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1.  Articular cartilage of the knee 3 years after ACL reconstruction 
Acta Orthopaedica  2015;86(5):605-610.
Background and purpose
T1ρ or T2 relaxation imaging has been increasingly used to evaluate the cartilage of the knee. We investigated the cartilage of ACL-reconstructed knees 3 years after surgery using T2 relaxation times.
Patients and methods
10 patients with a clinically successful unilateral ACL reconstruction were examined 3 years after surgery. Multiple-TE fast-spin echo sagittal images of both knees were acquired using a 3T MRI scanner for T2 mapping of the tibiofemoral cartilage. T2 values of the superficial and deep zones of the tibiofemoral cartilage were analyzed in sub-compartmental areas and compared between the ACL-reconstructed and uninjured contralateral knees.
Higher T2 values were observed in 1 or more sub-compartmental areas of each ACL-reconstructed knee compared to the uninjured contralateral side. Most of the T2 increases were observed at the superficial zones of the cartilage, especially at the medial compartment. At the medial compartment of the ACL-reconstructed knee, the T2 values of the femoral and tibial cartilage were increased by 3–81% compared to the uninjured contralateral side, at the superficial zones of the weight-bearing areas. T2 values in the superficial zone of the central medial femoral condyle differed between the 2 groups (p = 0.002).
The articular cartilage of ACL-reconstructed knees, although clinically satisfactory, had higher T2 values in the superficial zone of the central medial femoral condyle than in the uninjured contralateral side 3 years after surgery. Further studies are warranted to determine whether these patients would undergo cartilage degeneration over time.
PMCID: PMC4564784  PMID: 25854533
2.  Effects of Exercise and Lifestyle Modification on Fitness, Insulin Resistance, Skeletal Muscle Oxidative Phosphorylation, and Intramyocellular Lipid Content in Obese Children and Adolescents 
Pediatric obesity  2013;9(4):281-291.
Obesity is associated with poor fitness and adverse metabolic consequences in children.
To investigate how exercise and lifestyle modification may improve fitness and insulin sensitivity in this population.
Design and Subjects
RCT, 21 obese (BMI ≥ 95%ile) subjects, ages 10 to 17 years.
Subjects were given standardized healthful lifestyle advice for 8 weeks. In addition, they were randomized to an in-home supervised exercise intervention (n = 10) or control group (n=11).
Fasting laboratory studies (insulin, glucose, lipid profile) and assessments of fitness, body composition, skeletal muscle oxidative phosphorylation and intramyocellular lipid content (IMCL), were performed at baseline and study completion.
Subjects were 13.0 ± 1.9 (SD) years old, 72% female, and 44% non-white. Exercise improved fitness (p = 0.03) and power (p = 0.01), and increased IMCL (p = 0.02). HOMA-IR decreased among all subjects in response to lifestyle modification advice (p = 0.01), regardless of exercise training assignment. In univariate analysis over all subjects, change in cardiovascular fitness was associated with change in HOMA-IR. In exploratory analyses, increased IMCL was associated with greater resting energy expenditure (r = 0.78, p = 0.005) and a decrease in fasting RQ (r = −0.70, p = 0.02) (n=11).
Change in fitness was found to be related to change in insulin resistance in response to lifestyle modification and exercise in obese children. IMCL increased with exercise in these obese children, which may reflect greater muscle lipid oxidative capacity.
PMCID: PMC3808470  PMID: 23801526
fitness; insulin resistance; pediatric obesity; mitochondrial function; IMCL
3.  Effect of Tesamorelin on Liver Fat and Visceral Fat in HIV-Infected Patients With Abdominal Fat Accumulation: A Randomized Clinical Trial 
JAMA  2014;312(4):380-389.
Among HIV-infected patients, visceral adiposity is associated with metabolic dysregulation and ectopic fat accumulation. Tesamorelin, a growth hormone-releasing hormone analogue, specifically targets visceral fat reduction, but its effects on liver fat are unknown.
To investigate the effect of tesamorelin on visceral and liver fat.
