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1.  Hyperphagia: Current Concepts and Future Directions Proceedings of the 2nd International Conference on Hyperphagia 
Obesity (Silver Spring, Md.)  2014;22(0 1):S1-S17.
Hyperphagia is a central feature of inherited disorders (e.g., Prader–Willi Syndrome) in which obesity is a primary phenotypic component. Hyperphagia may also contribute to obesity as observed in the general population, thus raising the potential importance of common underlying mechanisms and treatments. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present as are a lack of mechanistic of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments.
Design and Methods
International conference with 28 experts, including scientists and caregivers, providing presentations, panel discussions, and debates.
The reviewed collective research and clinical experience provides a critical body of new and novel information on hyperphagia at levels ranging from molecular to population. Gaps in understanding and tools needed for additional research were identified.
This report documents the full scope of important topics reviewed at a comprehensive international meeting devoted to the topic of hyperphagia and identifies key areas for future funding and research.
PMCID: PMC4159941  PMID: 24574081
3.  Is Mortality Risk Reduced in Overweight or Obese Diabetics? 
PMCID: PMC3889934  PMID: 24002636
4.  Effect of Calcium Supplementation on Weight and Fat Loss in Women 
Data suggest that a diet deficient in calcium is associated with higher body weight and that augmenting calcium intake may reduce weight and fat gain or enhance loss. Our aim was to determine whether calcium supplementation during a weight loss intervention affects body fat or weight loss. Data were combined from three separate 25-wk randomized, double blind, placebo-controlled trials of 1000 mg/d calcium supplementation in 100 premenopausal and postmenopausal women. The primary outcome measures were change in body weight and fat mass adjusted for baseline values.
There were no significant differences in body weight or fat mass change between the placebo and the calcium-supplemented groups in the pooled analysis (adjusted mean ± SE; body weight, placebo –6.2 ± 0.7 vs. Ca –7.0 ± 0.7 kg; fat mass, placebo –4.5 ± 0.6 vs. Ca –5.5 ± 0.6 kg), and no significant interactions of calcium supplementation with menopausal/diet status. Analysis as separate trials also found no significant differences between the placebo and the calcium groups. Calcium supplementation did not significantly affect amount of weight or fat lost by women counseled to follow a moderately restricted diet for 25 wk. Nevertheless, the magnitude and direction of the differences for group means are consistent with a hypothesized small effect.
PMCID: PMC4010554  PMID: 14764774
5.  Can a Weight Loss of One Pound a Week be Achieved With a 3,500 kcal Deficit? Commentary on a Commonly Accepted Rule 
Despite theoretical evidence that the model commonly referred to as the 3500 kcal rule grossly overestimates actual weight loss, widespread application of the 3500 kcal formula continues to appear in textbooks, on respected government and health related websites, and scientific research publications. Here we demonstrate the risk of applying the 3500 kcal rule even as a convenient estimate by comparing predicted against actual weight loss in seven weight loss experiments conducted in confinement under total supervision or objectively measured energy intake. We offer three newly developed, downloadable applications housed in Microsoft® Excel and Java which simulates a rigorously validated, dynamic model of weight change. The first two tools available at, provide a convenient alternative method for providing patients with projected weight loss/gain estimates in response to changes in dietary intake. The second tool which can be downloaded from the URL,, projects estimated weight loss simultaneously for multiple subjects. This tool was developed to inform weight change experimental design and analysis. While complex dynamic models may not be directly tractable, the newly developed tools offer the opportunity to deliver dynamic model predictions as a convenient and significantly more accurate alternative to the 3500 kcal rule.
PMCID: PMC4024447  PMID: 23628852
3500 kcal Rule; Wishnofsky’s Rule; Dynamic Model; Energy Balance; First Law of Thermodynamics
6.  HbA1c and Lower-Extremity Amputation Risk in Low-Income Patients With Diabetes 
Diabetes Care  2013;36(11):3591-3598.
Diabetes confers a very high risk of lower-extremity amputation (LEA); however, few studies have assessed whether blood glucose control can reduce LEA risk among patients with diabetes, especially in practice settings where low-income patients predominate.
