OBJECTIVE:BMI alone does not capture obesity-related health heterogeneity. The Edmonton Obesity Staging System (EOSS) grades obesity severity based on comorbidities and functional impairment, whereas the Lancet Commission Diagnostic Model for Obesity (DMO) distinguishes preclinical from clinical obesity based on organ dysfunction. We compared classification patterns and concordance across both obesity frameworks in a large population-based cohort. METHODS:A modified EOSS and DMO were applied to the UK Biobank (N ≈ 411,000). Stage distributions, cross-classification, and the impact of combining BMI with fat distribution on obesity categorization were analyzed. RESULTS:About one-quarter of participants were classified with obesity under both frameworks. Most were assigned to advanced stages, with high concordance for established disease. Differences were most pronounced in early stages: DMO captured a broader spectrum of mild/subclinical organ dysfunction, whereas EOSS emphasized more advanced manifestations of obesity-related disease. Discrepancies reflected differences in operationalization of, for example, metabolic, cardiovascular, and mental health domains. Obesity thresholds influenced classification, with ~50% reclassified when BMI was combined with different fat distribution parameters, highlighting the sensitivity of early-stage assignment. CONCLUSIONS:EOSS and DMO provide complementary approaches to obesity classification, with differing classification patterns highlighting distinct concepts of obesity-related disease severity.
OBJECTIVE:Weight loss is often pursued to improve cardiometabolic health and quality of life. However, weight loss can lead to reductions in lean soft tissue mass and strength, compromising body composition and functional ability. Thus, identifying molecular predictors of muscular strength preservation during weight loss is critical to mitigating these effects. METHODS:We conducted a secondary analysis of the CALERIE trial, a 2-year randomized controlled study of caloric restriction or ad libitum intake in healthy adults without obesity. Changes in whole-body mass and knee extensor strength were assessed over the first 12 months of the study. Transcriptomic profiling was conducted in a subset who provided skeletal muscle samples. The relationship between strength change and gene expression change was modeled, controlling for whole-body mass change. RESULTS:Transcriptomics analysis on a subset of 42 individuals revealed 151 genes significantly associated with change in strength after accounting for change in whole-body mass, including HSP90AA1 and EIF3A. Pathway analyses revealed significant involvement of pathways related to cellular proliferation, immune regulation, and protein secretion. CONCLUSIONS:These findings highlight molecular pathways and genes supporting strength retention during caloric restriction-induced weight loss. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT00427194 www. CLINICALTRIALS:gov.
OBJECTIVE:Adiposity rebound (AR), the second rise in BMI during growth, increases the risk of obesity and metabolic diseases when it occurs early. We aimed to identify key factors influencing early AR (EAR) within two critical 1000-day periods and develop a predictive model. METHODS:Based on the Ma'anshan Birth Cohort (MABC), we collected serial BMI from birth through school age and applied linear mixed models to construct individual growth curves for determining AR. EAR was defined as AR timing at or below the sex-specific 25th percentile (≤ 55.46 months in boys and ≤ 60.54 months in girls) in MABC. Among the 2072 parent-offspring trios included, 65 potential factors were collected from maternal, pregnancy, paternal, and offspring sources. Ten machine learning techniques and SHAP were used to evaluate feature importance. RESULTS:Multimethod screening identified EAR determinants, including paternal and maternal pre-pregnancy overweight/obesity, pregnancy organic phosphate esters (OPE) exposures, offspring high genetic risk (the predominant contributor), catch-up BMI trajectory, and high waist circumference trajectory. The categorical boosting model demonstrated the best performance among 10 machine learning models for predicting EAR (AUCtraining = 0.764, 95% CI = 0.733-0.795; AUCtesting = 0.721, 95% CI = 0.669-0.773). CONCLUSIONS:EAR determinants may inform future interventions, including weight management, prenatal OPE exposure reduction, and early screening for genetically high-risk individuals.