Design, Setting, and Participants
Fifty antiretroviral-treated HIV-infected men and women with abdominal fat accumulation were recruited for this double-blind, randomized, placebo-controlled trial at Massachusetts General Hospital. The first patient was enrolled on 1/10/2011; the final patient completed his 6 month study visit on 9/6/2013.
Tesamorelin 2mg vs. placebo SC daily for 6 months
Main Outcomes
Primary endpoints were changes in visceral adipose tissue (VAT) and liver fat. Secondary endpoints included glucose and other metabolic endpoints.
76 patients were screened and 54 randomized. 50 presented for baseline assessment and 48 received treatment with study drug. Tesamorelin significantly reduced VAT (Δ −34 [−53, −15] vs. 8 [−14, 30] cm2, mean [95% CI], tesamorelin vs. placebo, treatment effect −42cm2 [95% CI −71, −14], P = 0.005) and liver fat (Δ −2.0 [−6.4, 0.1] vs. 0.9 [−0.6, 3.7] lipid-to-water %, median [IQR], tesamorelin vs. placebo, P=0.003) over 6 months, for a net treatment effect of −2.9 lipid-to-water %. Fasting glucose increased in the tesamorelin group at 2 weeks (Δ 9 [5, 13] vs. 2 [−3, 8] mg/dL, mean [95% CI], treatment effect 7mg/dL [95% CI 1, 14], P=0.03), but overall changes over 6 months in fasting glucose (Δ 4 [−2, 10] vs. 2 [−4, 7] mg/dL, mean [95% CI], treatment effect 2mg/dL [95% CI −6, 10], P=0.72) and 2 hour glucose (Δ −1 [−18, 15] vs. −8 [−24, 8] mg/dL, mean [95% CI], treatment effect 7mg/dL [95% CI −16, 29], P=0.53) were not significant.
Conclusions and Relevance
In this preliminary study of HIV-infected patients with abdominal fat accumulation, tesamorelin administered for 6 months was associated with reductions in visceral fat and, additionally, with modest reductions in liver fat. Further studies are needed to determine the clinical importance and long-term consequences of these findings.
Trial Registration NCT01263717
PMCID: PMC4363137  PMID: 25038357
liver fat; visceral fat; growth hormone releasing hormone; HIV
4.  Effects of growth hormone administration for 6 months on bone turnover and bone marrow fat in obese premenopausal women 
Bone  2014;62:29-35.
Abdominal adiposity is associated with low BMD and decreased growth hormone (GH) secretion, an important regulator of bone homeostasis. The purpose of our study was to determine the effects of a short course of GH on markers of bone turnover and bone marrow fat in premenopausal women with abdominal adiposity.
Materials and Methods
In a 6-month, randomized, double-blind, placebo-controlled trial we studied 79 abdominally obese premenopausal women (21–45y) who underwent daily sc injections of GH vs. placebo. Main outcome measures were body composition by DXA and CT, bone marrow fat by proton MR spectroscopy, P1NP, CTX, 25(OH)D, hsCRP, undercarboxylated osteocalcin (ucOC), preadipocyte factor 1 (Pref 1), apolipoprotein B (ApoB), and IGF-1.
GH increased IGF-1, P1NP, 25(OH)D, ucOC, bone marrow fat and lean mass, and decreased abdominal fat, hsCRP, and ApoB compared with placebo (p<0.05). There was a trend toward an increase in CTX and Pref-1. Among all participants, 6-month increase in IGF-1 correlated with 6-month increase in P1NP (p=0.0005), suggesting that subjects with the greatest increases in IGF-1 experienced the greatest increases in bone formation. Six-month decrease in abdominal fat, hsCRP, and ApoB inversely predicted 6-month change in P1NP, and 6-month increase in lean mass and 25(OH)D positively predicted 6-month change in P1NP (p≤0.05), suggesting that subjects with greatest decreases in abdominal fat, inflammation and ApoB, and the greatest increases in lean mass and 25(OH)D experienced the greatest increases in bone formation. Six-month increase in bone marrow fat correlated with 6-month increase in P1NP (trend), suggesting that subjects with the greatest increases in bone formation experienced the greatest increases in bone marrow fat. Forward stepwise regression analysis indicated that increase in lean mass and decrease in abdominal fat were positive predictors of P1NP. When IGF-1 was added to the model, it became the only predictor of P1NP.