We performed a prospective cohort study (2000–2009) on patients with diabetes that included 19,808 African Americans and 15,560 whites. The cohort was followed though 31 May 2012. Cox proportional hazards regression models were used to estimate the association of HbA1c with LEA risk.
During a mean follow-up of 6.83 years, 578 LEA incident cases were identified. The multivariable-adjusted hazard ratios of LEA associated with different levels of HbA1c at baseline (<6.0% [reference group], 6.0–6.9, 7.0–7.9, 8.0–8.9, 9.0–9.9, and ≥10.0%) were 1.00, 1.73 (95% CI 1.07–2.80), 1.65 (0.99–2.77), 1.96 (1.14–3.36), 3.02 (1.81–5.04), and 3.30 (2.10–5.20) (P trend <0.001) for African American patients with diabetes and 1.00, 1.16 (0.66–2.02), 2.28 (1.35–3.85), 2.38 (1.36–4.18), 2.99 (1.71–5.22), and 3.25 (1.98–5.33) (P trend <0.001) for white patients with diabetes, respectively. The graded positive association of HbA1c during follow-up with LEA risk was observed among both African American and white patients with diabetes (all P trend <0.001). With stratification by sex, age, smoking status, blood pressure, LDL cholesterol, BMI, use of glucose-lowering agents, and income, this graded association of HbA1c with LEA was still present.
The current study conducted in a low-income population suggests a graded association between HbA1c and the risk of LEA among both African American and white patients with type 2 diabetes.
PMCID: PMC3816880  PMID: 24062322
7.  Prealbumin is Associated with Visceral Fat Mass in Hemodialysis Patients 
Albumin and prealbumin are associated with nutritional status and inflammatory status. Each has a residual effect on mortality outcomes when included in regression models that include the other. Prealbumin is increased in the obese mouse model as a consequence of stabilization of prealbumin by Retinol Binding Protein 4 (RTB4), secreted by adipocytes. We carried out this study to establish the contribution of adiposity to prealbumin levels in prevalent dialysis patients and the relationship of prealbumin to RTB4.
We determined whether prealbumin was associated with adiposity in hemodialysis (HD) patients, controlling for the effects of inflammation and nutrition.
Subjects and Methods
We evaluated body composition in 48 prevalent HD patients by magnetic resonance imaging (MRI), measuring total skeletal muscle mass (SM), visceral and subcutaneous adipose tissue (VAT and SAT), and serum albumin, prealbumin, RTB4, and interleukin-6 (IL-6). We used normalized protein catabolic rate (nPCR) to report nutrition and separately analyzed the determinants of albumin and then of prealbumin by multiple stepwise regression.
Thirty two subjects were women, 16 were diabetic, median age and body mass index 54.5 and 27.3 kg/m2, respectively; median TAT 24.3 kg and VAT and 3.25 kg, respectively. Prealbumin was positively associated with VAT, nPCR and RTB4, and negatively associated with IL-6; r2 for the model 0.64. By contrast albumin was positively associated with nPCR and negatively with IL-6 but not with any measure of adiposity (r2 for the model = 0.2).
Prealbumin, like albumin, is associated with markers of nutrition (nPCR) and inflammation, but unlike albumin, prealbumin levels are positively associated with visceral adiposity.
PMCID: PMC4209593  PMID: 23623396
Prealbumin; Visceral Adipose Tissue; Retinol-Binding Protein 4; Interleukin-6; Inflammation; Hemodialysis
8.  Aggressive Blood Pressure Control Increases Coronary Heart Disease Risk Among Diabetic Patients 
Diabetes Care  2013;36(10):3287-3296.
Blood pressure control can reduce the risk of coronary heart disease (CHD) among diabetic patients; however, it is not known whether the lowest risk of CHD is among diabetic patients with the lowest blood pressure level.
We performed a prospective cohort study (2000–2009) on diabetic patients including 17,536 African Americans and 12,618 whites. Cox proportional hazards regression models were used to estimate the association of blood pressure with CHD risk.
