Recent studies have demonstrated an important physiologic link between bone and fat. Bone and fat cells arise from the same mesenchymal precursor cell within bone marrow, capable of differentiation into adipocytes or osteoblasts. Increased BMI appears to protect against osteoporosis. However, recent studies have suggested detrimental effects of visceral fat on bone health. Increased visceral fat may also be associated with decreased growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels which are important for maintenance of bone homeostasis. The purpose of our study was to assess the relationship between vertebral bone marrow fat and trabecular bone mineral density (BMD), abdominal fat depots, GH and IGF-1 in premenopausal women with obesity. We studied 47 premenopausal women of various BMI (range: 18–41 kg/m2, mean 30 ± 7 kg/m2) who underwent vertebral bone marrow fat measurement with proton magnetic resonance spectroscopy (1H-MRS), body composition, and trabecular BMD measurement with computed tomography (CT), and GH and IGF-1 levels. Women with high visceral fat had higher bone marrow fat than women with low visceral fat. There was a positive correlation between bone marrow fat and visceral fat, independent of BMD. There was an inverse association between vertebral bone marrow fat and trabecular BMD. Vertebral bone marrow fat was also inversely associated with IGF-1, independent of visceral fat. Our study showed that vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 and BMD. This suggests that the detrimental effect of visceral fat on bone health may be mediated in part by IGF-1 as an important regulator of the fat and bone lineage.

Despite being a risk factor for cardiovascular disease and diabetes mellitus, obesity has been thought to protect against osteoporosis. However, recent studies have demonstrated a differential impact of specific fat compartments on bone mineral density (BMD) with visceral adipose tissue (VAT) having potential detrimental effects on BMD. Visceral obesity is also associated with dysregulation of the GH/IGF-1 axis, an important regulator of bone homeostasis. The purpose of our study was to evaluate the differential effects of abdominal fat depots and muscle, vitamin D, and hormonal determinants, including insulin-like growth factor-1 (IGF-1), testosterone, and estradiol, on trabecular BMD of the lumbar spine. We studied 68 healthy obese premenopausal women (mean BMI: 36.7 ± 4.2 kg/m2). Quantitative computed tomography (QCT) was used to assess body composition and lumbar trabecular BMD. There was an inverse association between BMD and VAT, independent of age and BMI (p= 0.003). IGF-1 correlated positively with BMD and negatively with VAT and, in stepwise multivariate regression modeling, was the strongest predictor of BMD and procollagen type 1 amino-terminal propeptide (P1NP). Thigh muscle cross sectional area (CSA), and thigh muscle density were also associated with BMD (p<0.05), but 25-hydroxyvitamin D [25(OH)D], testosterone, free testosterone and estradiol levels were not. 25(OH)D was associated inversely with BMI, total and subcutaneous abdominal adipose tissue (p< 0.05). These findings support the hypothesis that VAT exerts detrimental effects, whereas muscle mass exerts positive effects on BMD in premenopausal obese women. Moreover, our findings suggest that IGF-1 may be a mediator of the deleterious effects of VAT on bone health through effects on bone formation.

Mitochondrial dysfunction may contribute to the development of insulin resistance and type 2 diabetes. Nucleoside reverse transcriptase inhibitors (NRTIs), specifically stavudine, are known to alter mitochondrial function in human immunodeficiency virus (HIV)-infected individuals, but the effects of stavudine on glucose disposal and mitochondrial function in muscle have not been prospectively evaluated. In this study, we investigated short-term stavudine administration among healthy control subjects to determine effects on insulin sensitivity. A secondary aim was to determine the effects of stavudine on mitochondrial DNA (mtDNA) and function. Sixteen participants without personal or family history of diabetes were enrolled. Subjects were randomized to receive stavudine, 30 – 40 mg, twice a day, or placebo for 1 mo. Insulin sensitivity determined by glucose infusion rate during the hyperinsulinemic euglycemic clamp was significantly reduced after 1-mo exposure in the stavudine-treated subjects compared with placebo (−0.8 ± 0.5 vs. +0.7 ± 0.3 mg· kg−1 · min−1, P = 0.04, stavudine vs. placebo). In addition, muscle biopsy specimens in the stavudine-treated group showed significant reduction in mtDNA/nuclear DNA (−52%, P = 0.005), with no change in placebo-treated subjects (+8%, P = 0.9). 31P magnetic resonance spectroscopy (MRS) studies of mitochondrial function correlated with insulin sensitivity measures (r2 = 0.5, P = 0.008). These findings demonstrate that stavudine administration has potent effects on insulin sensitivity among healthy subjects. Further studies are necessary to determine whether changes in mtDNA resulting from stavudine contribute to effects on insulin sensitivity.