GH replacement in abdominally obese premenopausal women for 6 months increased bone turnover and bone marrow fat. Reductions in abdominal fat, and inflammation, and increases in IGF-1, lean mass and vitamin D were associated with increased bone formation. The increase in bone marrow fat may reflect changes in energy demand from increased bone turnover.
PMCID: PMC4014200  PMID: 24508386
obesity; MR spectroscopy; bone; bone marrow fat; growth hormone; bone turnover
Skeletal radiology  2013;43(3):315-321.
To investigate the T2 relaxation values of infrapatellar fat pad (IFP) after arthroscopic surgery.
This study was approved by the institutional review board; all individuals signed informed consent. We performed MR imaging in sixteen knees from eight subjects. Prior to imaging, each subject had unilateral arthroscopic knee surgery and an asymptomatic non-operated contralateral knee. We used a 10-echo multiple-TE fast-spin echo pulse sequence for creation of T2 relaxation time maps. Two musculoskeletal radiologists independently placed regions of interest in the IFP, suprapatellar subcutaneous and deep intermuscular adipose tissue. Qualitative assessments were performed to assess fibrotic changes affecting patellar retinaculum and IFP. Statistical analyses of T2 values determined differences between groups, correlation with time after surgery, and cut-off values to differentiate groups.
The average time between arthroscopy and imaging was 3.5 ± 0.4 years. IFP of knees with prior surgery had significantly shorter mean T2 values (133 ± 14 ms) when compared to control knees (147 ± 8 ms, P = 0.03). There was no significant difference between operated and control knees regarding T2 values of suprapatellar subcutaneous (P = 0.3) or deep intermuscular adipose tissue (P = 0.2). There was no correlation between IFP T2 values and time after surgery (P > 0.2). IFP T2 values ≤ 139 ms had 75% sensitivity and 88% specificity to identify prior arthroscopy.
Shortening of T2 relaxation values is present in IFP chronically after arthroscopic surgery and may be an indicator of adipose tissue fibrosis.
PMCID: PMC3955756  PMID: 24343788
T2 relaxometry; infrapatellar fat pad; fibrosis; arthroscopy; MRI
6.  Positive effects of brown adipose tissue on femoral bone structure 
Bone  2013;58:10.1016/j.bone.2013.10.007.
Recent studies suggest a link between brown adipose tissue (BAT) and bone. The purpose of our study was to investigate the effects of BAT on femoral bone structure.
Materials and Methods
We studied 105 patients (19 m, 86 f, mean age 45.5±16.1 y) who underwent F18-FDG positron emission tomography/computed tomography (PET/CT) for benign etiologies (n=20) or follow-up of successfully treated malignancies (n=85); mean time between PET/CT and last form of treatment was 14.8±18.0 months. BAT volume by PET/CT; femoral bone structure by CT (total femoral cross-sectional area (CSA), cortical CSA); thigh muscle CSA and thigh subcutaneous fat CSA by CT were assessed.
There were positive correlations between BAT volume and total femoral CSA and cortical CSA, independent of age, BMI and history of malignancy (P<0.05). BAT volume correlated positively with thigh muscle CSA and thigh fat CSA (p<0.05). When total femoral CSA was entered as a dependent variable and BAT volume, age and BMI as independent variables in a forward stepwise regression model, BAT volume was the only predictor of total femoral CSA. When femoral cortical CSA was entered as a dependent variable and BAT volume, age and BMI as independent variables, BAT volume was the only predictor of femoral cortical CSA.
BAT volume is a positive predictor of femoral bone structure and correlates positively with thigh muscle and subcutaneous fat, possibly mediated by muscle. These results provide further evidence of a positive effect of BAT on bone.