During a mean follow-up of 6.0 years, 7,260 CHD incident cases were identified. The multivariable-adjusted hazard ratios of CHD associated with different levels of systolic/diastolic blood pressure at baseline (<110/65, 110–119/65–69, 120–129/70–80, and 130–139/80–90 mmHg [reference group]; 140–159/90–100; and ≥160/100 mmHg) were 1.73, 1.16, 1.04, 1.00, 1.06, and 1.11 (P trend <0.001), respectively, for African American diabetic patients, and 1.60, 1.27, 1.08, 1.00, 0.95, and 0.99 (P trend<0.001) for white diabetic patients, respectively. A U-shaped association of isolated systolic and diastolic blood pressure at baseline as well as blood pressure during follow-up with CHD risk was observed among both African American and white diabetic patients (all Ptrend <0.001). The U-shaped association was present in the younger age-group (30–49 years), and this U-shaped association changed to an inverse association in the older age-group (≥60 years).
Our study suggests that there is a U-shaped or inverse association between blood pressure and the risk of CHD, and aggressive blood pressure control (blood pressure <120/70 mmHg) is associated with an increased risk of CHD among both African American and white patients with diabetes.
PMCID: PMC3781514  PMID: 23690530
9.  Evolving Concepts on Adjusting Human Resting Energy Expenditure Measurements for Body Size 
Establishing if an adult’s resting energy expenditure (REE) is high or low for their body size is a pervasive question in nutrition research. Early workers applied body mass and height as size measures and formulated the Surface Law and Kleiber’s Law, although each has limitations when adjusting REE. Body composition methods introduced during the mid-twentieth century provided a new opportunity to identify metabolically homogeneous “active” compartments. These compartments all show improved correlations with REE estimates over body mass-height approaches, but collectively share a common limitation: REE-body composition ratios are not “constant” but vary across men and women and with race, age, and body size. The now-accepted alternative to ratio-based norms is to adjust for predictors by applying regression models to calculate “residuals” that establish if a REE is relatively high or low. The distinguishing feature of statistical REE-body composition models is a “non-zero” intercept of unknown origin. The recent introduction of imaging methods has allowed development of physiological tissue-organ based REE prediction models. Herein we apply these imaging methods to provide a mechanistic explanation, supported by experimental data, for the non-zero intercept phenomenon and in that context propose future research directions for establishing between subject differences in relative energy metabolism.
PMCID: PMC3477241  PMID: 22863371
Energy Metabolism; Body Composition; Mathematical Model
10.  Energy Content of Weight Loss: Kinetic Features During Voluntary Caloric Restriction 
Metabolism: clinical and experimental  2012;61(7):10.1016/j.metabol.2011.11.012.
The classic rule stating that restricting intake by 3500 kcal/wk will lead to a 1-lb/wk rate of weight loss has come under intense scrutiny. Generally not a component of most weight loss prediction models, the “early” rapid weight loss phase may represent a period during which the energy content of weight change (ΔEC/ΔW) is low and thus does not follow the classic “rule”. The current study tested this hypothesis.
Dynamic ΔEC/ΔW changes were examined in 23 CALERIE Study overweight men and women evaluated by dual-energy x-ray absorptiometry during weight loss at treatment weeks 4 to 24. Changes from baseline in body energy content were estimated from fat and fat-free mass. Repeated measures ANOVA was used to determine if ΔEC/ΔW changed significantly over time. The evaluation was expanded with addition of the Kiel 13-week weight loss study of 75 obese men and women to test with adequate power if there are sex differences in ΔEC/ΔW.
The ANOVA CALERIE time effect was significant (p <0.001) with post hoc tests indicating ΔEC/ΔW (kcal/kg) increased significantly from week 4 (X±SEM, 4, 858±388) to 6 (6, 041±376, p<0.01) and changed insignificantly thereafter; ΔEC/ΔW was significantly larger for Kiel women (6, 804±226) versus men (6, 119±240, p<0.05).
Sex-specific dynamic relative changes in body composition and related ΔEC/ΔW occur with weight loss initiation that extend one-month or more. These observations provide new information for developing energy balance models and further define limitations of the 3500 kcal energy deficit → 1 lb weight loss rule.
PMCID: PMC3810417  PMID: 22257646
Energy Balance; Body Composition; Weight Loss; Body Fat
11.  Effectiveness of Booster Seats Compared With No Restraint or Seat Belt Alone for Crash Injury Prevention 
The objective was to evaluate the effectiveness of belt-positioning booster seats, compared with no restraint use and with seat belt use only, during motor vehicle crashes among U.S. children.
