Cachexia: A systemic consequence of progressive, unresolved disease.

Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia.

Advances in body composition: a 100-year journey.

Knowledge of human body composition at the dawn of the twentieth century was based largely on cadaver studies and chemical analyses of isolated organs and tissues. Matters soon changed by the nineteen twenties when the Czech anthropologist Jindrich Matiegka introduced an influential new anthropometric method of fractionating body mass into subcutaneous adipose tissue and other major body components. Today, one century later, investigators can not only quantify every major body component in vivo at the atomic, molecular, cellular, tissue-organ, and whole-body organizational levels, but go far beyond to organ and tissue-specific composition and metabolite estimates. These advances are leading to an improved understanding of adiposity structure-function relations, discovery of new obesity phenotypes, and a mechanistic basis of some weight-related pathophysiological processes and adverse clinical outcomes. What factors over the past one hundred years combined to generate these profound new body composition measurement capabilities in living humans? This perspective tracks the origins of these scientific innovations with the aim of providing insights on current methodology gaps and future research needs.

Independent association of thigh muscle fat density with vascular events in Korean adults.

BACKGROUND: We aimed to explore the associations between thigh muscle fat density and vascular events. METHODS: A total of 3,595 adults (mean age, 57.2 years; women, 1,715 [47.7%]) without baseline cardiovascular events from the Korean Atherosclerosis Study-2 were included. Muscle and fat area at the mid-thigh level were measured by computed tomography (CT) using the following Hounsfield Unit range: 0-30 for low density muscle (LDM); 31-100 for normal density muscle (NDM); and - 250 to - 50 for fat. RESULTS: During a median follow-up period of 11.8 (4.3-13.9) years, vascular events occurred in 11.6% of men and 5.9% of women. Individuals with vascular events had a larger LDM area (men: 48.8 ± 15.5 cm2 vs. 44.6 ± 14.5 cm2; women: 39.4 ± 13.2 cm2 vs. 35.0 ± 11.8 cm2, both P < 0.001) compared with those who did not have vascular events during the follow-up of at least 5 years. The LDM/NDM ratio was also independently associated with vascular events after adjusting for cardiometabolic risk factors. Moreover, the LDM/NDM ratio improved the prognostic value for vascular events when added to conventional risk factors. CONCLUSIONS: The current study suggests that a higher thigh muscle fat infiltration is associated with an increased risk of developing vascular events among Korean adults.

Predictors of visceral and subcutaneous adipose tissue and muscle density: The ShapeUp! Kids study.

BACKGROUND AND AIMS: Body fat distribution, i.e., visceral (VAT), subcutaneous adipose tissue (SAT) and intramuscular fat, is important for disease prevention, but sex and ethnic differences are not well understood. Our aim was to identify anthropometric, demographic, and lifestyle predictors for these outcomes. METHODS AND RESULTS: The cross-sectional ShapeUp!Kids study was conducted among five ethnic groups aged 5-18 years. All participants completed questionnaires, anthropometric measurements, and abdominal MRI scans. VAT and SAT areas at four lumbar levels and muscle density were assessed manually. General linear models were applied to estimate coefficients of determination (R2) and to compare the fit of VAT and SAT prediction models. After exclusions, the study population had 133 male and 170 female participants. Girls had higher BMI-z scores, waist circumference (WC), and SAT than boys but lower VAT/SAT and muscle density. SAT, VAT, and VAT/SAT but not muscle density differed significantly by ethnicity. R2 values were higher for SAT than VAT across groups and improved slightly after adding WC. For SAT, R2 increased from 0.85 to 0.88 (girls) and 0.62 to 0.71 (boys) when WC was added while VAT models improved from 0.62 to 0.65 (girls) and 0.57 to 0.62 (boys). VAT values were significantly lower among Blacks than Whites with little difference for the other groups. CONCLUSION: This analysis in a multiethnic population identified BMI-z scores and WC as the major predictors of MRI-derived SAT and VAT and highlights the important ethnic differences that need to be considered in diverse populations.