PMCID: PMC3855336  PMID: 24140784
brown adipose tissue (BAT); bone; structure; muscle; fat
7.  Effects of recombinant human growth hormone (rhGH) administration on body composition and cardiovascular risk factors in obese adolescent girls 
Obesity is associated with a relative deficiency of growth hormone, which is predictive of greater visceral fat and markers of cardiovascular risk. The study’s purpose was to use recombinant human growth hormone (rhGH) as a physiologic probe to assess the effects of reversing obesity-related GH deficiency on body composition, cardiovascular risk markers, and insulin resistance.
22 obese girls 13–21 years old were followed for a randomized 6-month trial of rhGH vs. placebo/no treatment. At baseline and 6-months, DXA was performed for body composition, MRI to measure visceral, subcutaneous and total adipose tissue (VAT, SAT and TAT), and fasting blood drawn for IGF-1, inflammatory cardiovascular risk markers [soluble intercellular adhesion molecule (sICAM), high sensitivity CRP], lipids and HbA1C. An oral glucose tolerance test (OGTT) was performed. Twelve girls completed the 6-month visit. Baseline and mean 6-month change were compared between the groups using the Student t-test and the relationship between variables was determined through multiple regression analysis.
After 6-months, the rhGH group maintained IGF-1 levels, and had decreases in total cholesterol (p = 0.03), sICAM-1 (p = 0.04) and HbA1C (p = 0.03) compared to placebo/no treatment. The rhGH group trended towards greater decreases in LDL and 2-hour OGTT glucose. Glucose tolerance did not worsen with rhGH administration.
Administering rhGH in small doses is able to stabilize IGF-1 levels in obesity. We have also shown that rhGH administration leads to an improvement in some markers of cardiovacular risk with without adversely affecting glucose tolerance.
Trial registration
Clinical Trial Registration Number: NCT01169103.
PMCID: PMC4247194  PMID: 25435886
Adolescents; Growth hormone; Visceral fat; Body composition; Females; Inflammatory markers
8.  Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy 
The Journal of Clinical Investigation  2014;124(8):3339-3351.
miRNAs are important regulators of biological processes in many tissues, including the differentiation and function of brown and white adipocytes. The endoribonuclease dicer is a major component of the miRNA-processing pathway, and in adipose tissue, levels of dicer have been shown to decrease with age, increase with caloric restriction, and influence stress resistance. Here, we demonstrated that mice with a fat-specific KO of dicer develop a form of lipodystrophy that is characterized by loss of intra-abdominal and subcutaneous white fat, severe insulin resistance, and enlargement and “whitening” of interscapular brown fat. Additionally, KO of dicer in cultured brown preadipocytes promoted a white adipocyte–like phenotype and reduced expression of several miRNAs. Brown preadipocyte whitening was partially reversed by expression of miR-365, a miRNA known to promote brown fat differentiation; however, introduction of other miRNAs, including miR-346 and miR-362, also contributed to reversal of the loss of the dicer phenotype. Interestingly, fat samples from patients with HIV-related lipodystrophy exhibited a substantial downregulation of dicer mRNA expression. Together, these findings indicate the importance of miRNA processing in white and brown adipose tissue determination and provide a potential link between this process and HIV-related lipodystrophy.
PMCID: PMC4109560  PMID: 24983316
9.  Assessment of abdominal fat compartments using DXA in premenopausal women from anorexia nervosa to morbid obesity 
Obesity (Silver Spring, Md.)  2013;21(12):10.1002/oby.20424.
The purpose of this study was to test a newly developed DXA method for abdominal fat depot quantification in subjects with AN, normal weight, and obesity using CT as a gold standard.
Design and Methods
135 premenopausal women (overweight/obese: n=89, normal-weight: n=27, AN: n=19); abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and total adipose tissue (TAT) areas determined on CT and DXA.
There were strong correlations between DXA and CT measurements of abdominal fat compartments in all groups with the strongest correlation coefficients in the normal-weight and overweight/obese groups. Correlations of DXA and CT VAT measurements were strongest in the obese group and weakest in the AN group. DXA abdominal fat depots were higher in all groups compared to CT, with the largest % mean difference in the AN group and smallest in the obese group.