OBJECTIVE:This study aimed to identify sex-specific eating behavior profiles and assess the associations between eating behaviors subscales and profiles and body composition indices in Spanish preschoolers from the CORALS cohort. METHODS:We conducted a cross-sectional analysis of baseline data from 1208 children aged 3-6 years (50.1% girls) from the CORALS cohort. Eating behaviors were assessed using the Child Eating Behavior Questionnaire (CEBQ). Sex-specific latent profile analyses were conducted separately for girls and boys. Associations of CEBQ subscales and profiles with BMI, fat mass index, fat-free mass index, and waist to height ratio (z scores) were examined using multiple linear regression models adjusted for sociodemographic variables, energy intake, playing outdoors, and sleep duration. RESULTS:Four eating behavior profiles were identified in both sexes: controlled, avid, typical, and avoidant. Food approach subscales and avid eater profile were positively associated with body composition indices, whereas food avoidance subscales and avoidant and controlled profiles showed inverse associations. Controlled eater profile showed opposite associations with fat-free mass by sex: positive associations in boys (β = 0.42, 95% CI: 0.21, 0.62) but negative in girls (β = -0.55 95% CI: -0.77, -0.32). CONCLUSIONS:Eating behavior profiles were associated with body composition indices similarly in boys and girls, with the exception of the controlled eater profile in relation to fat-free mass index, for which the association differed by sex. Combining subscale-level and profile-level approaches may improve understanding of early eating behavior patterns and their role in body composition development. TRIAL REGISTRATION:ClinicalTrials.gov NCT06317883 (observational cohort).
OBJECTIVE:This study aimed to explore patients' perspectives on GLP-1 receptor agonists (GLP-1RAs) for weight loss across the continuum of contemplating use to discontinuation, with and without achieving weight loss goals. METHODS:From June to October 2025, participants completed a 30-item survey and ~30-question semi-structured interview regarding their perceptions of GLP-1RAs for weight loss. Interviews were tailored to six GLP-1RA groups: (1) considering use; (2) < 3 months on therapy; (3) ≥ 3 months on therapy without achieving weight loss goal; (4) ≥ 3 months on therapy with achieving weight loss goal; (5) discontinued without achieving goal; and (6) discontinued after achieving goal. Qualitative coding and thematic analysis were conducted in Dedoose (9.0.107); quantitative analyses used SAS 9.4. RESULTS:A total of 185 participants consented, and 141 completed data collection (76%). Descriptive profiles suggested heterogeneity across psychosocial and behavioral domains. Groups 3 and 4 showed stronger profiles (higher perceived competence, intrinsic motivation, and self-monitoring). After false discovery rate adjustment across 78 comparisons, perceived competence was the only statistically significant differentiator: Group 1 was lower (z = -3.15; q = 0.0347) and Group 4 higher (z = 4.44; q < 0.001). CONCLUSIONS:Findings underscore the importance of tailoring behavioral support to individuals' stage of engagement in GLP-1RA-supported weight loss journeys.
OBJECTIVE:Dairy consumption plays a protective role in obesity that may be mediated through the gut microbiota. This study examined the role of dairy proteins, casein, whey, and complete dairy (skim milk powder), and a plant-based alternative, soy, on gut microbiota composition, obesity susceptibility, and insulin sensitivity in early development. METHODS:Following weaning, rat pups were randomized into four isocaloric diets (n = 8-11/sex/diet) for 4 weeks: (1) complete dairy; (2) casein; (3) whey; and (4) soy. Primary outcomes included food intake, growth, body composition, glucose tolerance, and fecal microbiota composition. Animals were then metabolically challenged with a high-fat, high-sucrose diet (HFHS, 40% kilocalories from fat) for 5 weeks. RESULTS:The impacts on gut microbiota and metabolic outcomes were sex and protein dependent. Compared to casein, complete dairy consumption reduced diversity, while early exposure to complete dairy improved body fat percentage but not glucose tolerance or insulin sensitivity. Soy elicited differential effects in males and females. Despite preserved microbial patterns, diets were unable to overcome the detrimental metabolic impacts of HFHS diet exposure. CONCLUSIONS:Results show that complete dairy positively modulates gut microbial profiles and benefits body composition early in life, but it could not curtail the negative metabolic impacts of HFHS feeding.