The human immunodeficiency virus (HIV)-lipodystrophy syndrome is associated with fat redistribution and metabolic abnormalities, including insulin resistance. Increased intramyocellular lipid (IMCL) concentrations are thought to contribute to insulin resistance, being linked to metabolic and body composition variables. We examined 46 women: HIV infected with fat redistribution (n = 25), and age- and body mass index-matched HIV-negative controls (n = 21). IMCL was measured by 1H-magnetic resonance spectroscopy, and body composition was assessed with computed tomography, dual-energy X-ray absorptiometry (DEXA), and magnetic resonance imaging. Plasma lipid profile and markers of glucose homeostasis were obtained. IMCL was significantly increased in tibialis anterior [135.0 ± 11.5 vs. 85.1 ± 13.2 institutional units (IU); P = 0.007] and soleus [643.7 ± 61.0 vs. 443.6 ± 47.2 IU, P = 0.017] of HIV-infected subjects compared with controls. Among HIV-infected subjects, calf subcutaneous fat area (17.8 ± 2.3 vs. 35.0 ± 2.5 cm2, P < 0.0001) and extremity fat by DEXA (11.8 ± 1.1 vs. 15.6 ± 1.2 kg, P = 0.024) were reduced, whereas visceral abdominal fat (125.2 ± 11.3 vs. 74.4 ± 12.3 cm2, P = 0.004), triglycerides (131.1 ± 11.0 vs. 66.3 ± 12.3 mg/dl, P = 0.0003), and fasting insulin (10.8 ± 0.9 vs. 7.0 ± 0.9 μIU/ml, P = 0.004) were increased compared with control subjects. Triglycerides (r = 0.39, P = 0.05) and extremity fat as percentage of whole body fat by DEXA (r = −0.51, P = 0.01) correlated significantly with IMCL in the HIV but not the control group. Extremity fat (β = −633.53, P = 0.03) remained significantly associated with IMCL among HIV-infected patients, controlling for visceral abdominal fat, abdominal subcutaneous fat, and antiretroviral medications in a regression model. These data demonstrate increased IMCL in HIV-infected women with a mixed lipodystrophy pattern, being most significantly associated with reduced extremity fat. Further studies are necessary to determine the relationship between extremity fat loss and increased IMCL in HIV-infected women.

Context

Metabolic abnormalities such as hypertriglyceridemia remain a challenge for optimizing long-term health in HIV-infected patients.

Objective

Elevation of free fatty acids (FFAs) may contribute to hyperlipidemia and insulin resistance in HIV. We evaluated the efficacy and safety of chronic inhibition of lipolysis in HIV-infected men and women with hypertrigyceridemia. We hypothesized that acipimox would lead to significant reductions in triglycerides and improved insulin sensitivity, compared with placebo.

Design

A 3-month, randomized, double-blind, controlled trial of acipimox (250 mg thrice daily) vs. placebo was conducted in 23 HIV-infected men and women with hypertriglyceridemia (>150 mg/dl), abnormal fat distribution, and no current lipid-lowering therapy. The primary outcome variable was triglyceride concentration, and insulin sensitivity measured by hyperinsulinemic euglycemic clamp was a secondary outcome.

Setting

The study was conducted at an academic medical center.

Results

Acipimox resulted in significant reductions in FFAs [mean change −0.38 (0.06) vs. 0.08 (0.06) mEq/liter with placebo, −68 vs. +17% change from mean baseline, P < 0.0001], decreased rates of lipolysis (P < 0.0001), and a median triglyceride decrease from 238 mg/dl at baseline to 190 mg/dl, compared with an increase from 290 to 348 mg/dl in the placebo group (P = 0.01). Acipimox improved insulin sensitivity [acipimox +2.31 (0.74) vs. placebo −0.21 (0.90) mg glucose per kilogram lean body mass per minute, or +31 vs. −2% change from mean baseline values, P = 0.04]. Improvements in insulin sensitivity were significantly correlated with reductions in FFAs (r = −0.62, P = 0.003) and lipolysis (r = −0.59, P = 0.005).

Conclusions

Acipimox resulted in significant sustained reductions in lipolysis, improved glucose homeostasis, and significant but modest reductions in triglycerides in HIV-infected individuals with abnormal fat distribution and hypertriglyceridemia. Improvement in overall metabolic profile with acipimox suggests a potential clinical utility for this agent that requires further investigation.

In a prior study, we have shown that tumor necrosis factor (TNF)-α neutralization improves inflammatory markers and total adiponectin in patients with the metabolic syndrome, without improving insulin sensitivity. In this study, we sought to extend our understanding of the effects of TNF-α neutralization in this human model of obesity by investigating the responses of high-molecular-weight (HMW) adiponectin, resistin, leptin, and muscle adiposity to etanercept in patients with the metabolic syndrome. Fifty-six men and women with the metabolic syndrome enrolled in a double-blind randomized placebo-controlled trial. Circulating concentrations of total and HMW adiponectin, resistin, and leptin were determined at baseline and after 4 wk of treatment with etanercept. Muscle adiposity was measured by computed tomography (CT). Although etanercept increased total adiponectin concentration, the HMW form, which is thought to mediate insulin sensitivity, was unchanged. Thus the ratio of HMW to total adiponectin decreased following etanercept treatment compared with placebo (−0.03 ± 0.03 vs. 0.06 ± 0.03, P = 0.02). Resistin tended to decrease in the etanercept-treated group compared with placebo (−0.6 ± 0.7 vs. 1.2 ± 0.7 ng/ml, P = 0.06), whereas leptin was not altered. Etanercept decreased muscle attenuation on CT [−0.61 ± 0.64 Hounsfield units (HU) vs. 1.54 ± 0.77 HU in placebo, P = 0.04], suggesting an increase in muscle adiposity. Together, these results demonstrate that neutralization of TNF-α in obese humans results in differential effects on critical adipokines and body composition indexes. These findings may help to explain the lack of effect on insulin sensitivity and extend our knowledge of the biological effects of TNF-α neutralization in obesity.