A new DXA technique is able to assess abdominal fat compartments including VAT in premenopausal women across a large weight spectrum However, DXA measurements of abdominal fat were higher than CT, and this percent bias was most pronounced in the AN subjects and decreased with increasing weight, suggesting that this technique may be more useful in obese individuals.
PMCID: PMC3690161  PMID: 23512706
10.  Increased FDG uptake in Association with Reduced Extremity Fat in HIV Patients 
Antiviral therapy  2012;18(2):243-248.
HIV lipodystrophy - characterized by peripheral lipoatrophy, with or without central fat accumulation - confers increased metabolic risk. However, the functional activity of HIV lipodystrophic tissue in relation to metabolic risk has yet to be fully explored in vivo through the use of non-invasive imaging techniques. This study assesses the relationship between FDG uptake in various fat depots and metabolic/immune parameters among subjects with HIV lipodystrophy.
Lipodystrophic men on anti-retroviral therapy (ART) underwent whole-body 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) scans and detailed metabolic/immune phenotyping.
FDG uptake in the subcutaneous adipose tissue (SAT) of the extremities (mean standardized uptake value, or SUV, of the arm and leg SAT) was found to correlate with the degree of peripheral lipoatrophy (r = 0.7, p = 0.01). Extremity SAT FDG uptake was positively associated with HOMA-IR (r = 0.6, p = 0.02) and fasting hyperinsulinemia (r = 0.7, p 0.01), while fat percentage of extremities was not. Further, extremity SAT FDG uptake was significantly associated with CD4 count (r = 0.6, p = 0.05). In multivariate modeling for HOMA-IR, extremity SAT FDG uptake remained significant after controlling for BMI and TNF-α (R2 for model = 0.71, p = 0.02; SUV in the extremity SAT β-estimate 12.3, p = 0.009).
In HIV lipodystrophic patients, extremity SAT FDG uptake is increased in association with reduced extremity fat and may contribute to insulin resistance. Noninvasive assessments of in situ inflammation using FDG-PET may usefully complement histological and gene expression analyses of metabolic dysregulation in peripheral fat among HIV+ patients.
PMCID: PMC3670757  PMID: 23041595
HIV; lipodystrophy; FDG-PET/CT; insulin resistance
12.  Effects of Lifestyle Modification and Metformin on Atherosclerotic Indices among HIV-Infected Patients with the Metabolic Syndrome 
AIDS (London, England)  2012;26(5):587-597.
Metabolic abnormalities including diabetes, dyslipidemia, hypertension, and abdominal obesity occur commonly in HIV patients, are associated with increased coronary artery calcification (CAC), and contribute to increased cardiovascular disease (CVD) in this population. We hypothesized that lifestyle modification (LSM) and metformin would improve CVD indices in HIV patients with metabolic syndrome.
A randomized, placebo controlled trial to investigate LSM and metformin, alone and in combination, over one year, among 50 HIV-infected patients with metabolic syndrome.
We assessed CAC, cardiovascular and metabolic indices.
Among the participants, duration of HIV-infection was 14±1 yr and duration of antiretroviral therapy was 6±1 yr. Metformin-treated subjects demonstrated significantly less progression of CAC (−1±2 vs. 33±17, P=0.004, metformin vs. placebo) whereas the effect of LSM on CAC progression was not significant (8±6 vs. 21±14, P=0.82, LSM vs. no LSM). Metformin had a significantly greater effect on CAC than LSM (P=0.01). Metformin-treated subjects also demonstrated less progression in calcified plaque volume (−0.4±1.9 vs. 27.6±13.8 mm3, P=0.008) and improved HOMA-IR (P=0.05) compared to placebo. Subjects randomized to LSM vs. no LSM showed significant improvement in HDL (P=0.03), hsCRP (P=0.05), and cardiorespiratory fitness. Changes in CAC among the 4 groups: 1) no LSM, placebo (43±30); 2) LSM, placebo (19±7); 3) no LSM, metformin (1±1); and 4) LSM, metformin (−4±6) were different (P=0.03 for ANOVA and linear trend across groups), the majority of this effect was mediated by metformin. Results are mean ± SEM.