Emergence of the adolescent obesity epidemic in the United States: five-decade visualization with humanoid avatars.

BACKGROUND/OBJECTIVES: Body size and shape have increased over the past several decades with one in five adolescents now having obesity according to objective anthropometric measures such as weight, height, and body mass index (BMI). The gradual physical changes and their consequences may not be fully appreciated upon visual inspection by those managing the long-term health of adolescents. This study aimed to develop humanoid avatars representing the gradual changes in adolescent body size and shape over the past five decades and to align avatars with key BMI percentile cut points for underweight, normal weight, overweight, and obesity. PARTICIPANTS/METHODS: Participants included 223 children and adolescents between the ages of 5 and 18 years approximately representative of the race/ethnicity and BMI of the noninstitutionalized US population. Each participant completed a three-dimensional whole-body scan, and the collected data was used to develop manifold regression models for generating humanoid male and female avatars from specified ages, weights, and heights. Secular changes in the mean weights and heights of adolescents were acquired from six U.S. National Health and Nutrition Surveys beginning in 1971-1974 and ending in 2015-2018. Male and female avatars at two representative ages, 10 and 15 years, were developed for each survey and at the key BMI percentile cut points based on data from the 2015-2018 survey. RESULTS: The subtle changes in adolescent Americans' body size and shape over the past five decades are represented by 24 male and female 10- and 15-year-old avatars and 8 corresponding BMI percentile cut points. CONCLUSIONS: The current study, the first of its kind, aligns objective physical examination weights and heights with the visual appearance of adolescents. Aligning the biometric and visual information may help improve awareness and appropriate clinical management of adolescents with excess adiposity passing through health care systems. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03706612.

Agreement and Precision of Deuterium Dilution for Total Body Water and Multicompartment Body Composition Assessment in Collegiate Athletes.

BACKGROUND: Deuterium oxide (D2O) dilution is the criterion method for total body water (TBW) measurement, but results may vary depending on the specimen type, analysis method, and analyzing laboratory. Bioelectrical impedance (BIA) estimates TBW, but results may vary by device make and model. OBJECTIVES: We investigated the accuracy and precision of TBW estimates and how measurement conditions affected the accuracy of body composition using multicompartment body composition models. METHODS: Eighty collegiate athletes received duplicate TBW measures acquired from 3 BIA devices (S10, SFB7, and SOZO) and from unique D2O combinations of specimen type (saliva, urine), analysis methodology [Fourier transform infrared spectrophotometry (FTIR), isotope-ratio mass spectrometry (IRMS)], and 3 different laboratories. TBW measures were substituted into 2-compartment (2C) and 5-compartment (5C) body composition models. Criterion measures were compared using Lin's concordance correlation coefficient cutoff of poor (<0.90), moderate (0.90-0.95), substantial (0.95-0.99), and almost perfect (>0.99). RESULTS: Fifty-one participants (26 female) completed the protocol. Using IRMS saliva as the criterion TBW, all other measures produced a substantial or almost perfect agreement, except for SFB7 (poor) and SOZO (moderate). The 2C body composition measures using D2O and BIA produced poor agreement except for moderate agreement for lab 3 FTIR saliva. The 5C body composition measures using D2O produced a substantial agreement, whereas the BIA device S10 and SOZO had a moderate agreement, while the SFB7 had a poor agreement to the criterion. Test-retest precision varied between techniques from 0.3% to 1.2% for TBW. CONCLUSIONS: Small differences in TBW measurement led to significant differences in 2C models. The 5C models partially mitigate differences seen in 2C models when different TBW measures are used. Interchanging TBW measures in multicompartment models can be problematic and should be performed with these considerations.

Stimulated Insulin Secretion Predicts Changes in Body Composition Following Weight Loss in Adults with High BMI.