This was a retrospective matched cohort study with data from the 1998 through 2009 National Automotive Sampling System (NASS) Crashworthiness Data System (CDS). The study sample consisted of children aged 0 to 10 years who were not seated in the front seat of the vehicle. We used Cox proportional hazards models to estimate the risk of overall, fatal, and regional body injury.
Children using seat belts in belt-positioning booster seats experienced less overall injury (Injury Severity Score [ISS] > 0, adjusted risk ratio [RR] = 0.73, 95% confidence interval [CI] = 0.55 to 0.96; Abbreviated Injury Scale [AIS] score of 2 or higher, adjusted RR = 0.30, 95% CI = 0.16 to 0.58; ISS > 8, adjusted RR = 0.19, 95% CI = 0.06 to 0.56), and less injury in most body regions except the neck (adjusted RR = 4.79, 95% CI = 1.43 to 16.00) than did children with no restraint use. Children using seat belts in belt-positioning booster seats had an equal risk of injury but higher risks of neck (adjusted RR = 1.86, 95% CI = 1.02 to 3.40) and thorax (adjusted RR = 2.86, 95% CI = 1.33 to 6.15) injury than did children restrained by seat belts only.
Children using belt-positioning booster seats appear to experience a higher risk of AIS > 0 injury to the neck and thorax than do children using seat belts only. Future research should examine whether the observed increase in neck and thorax injuries can be attributed to improper use of booster seats.
PMCID: PMC3798005  PMID: 24050794
12.  Dynamic Model Predicting Overweight, Obesity, and Extreme Obesity Prevalence Trends 
Obesity (Silver Spring, Md.)  2013;22(2):590-597.
Obesity prevalence in the United States (US) appears to be leveling, but the reasons behind the plateau remain unknown. Mechanistic insights can be provided from a mathematical model. The objective of this study is to model known multiple population parameters associated with changes in body mass index (BMI) classes and to establish conditions under which obesity prevalence will plateau.
Design and Methods
A differential equation system was developed that predicts population-wide obesity prevalence trends. The model considers both social and non-social influences on weight gain, incorporates other known parameters affecting obesity trends, and allows for country specific population growth.
The dynamic model predicts that: obesity prevalence is a function of birth rate and the probability of being born in an obesogenic environment; obesity prevalence will plateau independent of current prevention strategies; and the US prevalence of obesity, overweight, and extreme obesity will plateau by about 2030 at 28%, 32%, and 9%, respectively.
The US prevalence of obesity is stabilizing and will plateau, independent of current preventative strategies. This trend has important implications in accurately evaluating the impact of various anti-obesity strategies aimed at reducing obesity prevalence.
PMCID: PMC3842399  PMID: 23804487
Mathematical model; differential equation; infectious disease model; obesity prevalence
13.  Effect of Body Composition Methodology on Heritability Estimation of Body Fatness 
Heritability estimates of human body fatness vary widely and the contribution of body composition methodology to this variability is unknown. The effect of body composition methodology on estimations of genetic and environmental contributions to body fatness variation was examined in 78 adult male and female monozygotic twin pairs reared apart or together. Body composition was assessed by six methods – body mass index (BMI), dual energy x-ray absorptiometry (DXA), underwater weighing (UWW), total body water (TBW), bioelectric impedance (BIA), and skinfold thickness. Body fatness was expressed as percent body fat, fat mass, and fat mass/height2 to assess the effect of body fatness expression on heritability estimates. Model-fitting multivariate analyses were used to assess the genetic and environmental components of variance. Mean BMI was 24.5 kg/m2 (range of 17.8–43.4 kg/m2). There was a significant effect of body composition methodology (p<0.001) on heritability estimates, with UWW giving the highest estimate (69%) and BIA giving the lowest estimate (47%) for fat mass/height2. Expression of body fatness as percent body fat resulted in significantly higher heritability estimates (on average 10.3% higher) compared to expression as fat mass/height2 (p=0.015). DXA and TBW methods expressing body fatness as fat mass/height2 gave the least biased heritability assessments, based on the small contribution of specific genetic factors to their genetic variance. A model combining DXA and TBW methods resulted in a relatively low FM/ht2 heritability estimate of 60%, and significant contributions of common and unique environmental factors (22% and 18%, respectively). The body fatness heritability estimate of 60% indicates a smaller contribution of genetic variance to total variance than many previous studies using less powerful research designs have indicated. The results also highlight the importance of environmental factors and possibly genotype by environmental interactions in the etiology of weight gain and the obesity epidemic.