Metformin prevents plaque progression in HIV-infected patients with the metabolic syndrome.
PMCID: PMC3675446  PMID: 22112605
Lifestyle modification; metformin; HIV; atherosclerosis
13.  Modular MR-compatible lower leg exercise device for whole-body scanners 
Skeletal radiology  2011;40(10):1349-1354.
To develop a modular MR-compatible lower leg exercise device for muscle testing using a clinical 3 T MR scanner.
Materials and methods
An exercise device to provide isotonic resistance to plantar- or dorsiflexion was constructed from nonferrous materials and designed for easy setup and use in a clinical environment. Validation tests were performed during dynamic MR acquisitions. For this purpose, the device was tested on the posterior lower leg musculature of five subjects during 3 min of exercise at 30% of maximum voluntary plantarflexion during 31-phosphorus MR spectroscopy (31P-MRS). Measures of muscle phosphocreatine (PCr), inorganic phosphate (Pi), and pH were obtained before, during, and after the exercise protocol.
At the end of exercise regimen, muscle PCr showed a 28% decrease from resting levels (to 21.8±3.9 from 30.4±3.0 mM) and the average PCr recovery rate was 35.3±8.3 s. Muscle Pi concentrations increased 123% (to 14.6±4.7 from 6.5±3.3 mM) and pH decreased 1.5% (to 7.06±0.14 from 7.17±0.07) from resting levels.
The described MR-compatible lower leg exercise was an effective tool for data acquisition during dynamic MR acquisitions of the calf muscles. The modular design allows for adaptation to other whole-body MR scanners and incorporation of custom-built mechanical or electronic interfaces and can be used for any MR protocol requiring dynamic evaluation of calf muscles.
PMCID: PMC3667703  PMID: 21271342
Exercise; Ergometer; MR-compatible
14.  Comparison of 3.0 T Proton Magnetic Resonance Spectroscopy Short and Long Echo-Time Measures of Intramyocellular Lipids in Obese and Normal-Weight Women 
To compare correlations of intramyocellular lipids (IMCL) measured by short and long echo-time proton magnetic resonance spectroscopy (1H-MRS) with indices of body composition and insulin resistance in obese and normal-weight women.
Materials and Methods
We quantified IMCL of tibialis anterior (TA) and soleus (SOL) muscles in 52 premenopausal women (37 obese and 15 normal weight) using single-voxel 1H-MRS PRESS at 3.0 T with short (30 msec) and long (144 msec) echo times. Statistical analyses were performed to determine correlations of IMCL with body composition as determined by computed tomography (CT) and insulin resistance indices and to compare correlation coefficients from short and long echo-time data. Signal-to-noise ratio (SNR), linewidth, and coefficients of variation (CV) of short and long echo-time spectra were calculated.
Short and long echo-time IMCL from TA and SOL significantly correlated with body mass index (BMI) and abdominal fat depots (r = 0.32 to 0.70, P = <0.05), liver density (r = −0.39 to −0.50, P < 0.05), and glucose area under the curve as a measure of insulin resistance (r = 0.47 to 0.49, P < 0.05). There was no significant difference between correlation coefficients of short and long echo-time spectra (P > 0.5). Short echo-time IMCL in both muscles showed significantly higher SNR (P < 0.0001) and lower CVs when compared to long echo-time acquisitions. Linewidth measures were not significantly different between groups.
IMCL quantification using short and long echo-time 1H-MRS at 3.0 T is useful to detect differences in muscle lipid content in obese and normal-weight subjects. In addition, IMCL correlates with body composition and markers of insulin resistance in this population with no significant difference in correlations between short and long echo-times. Short echo-time IMCL quantification of TA and SOL muscles at 3.0 T was superior to long echo-time due to better SNR and better reproducibility.