BACKGROUND: The aim of obesity treatment is to promote loss of fat relative to lean mass. However, body composition changes with calorie restriction differ among individuals. OBJECTIVES: The goal of this study was to test the hypothesis that insulin secretion predicts body composition changes among young and middle-age adults with high BMI (in kg/m2) following major weight loss. METHODS: Exploratory analyses were conducted with pre-randomization data from 2 large feeding trials: the Framingham, Boston, Bloomington, Birmingham, and Baylor study (FB4; n = 82, 43.9% women, BMI ≥27) and the Framingham State Food Study [(FS)2; n = 161, 69.6% women, BMI ≥25]. Participants in the 2 trials consumed calorie-restricted moderate-carbohydrate or very-low-carbohydrate diets to produce 12-18% weight loss in ∼14 wk or 10-14% in ∼10 wk, respectively. We determined insulin concentration 30 min after a 75-g oral glucose load (insulin-30) as a measure of insulin secretion and HOMA-IR as a measure of insulin resistance at baseline. Body composition was determined by DXA at baseline and post-weight loss. Associations were analyzed using general linear models with adjustment for covariates. RESULTS: In FB4, higher insulin-30 was associated with a smaller decrease in fat mass (0.441 kg per 100 µIU/mL increment in baseline insulin-30; P = 0.005; -1.20-kg mean difference between the first compared with the fifth group of insulin-30) and a larger decrease in lean mass (-0.465 kg per 100 µIU/mL; P = 0.004; 1.27-kg difference). Participants with higher insulin-30 lost a smaller proportion of weight loss as fat (-3.37% per 100 µIU/mL; P = 0.003; 9.20% difference). Greater HOMA-IR was also significantly associated with adverse body composition changes. Results from (FS)2 were qualitatively similar but of a smaller magnitude. CONCLUSIONS: Baseline insulin dynamics predict substantial individual differences in body composition following weight loss. These findings may inform understanding of the pathophysiological basis for weight regain and the design of more effective obesity treatment. Registered at clinicaltrials.gov as NCT03394664 and NCT02068885.

Adaptive thermogenesis after moderate weight loss: magnitude and methodological issues.

PURPOSE: The aim of this study was (1) to assess AT through 13 different mathematical approaches and to compare their results; and (2) to understand if AT occurs after moderate WL. METHODS: Ninety-four participants [mean (SD); BMI, 31.1 (4.3) kg/m2; age, 43.0 (9.4) years; 34% females] underwent a 1-year lifestyle intervention (clinicaltrials.gov ID: NCT03031951) and were randomized to intervention (IG, n = 49) or control groups (CG, n = 45), and all measurements were made at baseline and after 4 months. Fat mass (FM) and fat-free mass (FFM) were measured by dual-energy X-ray absorptiometry and REE by indirect calorimetry. AT was assessed through 13 different approaches, varying in how REE was predicted and/or how AT was assessed. RESULTS: IG underwent a mean negative energy balance (EB) of 270 (289) kcal/day, p < 0.001), resulting in a WL of - 4.8 (4.9)% and an FM loss of - 11.3 (10.8)%. Regardless of approach, AT occurred in the IG, ranging from ~ - 65 to ~ - 230 kcal/day and three approaches showed significant AT in the CG. CONCLUSIONS: Regardless of approach, AT occurred after moderate WL in the IG. AT assessment should be standardized and comparisons among studies with different methodologies to assess AT must be avoided.

Gastrointestinal genetic reprogramming of vitamin A metabolic pathways in response of Roux-en-Y gastric bypass.