PMCID: PMC4110980  PMID: 25067962
body composition; adiposity; twins; heritability; genetics
14.  Rate of weight loss can be predicted by patient characteristics and intervention strategies 
Although dietary weight loss counseling usually employs a 500-1000 kcal/d energy deficit to induce weight loss of 0.5-1 kg/wk, this rate of weight loss is rarely achieved in research settings. Biological factors, such as changes in metabolic rate, are partly responsible but would account for a small deviation from expected weight loss. There must be other factors, behavioral or related to study design and implementation that affect the rate of weight loss observed.
To examine factors that influence the rate of weight loss obtained in clinical studies.
Thirty-five weight loss studies published between 1995 and 2009 were identified that used dietary counseling to induce weight loss in healthy subjects. Studies were included if they had a duration of at least 6 wk, used a strategy to counsel subjects to reduce free-living energy intakes, and reported weight loss data based on a completers analysis. Variables that were associated with the rate of weight loss among age, gender (% female subjects), initial body weight, frequency of dietary counseling, placebo use, exercise level, study length, and prescribed energy deficit were examined using linear regression analysis.
Study length was negatively related to the rate of weight loss (P<0.0001) whereas subject age (P<0.002), subject age squared (P=0.0073), initial body weight (P=0.0003), frequency of dietary counseling (P=0.0197), and prescribed energy deficit (P<0.0001) were positively related to the rate of weight loss observed in clinical studies.
These findings provide a tool for investigators and clinical dietitians to predict the rate of weight loss that can be expected within a population given the age, initial body weight, frequency of dietary counseling, and energy deficit prescription. These data, from clinical studies, suggest that the rate of weight loss is greater in older and heavier subjects and with higher contact frequency and caloric restriction.
PMCID: PMC3447534  PMID: 22717178
Obesity; duration; weight loss; caloric deficit; dietary counseling; diet
15.  Clinical Utility and Reproducibility of Visceral Adipose Tissue Measurements Derived from Dual-energy X-ray Absorptiometry in White and African American Adults 
Obesity (Silver Spring, Md.)  2013;21(11):2221-2224.
Computed tomography and magnetic resonance imaging are currently used to measure abdominal visceral adipose tissue (VAT) in humans; however, more widely available and less costly dual-energy x-ray absorptiometry (DXA) also has the potential to measure VAT.
The purpose of this study was to determine reproducibility and clinical thresholds for DXA-derived VAT.
Design and Methods
The sample included 2317 white and African American adults 18–74 years of age. VAT areas (cm2) were measured using a Hologic DXA scanner equipped with APEX 4.0 software. Reproducibility was assessed using repeated measurements on 101 participants scanned 14 days apart. Receiver Operating Characteristic (ROC) curves were used to assess clinical utility and select thresholds that identified elevated cardiometabolic risk, defined as the presence of ≥2 risk factors.
Reproducibility of DXA-VAT was 8.1%. The areas under the ROC curves ranged from 0.754 in African American men to 0.807 in white women. The thresholds were higher in white men (154 cm2) and women (143 cm2) compared to African American men (101 cm2) and women (114 cm2).
The results demonstrate that DXA VAT is a useful clinical marker of cardiometabolic risk; however, further research is required to determine associations with health outcomes using longitudinal studies.
PMCID: PMC3819404  PMID: 23794256
imaging; abdominal obesity; ethnicity; race differences; risk factors
16.  Relationships between body roundness with body fat and visceral adipose tissue emerging from a new geometrical model 
Obesity (Silver Spring, Md.)  2013;21(11):2264-2271.
To develop a new geometrical index that combines height, waist circumference (WC), and hip circumference (HC) and relate this index to total and visceral body fat.