Objective

To compare breath-hold 1H-MRS to respiratory-gated 1H-MRS and CT for quantification of hepatic lipid content.

Methods

Twenty-three premenopausal women underwent breath-hold point-resolved single voxel (PRESS) 1H-MRS of the liver followed by respiratory-gated 1H-MRS at 3Tesla and CT slice through the liver. Interscan variability for 1H-MRS was assessed in six volunteers. Pearson correlation coefficients, Bland-Altman 95% limit of agreement, and concordance correlation coefficients were calculated.

Results

There was a strong correlation between breath-hold and respiratory-gated 1H-MRS (r=0.94, p<0.0001, concordance correlation coefficient:0.75). Using Bland-Altman analysis, all but two data points were within the limits of agreement. Both 1H-MRS techniques had low inter-scan variability. There was an inverse correlation of both 1H-MRS techniques with CT attenuation values of the liver.

Conclusions

Breath-hold 1H-MRS is a reliable method to measure hepatic lipid content at 3Tesla. Breath-hold 1H-MRS of the liver provides data that closely correlates with that obtained from longer duration respiratory-gated technique.

OBJECTIVE

To prospectively compare measurement precision of calf intramyocellular lipid (IMCL) quantification at 3.0T and 1.5T using 1H magnetic resonance spectroscopy (1H-MRS).

MATERIALS AND METHODS

We examined the soleus and tibialis anterior (TA) muscles of 15 male adults [21–48 years of age, body mass index (BMI)=21.9–38.0 kg/m2]. Each subject underwent 3.0T and 1.5T single-voxel short-echo-time point-resolved 1H-MRS both at baseline and 31-day follow-up. The IMCL-methylene peak (1.3 ppm) was scaled to unsuppressed water peak (4.7 ppm) using the LCModel routine. Full width at half maximum (FWHM) and signal-to-noise ratios (SNR) of unsuppressed water peak were measured using jMRUI software. Measurement precision was tested by comparing interexamination coefficients of variation (CV) between different field strengths using Wilcoxon matched pairs rank test in all subjects. Overweight subjects (BMI>25 kg/m2) were analyzed separately to examine benefits of 3.0T acquisitions in subjects with increased adiposity.

RESULTS

No significant difference between 3.0T and 1.5T was noted in CVs for IMCL of soleus (P=0.5). CVs of TA were significantly higher at 3.0T (P=0.02). SNR was significantly increased at 3.0T for soleus (64%, P<0.001) and TA (62%, P<0.001), however lower than the expected improvement of 100%. FWHM at 3.0T was significantly increased for soleus (19%, P<0.001) and TA (7%, P<0.01). Separate analysis of overweight subjects showed no significant difference between 3.0T and 1.5T CVs for IMCL of soleus (P=0.8) and TA (P=0.4).

CONCLUSION

Using current technology, 1H-MRS for IMCL at 3.0T did not improve measurement precision compared to 1.5T.

Objective

The objective was to evaluate the use of fluorodeoxyglucose positron emission tomography (FDG-PET) in differentiating benign from malignant compression fractures.

Patients and methods

In a retrospective analysis, we identified 33 patients with 43 compression fractures who underwent FDG-PET. On FDG-PET the uptake pattern was recorded qualitatively and semiquantitatively and fractures were categorized as benign or malignant. Standardized uptake values (SUV) were obtained. MRI, CT, and biopsy results as well as clinical follow-up for 1–3 years served as standards of reference. The Student’s t test was used to determine whether there was a statistically significant difference between the SUV for benign and malignant compression fractures.

Results

There were 14 malignant and 29 benign compression fractures, including 5 acute benign fractures. On FDG-PET, 5 benign fractures were falsely classified as malignant (false-positive). Three of these patients underwent prior treatment with bone marrow-stimulating agents. There were two false-negative results. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FDG-PET in differentiating benign from malignant compression fractures were 86%, 83%, 84%, 71%, and 92% respectively. The difference between SUV values of benign and malignant fractures was statistically significant (1.9 ± 0.97 for benign and 3.9 ± 1.52 for malignant fractures, p < 0.001). SUV of benign acute and chronic fractures were not statistically significant.

Conclusion

Fluorodeoxyglucose positron emission tomography is useful in differentiating benign from malignant compression fractures. Therapy with bone marrow-stimulating agents can mimic malignant involvement.