Roux-en-Y gastric bypass (RYGB) is one of the most performed bariatric surgical techniques. However, RYGB commonly results, as side effects, in nutritional deficiencies. This study aimed to examine changes in the expression of vitamin A pathway encoding genes in the gastrointestinal tract (GI) and to evaluate the potential mechanisms associated with hypovitaminosis A after RYGB. Intestinal biopsies were obtained through double-balloon endoscopy in 20 women with obesity (age 46.9±6.2 years; body mass index [BMI] 46.5±5.3 kg/m2 [mean±SD]) before and three months after RYGB (BMI, 38.2±4.2 kg/m2). Intestinal mucosal gene microarray analyses were performed in samples using a Human GeneChip 1.0 ST array (Affymetrix). Vitamin A intake was assessed from 7-day food records and serum retinol levels were evaluated by electrochemiluminescence immunoassay. Our results showed the following genes with significant downregulation (p≤0.05): LIPF (-0.60), NPC1L1 (-0.71), BCO1 (-0.45), and RBP4 (-0.13) in duodenum; CD36 (-0.33), and ISX (-0.43) in jejunum and BCO1 (-0.29) in ileum. No significant changes in vitamin A intake were found (784±694 retinol equivalents [RE] pre-operative vs. 809±753 RE post-operative [mean±SD]). Although patients were routinely supplemented with 3500 international units IU/day (equivalent to 1050 µg RE/day) of oral retinol palmitate, serum concentrations were lower in the post-operative when compared to pre-operative period (0.35±0.14 µg/L vs. 0.52±0.33 µg/L, respectively - P=0.07), both within the normal range. After RYGB, the simultaneous change in expression of GI genes, may impair carotenoid metabolism in the enterocytes, formation of nascent chylomicrons and transport of retinol, resulting in lower availability of vitamin A.

Errors in the implementation, analysis, and reporting of randomization within obesity and nutrition research: a guide to their avoidance.

Randomization is an important tool used to establish causal inferences in studies designed to further our understanding of questions related to obesity and nutrition. To take advantage of the inferences afforded by randomization, scientific standards must be upheld during the planning, execution, analysis, and reporting of such studies. We discuss ten errors in randomized experiments from real-world examples from the literature and outline best practices for their avoidance. These ten errors include: representing nonrandom allocation as random, failing to adequately conceal allocation, not accounting for changing allocation ratios, replacing subjects in nonrandom ways, failing to account for non-independence, drawing inferences by comparing statistical significance from within-group comparisons instead of between-groups, pooling data and breaking the randomized design, failing to account for missing data, failing to report sufficient information to understand study methods, and failing to frame the causal question as testing the randomized assignment per se. We hope that these examples will aid researchers, reviewers, journal editors, and other readers to endeavor to a high standard of scientific rigor in randomized experiments within obesity and nutrition research.

Total body and regional surface area: Quantification with low-cost three-dimensional optical imaging systems.

OBJECTIVES: Body surface area (SA) is a widely used physical measure incorporated into multiple thermophysiology and evolutionary biology models currently estimated in humans either with empirical prediction equations or costly whole-body laser imaging systems. The introduction of low-cost 3D scanners provides a new opportunity to quantify total body (TB) and regional SA, although a critical question prevails: can these devices acquire the quality of depth information and process this initial data to form a mesh that has the fidelity needed to generate accurate SA estimates? MATERIALS AND METHODS: This question was answered by comparing SA estimates calculated using images from four commercial 3D scanners in 108 adults to corresponding estimates acquired with a whole-body laser system. This was accomplished by processing initial mesh data from all devices, including the laser system, with the same universal software adapted specifically for repairing mesh gaps, identifying landmarks, and generating SA measurements. RESULTS: TB SA measured on all four 3D scanners was highly correlated with corresponding laser system estimates (R2 s, 0.98-0.99; all p < 0.001) with some small but significant mean differences (-0.19 to 0.06 m2 ); root-mean square errors (RMSEs) were small (0.02-0.03 m2 ); and significant bias was present for one device. Qualitatively similar results (e.g., R2 s, 0.78-0.95; mean Δs, -0.05 to 0.02 m2 ; RMSEs, 0.01-0.03 m2 ) were present for trunk, arm, and leg SA comparisons. DISCUSSION: The current study observations demonstrate that low-cost and practical 3D optical scanners are capable of accurately quantifying TB and regional SA, thus opening new opportunities for evaluating human phenotypes and related physiological characteristics.