Design and Methods
Subject data were pooled from three databases that contained demographic, anthropometric, dual energy X-ray absorptiometry (DXA) measured fat mass, and magnetic resonance imaging measured visceral adipose tissue (VAT) volume. Two elliptical models of the human body were developed. Body roundness was calculated from the model using a well-established constant arising from the theory. Regression models based on eccentricity and other variables were used to predict % body fat and % VAT.
A body roundness index (BRI) was derived to quantify the individual body shape in a height-independent manner. Body roundness slightly improved predictions of % body fat and % VAT compared to the traditional metrics of body mass index (BMI), WC, or HC. On this basis, healthy body roundness ranges were established. An automated graphical program simulating study results was placed at
Body roundness index, a new shape measure, is a predictor of % body fat and % VAT and can be applied as a visual tool for health status evaluations.
PMCID: PMC3692604  PMID: 23519954
18.  Assessing skeletal muscle mass: historical overview and state of the art 
Even though skeletal muscle (SM) is the largest body compartment in most adults and a key phenotypic marker of sarcopenia and cachexia, SM mass was until recently difficult and often impractical to quantify in vivo. This review traces the historical development of SM mass measurement methods and their evolution to advances that now promise to provide in-depth noninvasive measures of SM composition.
Key steps in the advancement of SM measurement methods and their application were obtained from historical records and widely cited publications over the past two centuries. Recent advances were established by collecting information on notable studies presented at scientific meetings and their related publications.
The year 1835 marks the discovery of creatine in meat by Chevreul, a finding that still resonates today in the D3-creatine method of measuring SM mass. Matiegka introduced an anthropometric approach for estimating SM mass in 1921 with the vision of creating a human “capacity” marker. The 1940s saw technological advances eventually leading up to the development of ultrasound and bioimpedance analysis methods of quantifying SM mass in vivo. Continuing to seek an elusive SM mass “reference” method, Burkinshaw and Cohn introduced the whole-body counting-neutron activation analysis method and provided some of the first detailed reports of cancer cachexia in the late 1970s. Three transformative breakthroughs leading to the current SM mass reference methods appeared in the 1970s and early 1980s as follows: the introduction of computed tomography (CT), photon absorptiometry, and magnetic resonance (MR) imaging. Each is advanced as an accurate and/or practical approach to quantifying whole-body and regional SM mass across the lifespan. These advances have led to a new understanding of fundamental body size-SM mass relationships that are now widely applied in the evaluation and monitoring of patients with sarcopenia and cachexia. An intermediate link between SM mass and function is SM composition. Advances in water-fat MR imaging, diffusion tensor imaging, MR elastography, imaging of connective tissue structures by ultra-short echo time MR, and other new MR approaches promise to close the gap that now exists between SM anatomy and function.
The global efforts of scientists over the past two centuries provides us with highly accurate means by which to measure SM mass across the lifespan with new advances promising to extend these efforts to noninvasive methods for quantifying SM composition.
PMCID: PMC3953319  PMID: 24532493
Body composition; Nutritional assessment; Sarcopenia; Cachexia
19.  Relationship between abdominal fat and bone mineral density in white and African American adults☆, ☆☆ 
Bone  2011;50(2):576-579.
Several studies have documented relationships between adipose tissue and bone mineral density (BMD); however, the degree to which there are racial differences in this relationship is not known. The purpose of this study was to examine the relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) and BMD among white and African American adults. The sample included 330 white women, 328 African American women, 307 white men, and 116 African American men 18–74 years of age. Dual-energy X-ray absorptiometry scans were used to measure BMD and computed tomography scans were used to measure abdominal VAT and SAT. Linear regression was used to assess the relationships between abdominal adiposity and BMD and to explore possible sex and race differences in the associations. In the total sample as well as in all sex-by-race groups, VAT and SAT were negatively related to BMD, after adjustment for lean body mass (LBM) and several covariates. The VAT model (including covariates) explained 33.3% of the variance in BMD and the SAT model (including covariates) explained 32.7% of the variance in BMD. Being African American, being male, and having high LBM were all associated with higher BMD. Race and sex interactions were not significant, indicating that the relationships were similar across race and sex groups. In conclusion, BMD was inversely related to abdominal VAT and SAT in white and African American adults after adjustment for LBM.
