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Visceral Fat Causes Inflammation and Cytokines Leading To Bone Loss
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"Of importance, in our study, obese girls with the highest VAT and the lowest SAT (thus the highest VAT to SAT ratio) had the lowest bone density measures."
In our study, SAT and VAT had reciprocal associations with bone density measures, with SAT demonstrating positive associations and VAT demonstrating inverse associations (after controlling for SAT) (from Jules: in other words SAT, higher subcutaneous fat was good for bone & visceral fat was bad for bone causing bone loss, suggesting also that lower SAT is associated with bone loss SO this lends itself well to the idea that the HIV lipodystrophy situation is a perfect storm encouraging bone loss, less SAT & greater VAT, belly fat, both encourage bone loss, so this appears to be a contributing factor in explaining the high bone loss in HIV+ individuals...... Inflammatory cytokines stimulate osteoclastic activity (9), and a stimulatory effect of adiponectin on osteoclast differentiation and action [through activation of the receptor activator of nuclear factor-_B (RANK)-RANK ligand pathway] has been reported (10).....Importantly, data indicate differential expression and secretion of these inflammatory and other adipokines by regional fat depots. We previously reported that VAT is an independent predictor of E-selectin and sICAM1, whereas SAT predicts IL-6 (14), and both SAT and VAT predict adiponectin levels (6). Leptin is best predicted by SAT.
Adipose tissue secretes various inflammatory cytokines and hormones, from either adipocytes or endothelial cells in blood vessels in fat. Of note, site-specific fat depots have a differential impact on the secretion of inflammatory cytokines and adipokines. For example, we previously reported in obese and normal-weight girls that VAT is an important determinant of levels of sICAM1, E-selectin, and TNF-α receptors 1 and 2, and studies by others confirmed these findings (20, 21). Both SAT and VAT have been related to IL-6 levels (14, 22). Inflammatory cytokines such as TNF-α and IL-6 are known to activate osteoclast differentiation and activation and inhibit osteoclast apoptosis, and increased secretion of these cytokines from visceral fat may cause a decrease in bone density from increased bone resorption (9).
In addition to inflammatory cytokines, adipocytes secrete adiponectin and leptin, both of which have an impact on bone metabolism.
leptin positively predicted lumbar BMD, whole-body BMD, and whole-body BMC to height in our subjects after controlling for various covariates. In addition, adiponectin and leptin replaced VAT and SAT as predictors of some bone density measures in our regression model, suggesting that these hormones may also mediate the impact of regional fat on bone.
After controlling for SAT, we noted that VAT was a negative predictor of lumbar BMAD, whole-body BMD, and BMC to height for the group as a whole and lumbar BMD, BMAD, whole-body BMD, and BMC to height in obese girls (Table 2 shows data from regression modeling with SAT and VAT entered into the model).
Because VAT correlated negatively and SAT positively with bone density measures, we anticipated that girls with the highest VAT and lowest SAT would have the lowest measures of bone density.
When we divided the obese girls into two groups based on VAT to SAT above or below the median, we noted that those with VAT to SAT ratio above the median had lower bone density measures at multiple sites compared with girls with VAT to SAT ratio below the median (Table 3), despite the fact that BMI, BMI SDS, fat mass, and percent body fat did not differ.
Visceral Fat Is a Negative Predictor of Bone Density Measures in Obese Adolescent Girls
This version published online on January 15, 2010br clear="all" />
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-1475
Melissa Russell, Nara Mendes, Karen K. Miller, Clifford J. Rosen, Hang Lee, Anne Klibanski, and Madhusmita Misra*
Neuroendocrine Unit (M.R., N.M., K.K.M., A.K., M.M.), Massachusetts General Hospital and Harvard Medical School, Pediatric Endocrine Unit (M.R., M.M.), Mass General Hospital for Children and Harvard Medical School, and Biostatistical Core (H.L.), Harvard Catalyst, Boston, Massachusetts 02114; and Maine Medical Center Research Institute (C.J.R.), Scarborough, Maine 04074
* To whom correspondence should be addressed. E-mail: mmisra@partners.org.
ABSTRACTbr clear="all" />
Context: Regional fat is increasingly recognized as a determinant of bone mineral density (BMD), an association that may be mediated by adipokines, such as adiponectin and leptin, and inflammatory fat products. Chronic inflammation is deleterious to bone, and visceral adipose tissue (VAT) predicts inflammatory markers such as soluble intercellular adhesion molecule-1 and E-selectin, whereas sc adipose tissue (SAT) and VAT predict IL-6 in adolescents.
