assessment of proximal tibial bone volume/total volume (appBV/TV), trabecular separation (appTb.Sp), vertebral bone marrow adiposity (BMA), and abdominal adipose tissue and biochemical markers of GH/IGF‐1 axis (IGF‐1, IGFBP3, ALS) and bone turnover. Median appBV/TV in cases and controls was 0.3 (0.22, 0.37) and 0.33 (0.26, 0.4), respectively (p = 0.018) and median appTb.Sp in T1DM was 2.59 (2.24, 3.38) and 2.32 (2.03, 2.97), respectively (p = 0.012). The median appBV/TV was 0.28 (0.22, 0.33) in those cases with retinopathy (n = 15) compared with 0.33 (0.25, 0.37) in those without retinopathy (p = 0.02). Although median visceral adipose tissue in cases was higher than in controls at 5733 mm³ (2030, 11,144) and 3460 mm³ (1808, 6832), respectively (p = 0.012), there was no difference in median BMA, which was 31.1% (9.9, 59.9) and 26.3% (8.5, 49.8) in cases and controls, respectively (p = 0.2). Serum IGF‐1 and ALS were also lower in cases, and the latter showed an inverse association to appTbSp (r = –0.30, p = 0.04). Detailed MRI studies in young women with childhood‐onset T1DM have shown clear deficits in trabecular microarchitecture of the tibia. Underlying pathophysiological mechanisms may include a microvasculopathy. © 2015 American Society for Bone and Mineral Research.