PMCID: PMC3936414  PMID: 21549867
Obesity; Osteoporosis; Race/ethnicity; Gender; Adiposity
20.  Decreased limb muscle and increased central adiposity are associated with 5-year all-cause mortality in HIV infection 
AIDS (London, England)  2011;25(11):1405-1414.
Unintentional loss of weight and muscle due to aging and disease has been associated with increased mortality. Wasting and weight loss occur in HIV infection even in the modern era of effective antiretroviral therapy.
We determined the association of MRI-measured regional and total skeletal muscle and adipose tissue with 5-year, all-cause mortality in 922 HIV-infected persons in the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM).
After 5 years of follow-up, HIV-infected participants with arm skeletal muscle in the lowest tertile had a mortality rate of 23%, compared with 11 and 8% for those in the middle and highest tertiles. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, inflammatory markers, and renal disease, we found that lower arm skeletal muscle, lower leg skeletal muscle and higher visceral adipose tissue (VAT) were each independently associated with increased mortality. Those in the lowest tertile of arm or leg skeletal muscle had higher odds of death [arm: odds ratio (OR)=2.0, 95% confidence interval (CI) 0.96–4.0; leg: OR=2.4, 95% CI 1.2–4.8] compared with the highest respective tertiles. Those in the highest tertile of VAT had 2.1-fold higher odds of death (95% CI 1.1–4.0) compared with the lowest VAT tertile.
Lower muscle mass and central adiposity appear to be important risk factors for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on body mass index in clinical practice.
PMCID: PMC3933309  PMID: 21572308
body composition; cachexia; fat redistribution; HIV infection; lipoatrophy; lipodystrophy; mortality; sarcopenia
21.  Pharmacologic Treatment of Obesity 
Journal of Obesity  2012;2011:751063.
PMCID: PMC3362918  PMID: 22675609
22.  Defining Clinical Leptin Resistance - Challenges and Opportunities 
Cell Metabolism  2012;15(2):150-156.
The lack of a universally accepted definition of the term “leptin resistance” led the National Institutes of Health to hold a workshop, “Toward a Clinical Definition of Leptin Resistance”. Leptin resistance is generally defined as the failure of endogenous or exogenous leptin to promote anticipated salutary metabolic outcomes in states of over-nutrition or obesity, although the hormone's inability to promote desired responses in specific situations results from multiple molecular, neural, behavioral, and environmental mechanisms. Thus, the term “leptin resistance” does not imply a single specific mechanism, but rather connotes distinct meanings across investigators and in different contexts. Clinically, exploiting behavioral and metabolic sensitivity to the hormone, rather than elaborating a universal, quantifiable definition of “leptin resistance”, is the goal and specific predictors of sensitivity should be established. It is clear that the availability of relevant human data is limited, however, and a substantial amount of new information must be acquired and disseminated to accomplish these goals.
PMCID: PMC3281561  PMID: 22326217
Leptin; obesity; genetic models; humans; therapy
23.  Body Mass Index as a Phenotypic Expression of Adiposity: Quantitative Contribution of Muscularity in a Population-Based Sample 
Although widely applied as a phenotypic expression of adiposity in population and gene-search studies, body mass index (BMI) is also acknowledged to reflect muscularity even though relevant studies directly measuring skeletal muscle (SM) mass are lacking. The current study aimed to fill this important gap by applying advanced imaging methods to test the hypothesis that, after controlling first for adiposity, SM mass is also a significant determinant of BMI in a population-based sample.
Whole-body magnetic resonance imaging scans were completed in CARDIA Study subjects aged 33-45 years. Physical activity (PA) levels, alcohol intake, and adequacy of food intake were assessed by standardized questionnaires.
58 African-American (AA) and 78 Caucasian (C) men; 63 AA and 64 C women.
Whole-body AT and SM volumes.