PMCID: PMC3662051  PMID: 20677267
IMCL; 1H-MR spectroscopy; echo-time; obesity
15.  Effects of growth hormone in women with abdominal adiposity: a 6-month randomized, double-blind, placebo-controlled trial 
Abdominal adiposity is associated with increased cardiovascular risk and decreased growth hormone (GH) secretion. The objective of our study was to determine the effects of GH in abdominally obese women on body composition and cardiovascular risk markers.
Materials and Methods
In this randomized, double-blind, placebo-controlled study, 79 obese premenopausal women received GH vs. placebo for six months. Primary endpoints were: 1) total abdominal (TAT) fat by CT (body composition) and 2) high-sensitivity C-reactive protein (hsCRP) (cardiovascular risk marker). Body composition was assessed by CT, DXA and proton MR spectroscopy. Serum cardiovascular risk markers, carotid intima-media thickness and endothelial function were measured.
Mean 6-month GH dose was 1.7±0.1 mg/day, resulting in a mean IGF-1 SDS increase from −1.7±0.08 to −0.1±0.3 in the GH group. GH administration decreased TAT and hsCRP compared with placebo. In addition, it increased thigh muscle mass and lean body mass, and decreased subcutaneous abdominal and trunk fat, tPA, apoB, and apoB/LDL compared with placebo. Visceral adipose tissue decreased and IMCL increased within the GH group. Six-month change in IGF-1 levels was negatively associated with 6-month decrease in TAT and VAT. One subject had a 2-hour glucose >200 mg/mL at 3 months; four subjects, three of whom were randomized to GH, had 2-hour glucose levels >200 mg/mL at study end.
GH administration in abdominally obese premenopausal women exerts beneficial effects on body composition and cardiovascular risk markers, but is associated with a decrease in glucose tolerance in a minority of women.
PMCID: PMC3651853  PMID: 22275471
growth hormone; visceral obesity; body composition; cardiovascular risk
16.  Adiponectin Is Inversely Associated With Intramyocellular and Intrahepatic Lipids in Obese Premenopausal Women 
Obesity (Silver Spring, Md.)  2010;19(5):911-916.
Adiponectin, an adipokine secreted by adipocytes, exerts beneficial effects on glucose and lipid metabolism and has been found to improve insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. Adiponectin is found in several isoforms and the high-molecular weight (HMW) form has been linked most strongly to the insulin-sensitizing effects. Fat content in skeletal muscle (intramyocellular lipids, IMCL) and liver (intrahepatic lipids, IHL) can be quantified noninvasively using proton magnetic resonance spectroscopy (1H-MRS). The purpose of our study was to assess the relationship between HMW adiponectin and measures of glucose homeostasis, IMCL and IHL, and to determine predictors of adiponectin levels. We studied 66 premenopausal women (mean BMI 31.0 ± 6.6 kg/m2) who underwent 1H-MRS of calf muscles and liver for IMCL and IHL, computed tomography (CT) of the abdomen for abdominal fat depots, dual-energy X-ray absorptiometry (DXA) for fat and lean mass assessments, HMW and total adiponectin, fasting lipid profile and an oral glucose tolerance test (homeostasis model assessment of insulin resistance (HOMAIR), glucose and insulin area under the curve). There were strong inverse associations between HMW adiponectin and measures of insulin resistance, IMCL and IHL, independent of visceral adipose tissue (VAT) and total body fat. IHL was the strongest predictor of adiponectin and adiponectin was a predictor of HOMAIR. Our study showed that in premenopausal obese women HMW adiponectin is inversely associated with IMCL and IHL content. This suggests that adiponectin exerts positive effects on insulin sensitivity in obesity by decreasing intracellular triglyceride content in skeletal muscle and liver; it is also possible that our results reflect effects of insulin on adiponectin.
PMCID: PMC3607306  PMID: 21151017
17.  Comparison of DXA and CT in the Assessment of Body Composition in Premenopausal Women With Obesity and Anorexia Nervosa 
Obesity (Silver Spring, Md.)  2010;18(11):2227-2233.