Objective: Our objective was to determine associations of regional fat mass and adipokines with BMD. We hypothesized that girls with greater VAT relative to SAT would have lower bone density mediated by inflammatory cytokines, adiponectin, and leptin.
Design: This was a cross-sectional study.
Setting: The study was conducted at a clinical research center.
Subjects: Subjects included 30 girls (15 obese, 15 normal weight) 12-18 yr old, matched for maturity (bone age), race, and ethnicity.
Outcome Measures: We assessed regional fat (SAT, VAT) using magnetic resonance imaging, total fat, and BMD using dual-energy x-ray absorptiometry. Fasting leptin, adiponectin, IL-6, soluble intercellular adhesion molecule-1, and E-selectin were obtained.
Results: Mean body mass index SD score was 3.7 ± 1.5 in obese subjects and 0.1 ± 0.4 kg/m2 in controls. VAT was a negative predictor of spine BMD and bone mineral apparent density, whole-body BMD and bone mineral content/height in obese girls and whole-body BMD and bone mineral content/height for the group as a whole after controlling for SAT, as was the ratio of VAT to SAT. In a regression model that included VAT/SAT, adipokines, and cytokines, E-selectin and adiponectin were negative predictors of BMD and leptin a positive predictor.
Conclusion: VAT is an independent inverse determinant of bone density in obesity. This association may be mediated by adipokines and a chronic inflammatory state.
There is a growing understanding of the impact of fat mass on bone density, and recent studies have reported differential effects of regional fat mass on bone in both animals and humans (1- 4). Importantly, the impact of specific fat compartments on insulin sensitivity and lipid levels is well known, with visceral adipose tissue (VAT) imparting greater risk of insulin resistance and hyperlipidemia than sc adipose tissue (SAT) (5, 6), and it is possible that VAT and SAT also differ in their impact on bone. A positive association of SAT with bone density has been consistently reported (1, 2); however, data are conflicting regarding the association of VAT and bone, with studies reporting positive, negative, or no associations (1- 4). Most studies examined these associations in adult men and women (1, 4, 7, 8), sometimes using surrogates for VAT such as waist circumference or waist to hip ratio (7, 8), although one recent report indicated that SAT was a positive and VAT a negative predictor of bone structural parameters in young adults (2). However, studies have not consistently examined the impact ofVATafter controlling for SAT or the impact of the relative proportion of VAT to SAT (VAT/SAT) on bone.
Importantly, there is also a significant knowledge deficit regarding chemical mediators of the associations between regional fat and bone. Potential mediators such as inflammatory cytokines and hormones secreted by adipocytes or vascular endothelium within fat have not been examined in this context in a pediatric population. These include inflammatory cytokines such as IL-6, TNF-α, adhesion molecules such as E-selectin and soluble intercellular adhesion molecule-(sICAM)-1, and hormones such as adiponectin and leptin. Inflammatory cytokines stimulate osteoclastic activity (9), and a stimulatory effect of adiponectin on osteoclast differentiation and action [through activation of the receptor activator of nuclear factor-_B (RANK)-RANK ligand pathway] has been reported (10). Although the leptin knockout mouse has high trabecular bone density (11), cortical bone is impacted negatively, and these changes are reversed with leptin administration; studies in humans reported positive associations between leptin and bone (12, 13).
Importantly, data indicate differential expression and secretion of these inflammatory and other adipokines by regional fat depots. We previously reported that VAT is an independent predictor of E-selectin and sICAM1, whereas SAT predicts IL-6 (14), and both SAT and VAT predict adiponectin levels (6). Leptin is best predicted by SAT.
The adolescent years are characterized by marked increases in bone mass accrual rates and gender-specific changes in body composition. It is unclear whether reported associations between regional fat and bone in older people apply to this younger population. Potential mediators of associations between regional fat and bone have also not been reported.We examined associations of VAT and SAT, and the relative proportion of VAT to SAT with bone density measures in adolescent obese and normalweight girls and determined whether these associations are influenced by inflammatory cytokines (IL-6, sICAM1, and E-selectin), adiponectin, and leptin. We hypothesized a negative association between VAT and the ratio of VAT to SAT with bone density measures in adolescent girls mediated by inflammatory cytokines and adiponectin.
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