AT was significantly predicted by not only BMI, but PA and alcohol intake with total model R2s of 0.68 (p<0.0001) for men and 0.89 (p<0.0001) for women. Men had more SM than AT at all levels of BMI while SM predominated in women at lower BMIs (C <26 kg/m2; AA <28 kg/m2). Both AT and SM contributed a similar proportion of between-subject variation in BMI in men. In contrast, AT contributed ~30% more than SM to the variation in BMI in women. Developed allometric models indicated SM associations with AT, PA, and race after adjusting for height. There was little association of age, lifestyle factors, or race with BMI after controlling for both AT and SM.
Variation in muscularity provides a mechanistic basis for the previously observed non-specificity of BMI as a phenotypic expression of adiposity. These quantitative observations have important implications when choosing adiposity measures in population and gene-search studies.
PMCID: PMC3156622  PMID: 19773739
Body Composition; Ethnicity; Obesity; Body Mass Index
24.  The Metabolic Syndrome 
Archives of internal medicine  2003;163(4):427-436.
The metabolic syndrome is an important cluster of coronary heart disease risk factors with common insulin resistance. The extent to which the metabolic syndrome is associated with demographic and potentially modifiable lifestyle factors in the US population is unknown.
Metabolic syndrome–associated factors and prevalence, as defined by Adult Treatment Panel III criteria, were evaluated in a representative US sample of 3305 black, 3477 Mexican American, and 5581 white men and nonpregnant or lactating women aged 20 years and older who participated in the cross-sectional Third National Health and Nutrition Examination Survey.
The metabolic syndrome was present in 22.8% and 22.6% of US men and women, respectively (P=.86). The age-specific prevalence was highest in Mexican Americans and lowest in blacks of both sexes. Ethnic differences persisted even after adjusting for age, body mass index, and socioeconomic status. The metabolic syndrome was present in 4.6%, 22.4%, and 59.6% of normal-weight, overweight, and obese men, respectively, and a similar distribution was observed in women. Older age, postmenopausal status, Mexican American ethnicity, higher body mass index, current smoking, low household income, high carbohydrate intake, no alcohol consumption, and physical inactivity were associated with increased odds of the metabolic syndrome.
The metabolic syndrome is present in more than 20% of the US adult population; varies substantially by ethnicity even after adjusting for body mass index, age, socioeconomic status, and other predictor variables; and is associated with several potentially modifiable lifestyle factors. Identification and clinical management of this high-risk group is an important aspect of coronary heart disease prevention.
PMCID: PMC3146257  PMID: 12588201
25.  Anthropometric Markers of Obesity and Mortality in White and African American Adults: The Pennington Center Longitudinal Study 
Obesity (Silver Spring, Md.)  2013;21(5):1070-1075.
The purpose of this study was to determine the association between anthropometric measures of obesity and all-cause mortality in white and African American men and women. The sample included 14,343 adults 18 to 89 years of age. Height, weight, and waist and hip circumferences were measured, and the BMI (kg/m2), body adiposity index (BAI = ([hip circumference in centimeters]/[height in meters])1.5–18), waist-to-height ratio (WHtR) and waist-to-hip ratio (WHR) were computed. Vital status of the participants was determined from linkage with the National Death Index through 2009. Cox regression was used to assess the association between anthropometry and all1cause mortality, adjusting for age, sex, year of baseline examination, study code, smoking status, alcohol consumption and physical activity. Hazard ratios (HR) are expressed per standard deviation of each variable. A total of 438 deaths occurred during 120,637 person-years of follow-up. All anthropometric markers demonstrated significant associations with all-cause mortality in white subjects. In multivariable-adjusted models, BMI (HR 1.34; 95% CI: 1.19 - 1.50), waist circumference (1.41; 1.25 - 1.60), BAI (1.34; 1.17 - 1.53), WHtR (1.46; 1.28 - 1.65) and WHR (1.40; 1.23 - 1.61) all demonstrated significant relationships with mortality in white participants, but not in African Americans. In categorical analyses, there was a significant association between BMI status and mortality in whites but not African Americans. However, the risk associated with elevated waist circumference was almost identical in whites (1.49; 1.15 – 1.94) and African Americans (1.60; 1.06 – 2.40). In summary, this study has demonstrated race differences in the association between anthropometry and all-cause mortality.
PMCID: PMC3695407  PMID: 23784912

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