Validity of water compartments estimated using bioimpedance spectroscopy in athletes differing in hydration status.

We aimed to validate bioelectrical impedance spectroscopy (BIS), compared with tracer dilution measurements, for assessing total body water (TBW), intracellular water (ICW), and extracellular water (ECW) in athletes differing in hydration status. A total of 201 athletes participated. Reference TBW and ECW were determined by deuterium and bromide dilution methods, respectively; ICW was calculated as TBW-ECW. Water compartments were estimated by BIS. Urine specific gravity (USG) classified athletes into well-hydrated (WH) (USG < 1.023), euhydrated (EH) (USG:1.024-1.026), and dehydrated (DH) (USG>1.027). No significant differences were found between BIS and the reference methods for WH, EH, and DH athletes for TBW, ICW nor ECW (p>0.05). Concordance of TBW and its compartments by method was significant (p < 0.001) with coefficients of determination ranging by hydration classification [EH:52-96%;DH:56-98%;WH:71-96%]. Bland-Altman analyses showed no trend for TBW and its compartments with the exception of ICW in the WH athletes. The 95% confidence BIS intervals for the WH group ranged from -3.08 to 2.68 kg for TBW, -4.28 to 4.14 kg for ICW, and -3.29 to 3.02 kg for ECW. For the EH athletes, the 95% confidence intervals ranged from -2.78 to 2.24 kg for TBW, -4.10 to 3.94 kg for ICW, and -3.44 to 3.06 kg for ECW. In DH group, TBW ranged between -1.99 and 2.01 kg, ICW between -3.78 and 6.34 kg, and ECW between -6.22 and 3.74 kg. These findings show that BIS is useful at a group level in assessing water compartments in athletes differing in hydration status. However, the usefulness of BIS is limited at an individual level, especially in dehydrated athletes.

Validation of the Activity Preference Assessment: a tool for quantifying children's implicit preferences for sedentary and physical activities.

BACKGROUND: High levels of sedentary behavior and low physical activity are associated with poor health, and the cognitive determinants of these behaviors in children and adolescents are not well understood. To address this gap, we developed a novel, non-verbal, computer-based assessment to quantify the degree to which youth prefer to be sedentary relative to physically active in their leisure time. METHODS: The Activity Preference Assessment (APA) uses a forced-choice paradigm to understand implicit decision-making processes when presented with common sedentary and physical activities. The APA bias score ranges from - 100 to + 100, with positive scores indicating a relative preference for sedentary activities, and negative scores representing a preference for physical activities. In 60 children ages 8-17 years, we assessed the validity of this behavioral task against a free-choice play observation, accelerometry-measured activity, anthropometrics and body composition, and cardiorespiratory fitness. We explored neighborhood, family, and individual-level factors that may influence implicit activity preferences. Test-retest reliability was assessed over one week. RESULTS: The majority of children (67%) preferred sedentary relative to physical activities. APA bias scores were positively associated with sedentary time during free-choice play. In girls, bias scores were negatively associated with average daily MVPA. APA bias scores were positively associated with body fat and negatively associated with cardiorespiratory fitness. These findings were independent of age, sex, and race/ethnicity. Neighborhood access to physical activity spaces, the number of people in the home, perceived physical self-competence (e.g., coordination, strength), and self-reported depressive symptoms were associated with activity preferences. The intra-class correlation for test-retest reliability was r = 0.59. CONCLUSIONS: The APA shows promise as a novel tool for quantifying children's relative preference for sedentary versus physical activities. Implicit bias scores from the APA are clinically meaningful, as shown by significant associations with adiposity and cardiorespiratory fitness. Future longitudinal studies should examine the directionality of the association between preferences and health markers, and the degree to which implicit activity preferences are modifiable. Importantly, the task only takes an average of 10 min to complete, highlighting a potential role as an efficient screening tool for the propensity to be sedentary versus physically active. TRIAL REGISTRATION: ClinicalTrials.gov NCT03624582 .