Accurate methods for assessing body composition in subjects with obesity and anorexia nervosa (AN) are important for determination of metabolic and cardiovascular risk factors and to monitor therapeutic interventions. The purpose of our study was to assess the accuracy of dual-energy X-ray absorptiometry (DXA) for measuring abdominal and thigh fat, and thigh muscle mass in premenopausal women with obesity, AN, and normal weight compared to computed tomography (CT). In addition, we wanted to assess the impact of hydration on DXA-derived measures of body composition by using bioelectrical impedance analysis (BIA). We studied a total of 91 premenopausal women (34 obese, 39 with AN, and 18 lean controls). Our results demonstrate strong correlations between DXA- and CT-derived body composition measurements in AN, obese, and lean controls (r = 0.77–0.95, P < 0.0001). After controlling for total body water (TBW), the correlation coefficients were comparable. DXA trunk fat correlated with CT visceral fat (r = 0.51–0.70, P < 0.0001). DXA underestimated trunk and thigh fat and overestimated thigh muscle mass and this error increased with increasing weight. Our study showed that DXA is a useful method for assessing body composition in premenopausal women within the phenotypic spectrum ranging from obesity to AN. However, it is important to recognize that DXA may not accurately assess body composition in markedly obese women. The level of hydration does not significantly affect most DXA body composition measurements, with the exceptions of thigh fat.
PMCID: PMC3607308  PMID: 20111013
18.  Vertebral Bone Marrow Fat Is Positively Associated With Visceral Fat and Inversely Associated With IGF-1 in Obese Women 
Obesity (Silver Spring, Md.)  2010;19(1):49-53.
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.
PMCID: PMC3593350  PMID: 20467419
19.  Determinants of bone mineral density in obese premenopausal women 
Bone  2010;48(4):748-754.
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.
PMCID: PMC3073669  PMID: 21195217
bone mineral density; obesity; visceral adipose tissue; IGF -1; P1NP; quantitative computed tomography (QCT)
20.  Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults 
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.
PMCID: PMC3206591  PMID: 17284576
human immunodeficiency virus; insulin resistance; magnetic resonance spectroscopy
21.  Increased intramyocellular lipid accumulation in HIV-infected women with fat redistribution 
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.
PMCID: PMC3205444  PMID: 16223978
magnetic resonance spectroscopy; insulin resistance; protease inhibitor; acquired immunodeficiency syndrome
22.  Improved Triglycerides and Insulin Sensitivity with 3 Months of Acipimox in Human Immunodeficiency Virus-infected Patients with Hypertriglyceridemia 
Metabolic abnormalities such as hypertriglyceridemia remain a challenge for optimizing long-term health in HIV-infected patients.
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.
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.
The study was conducted at an academic medical center.
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).
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.
PMCID: PMC3196527  PMID: 16940448
23.  Effects of TNF-α neutralization on adipocytokines and skeletal muscle adiposity in the metabolic syndrome 
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.
PMCID: PMC3196534  PMID: 17374698
tumor necrosis factor-α; adiponectin; resistin; muscle adiposity; metabolic syndrome
24.  Breath-hold 1H-MR spectroscopy for intrahepatic lipid quantification at 3 Tesla 
To compare breath-hold 1H-MRS to respiratory-gated 1H-MRS and CT for quantification of hepatic lipid content.
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.
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.
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.
PMCID: PMC2877282  PMID: 20498538
MR spectroscopy; liver; lipids
Magnetic resonance imaging  2007;25(7):1105-1111.
To prospectively compare measurement precision of calf intramyocellular lipid (IMCL) quantification at 3.0T and 1.5T using 1H magnetic resonance spectroscopy (1H-MRS).
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.
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).
Using current technology, 1H-MRS for IMCL at 3.0T did not improve measurement precision compared to 1.5T.
PMCID: PMC2034287  PMID: 17707173
Proton magnetic resonance spectroscopy; Muscle; Lipids; 3.0-Tesla

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