Allometric models of adult regional body lengths and circumferences to height: Insights from a three-dimensional body image scanner.

OBJECTIVES: Recent reports on body regional mass scalings to height have advanced understanding differences in adult heights. These studies resulted in conjectures on how regional lengths and circumferences may scale to height. We provide evidence for these conjectures by analyzing a large sample of regional limb, trunk, chest, and head lengths and circumferences in a large sample of US Army basic training recruits. METHODS: Participants consisted of 10 271 males and 2760 females ages 17 to 21 years old who reported for basic training at Fort Jackson, SC. Participants were imaged by a three-dimensional (3D) body scanner for uniform sizing which yielded 159 body measurements of total mass, lengths and circumferences at regional sites of arms, legs, trunk, chest, and head. The allometric model, Body Measur e i = α i H ß i was applied to derive scaling exponents which were applied to estimate regional mass scalings. RESULTS: Body mass scaled to height with powers of ∼2.0 (mean ß ± SE, 1.98 ± 0.04, 1.93 ± 0.06). Arm and leg lengths scaled to exponents larger than 1.0 and head height and circumferences at regional sites scaled to exponents smaller than 1.0. The leg, arm, and trunk mass scaling exponents were all above 2.0. Head mass scaled to powers smaller than 2.0. CONCLUSIONS: The 3D scanner allowed hundreds of anthropometric measurements to be obtained within seconds. The ensuing analysis revealed that greater height yielded disproportional increases in limb lengths, limb mass and trunk mass. These analyses provide evidence that could not be previously measured that further both biomechanical and metabolic conjectures.

Exceptional Reported Effects and Data Anomalies Merit Explanation from "A randomized controlled trial of coordination exercise on cognitive function in obese adolescents" by.

We read the recent article in Psychology of Sport and Exercise by Liu et al. ("A randomized controlled trial of coordination exercise on cognitive function in obese adolescents") with great interest. Our interest in the article stemmed from the extraordinary differences in obesity-related outcomes reported in response to a rope-jumping intervention. We requested the raw data from the authors to confirm the results and, after the journal editors reinforced our request, the authors graciously provided us with their data. We share our evaluation of the original data herein, which includes concerns that weight and BMI loss by the intervention appears extraordinary in both magnitude and aspects of the distributions. We request that the authors address our findings by providing explanations of the extraordinary data or correcting any errors that may have occurred in the original report, as appropriate.

Predictive Mathematical Models of Weight Loss.

PURPOSE OF REVIEW: Validated thermodynamic energy balance models that predict weight change are ever more in use today. Delivery of model predictions using web-based applets and/or smart phones has transformed these models into viable clinical tools. Here, we provide the general framework for thermodynamic energy balance model derivation and highlight differences between thermodynamic energy balance models using four representatives. RECENT FINDINGS: Energy balance models have been used to successfully improve dietary adherence, estimate the magnitude of food waste, and predict dropout from clinical weight loss trials. They are also being used to generate hypotheses in nutrition experiments. Applications of thermodynamic energy balance weight change prediction models range from clinical applications to modify behavior to deriving epidemiological conclusions. Novel future applications involve using these models to design experiments and provide support for treatment recommendations.

Scaling of adult human bone and skeletal muscle mass to height in the US population.

OBJECTIVES: The scaling of structural components to body size is well studied in mammals, although comparable human observations in a large and diverse sample are lacking. The current study aimed to fill this gap by examining the scaling relationships between total body (TB) and regional bone and skeletal muscle (SM) mass with body size, as defined by stature, in a nationally representative sample of the US population. METHODS: Subjects were 17,126 non-Hispanic (NH) white, NH black, and Mexican American men and women, aged ≥18 years, evaluated in the National Health and Nutrition Examination Survey who had TB and regional bone mineral (BMin) and lean soft tissue (LST) mass measured by dual-energy X-ray absorptiometry. BMin and appendicular LST served as surrogate bone and SM mass measures, respectively. The allometric model, BMin or LST = α(height)ß , in a logarithmic form was used to generate scaling exponents. RESULTS: The findings were similar across all gender and race groups: body mass scaled to height with powers of ~2.0 (mean ß ± SE, 1.94 ± 0.08-2.29 ± 0.09) while TB and appendicular BMin and appendicular LST scaled to height with consistently larger powers than those for body mass (eg, all P < .05 in NH white men and women); the largest BMin and LST scaling powers to height were observed in the lower extremities. CONCLUSIONS: Bone and SM mass, notably those of the lower extremities, increase as proportions of body mass with greater adult height. Metabolic and biomechanical implications emerge from these observations, the first of their kind in a representative adult US population sample.

Adult energy requirements predicted from doubly labeled water.

BACKGROUND: Estimating energy requirements forms an integral part of developing diet and activity interventions. Current estimates often rely on a product of physical activity level (PAL) and a resting metabolic rate (RMR) prediction. PAL estimates, however, typically depend on subjective self-reported activity or a clinician's best guess. Energy-requirement models that do not depend on an input of PAL may provide an attractive alternative. METHODS: Total daily energy expenditure (TEE) measured by doubly labeled water (DLW) and a metabolic chamber from 119 subjects obtained from a database of pre-intervention measurements measured at Pennington Biomedical Research Center were used to develop a metabolic ward and free-living models that predict energy requirements. Graded models, including different combinations of input variables consisting of age, height, weight, waist circumference, body composition, and the resting metabolic rate were developed. The newly developed models were validated and compared to three independent databases. RESULTS: Sixty-four different linear and nonlinear regression models were developed. The adjusted R2 for models predicting free-living energy requirements ranged from 0.65 with covariates of age, height, and weight to 0.74 in models that included body composition and RMR. Independent validation R2 between actual and predicted TEE varied greatly across studies and between genders with higher coefficients of determination, lower bias, slopes closer to 1, and intercepts closer to zero, associated with inclusion of body composition and RMR covariates. The models were programmed into a user-friendly web-based app available at: http://www.pbrc.edu/research-and-faculty/calculators/energy-requirements/ (Video Demo for Reviewers at: https://www.youtube.com/watch?v=5UKjJeQdODQ ) CONCLUSIONS: Energy-requirement equations that do not require knowledge of activity levels and include all available input variables can provide more accurate baseline estimates. The models are clinically accessible through the web-based application.

The case of GWAS of obesity: does body weight control play by the rules?

As yet, genome-wide association studies (GWAS) have not added much to our understanding of the mechanisms of body weight control and of the etiology of obesity. This shortcoming is widely attributed to the complexity of the issues. The appeal of this explanation notwithstanding, we surmise that (i) an oversimplification of the phenotype (namely by the use of crude anthropometric traits) and (ii) a lack of sound concepts of body weight control and, thus, a lack of a clear research focus have impeded better insights most. The idea of searching for polygenetic mechanisms underlying common forms of obesity was born out of the impressive findings made for monogenetic forms of extreme obesity. In the case of common obesity, however, observational studies on normal weight and overweight subjects never provided any strong evidence for a tight internal control of body weight. In addition, empirical studies of weight changes in normal weight and overweight subjects revealed an intra-individual variance that was similar to inter-individual variance suggesting the absence of tight control of body weight. Not least, this lack of coerciveness is reflected by the present obesity epidemic. Finally, data on detailed body composition highlight that body weight is too heterogeneous a phenotype to be controlled as a single entity. In summary GWAS of obesity using crude anthropometric traits have likely been misled by popular heritability estimates that may have been inflated in the first place. To facilitate more robust and useful insights into the mechanisms of internal control of human body weight and, consequently, the genetic basis of obesity, we argue in favor of a broad discussion between scientists from the areas of integrative physiologic and of genomics. This discussion should aim at better conceived studies employing biologically more meaningful phenotypes based on in depth body composition analysis. To advance the scientific community-including the editors of our top journals-needs a re-launch of future GWAS of obesity.