OBJECTIVE:Metabolic bariatric surgery, such as vertical sleeve gastrectomy (VSG), is the most effective treatment for obesity, yet the molecular mechanisms remain incompletely defined. This study aims to explore the role of hepatic flavin monooxygenase 3 (FMO3) in the metabolic improvements of VSG. METHODS:Hepatic FMO3 was assessed in liver biopsies from human patients. Diet-induced obese mice underwent VSG, targeted hepatic FMO3 inhibition with antisense oligonucleotides, or VSG with concurrent FMO3 knockdown. Outcomes included weight loss, glucose tolerance, insulin sensitivity, serum lipids, hepatic steatosis, circulating bile acid profiling, hepatic gene expression involved in the FXR pathway, and bile acid synthesis/transport. RESULTS:In mouse models, VSG suppressed hepatic FMO3 expression, leading to significant weight loss, enhanced glucose and lipid metabolism, and reduced hepatic steatosis. Inhibition of FMO3 using antisense oligonucleotides recapitulated many of these effects, while silencing FMO3 diminished VSG's metabolic benefits. Clinical data revealed elevated hepatic FMO3 expression in patients with obesity and its downregulation after VSG, correlating with metabolic improvements. Additionally, FMO3 downregulation was associated with alterations in bile acid metabolism and FXR signaling. CONCLUSIONS:Hepatic FMO3 downregulation contributes importantly to the metabolic benefits of VSG. Targeting hepatic FMO3 may offer a nonsurgical strategy to reproduce key clinical benefits of metabolic bariatric surgery.
OBJECTIVE:This study assessed the association between early pregnancy body roundness index (BRI) and adverse pregnancy outcomes in nulliparas. METHODS:In this secondary analysis of a multicenter prospective cohort study, waist circumference, height, and weight were measured between 6 and 13 6/7 weeks' gestation and used to calculate BMI and BRI (364.2-365.5 × {1 - [(waist circumference/2π)/(0.5 × height)]2}0.5). Four BRI and BMI quantiles (Q1-Q4) were defined, and rates of adverse pregnancy outcomes were compared using multivariable logistic regression. RESULTS:Among 9671 individuals, greater BRI was associated with gestational diabetes (GDM), hypertensive disorders, preterm birth, cesarean delivery, and large-for-gestational age infants. Discordant BRI and BMI assignments affected GDM and cesarean odds. Those with Q2 BMI but Q3-Q4 BRI had increased odds of GDM (aOR 2.28, 1.49-3.47) and cesarean (aOR 1.39, 1.15-1.68). Those with Q3 BMI and Q1-Q2 BRI demonstrated reduced odds for GDM (aOR 0.31, 0.15-0.63) and cesarean (aOR 0.75, 0.60-0.94). Participants with Q4 BMI and Q1-Q3 BRI experienced decreased odds for cesarean (aOR 0.55, 0.43-0.70) but similar GDM odds. CONCLUSIONS:Greater first trimester BRI, a reflection of central adiposity, is associated with adverse pregnancy outcomes. Early pregnancy BRI may improve risk stratification for GDM and cesarean delivery beyond BMI.
OBJECTIVE:This study aimed to explore personalized weight-loss targets for metabolic syndrome (MetS) reversal by introducing the BMI-normalization achievement rate (BMI-NAR), a novel baseline-BMI-scaled metric. METHODS:In a longitudinal cohort of 7340 adults with overweight/obesity and MetS from the ChinaHEART project, BMI-NAR was defined as the percentage of progress toward a normal BMI (< 24 kg/m2). Logistic regression and restricted cubic splines assessed the dose-response relationship between BMI-NAR and MetS reversal. RESULTS:Each 50% increase in BMI-NAR was significantly associated with MetS reversal (overall: OR = 1.10, 95% CI: 1.07-1.12; overweight: OR = 1.08, 95% CI: 1.06-1.11; obesity: OR = 2.36, 95% CI: 2.00-2.80). The probability of reversal increased steeply beyond exploratory minimum effective thresholds (37% BMI-NAR for overall; 53% for overweight; 22% for obesity), with benefits observed up to ~165% in the total population, beyond which data were sparse. No clear upper plateau was identified in populations with overweight and obesity. These exploratory thresholds translate into personalized weight-loss targets: a minimum reduction of 2%-8% for typical overweight (baseline BMI 25-27.99 kg/m2) and 3%-9% for obesity. CONCLUSIONS:MetS reversal does not require full BMI normalization. BMI-NAR provides a hypothesis-generating, quantifiable framework for exploring personalized minimum effective weight-loss goals in this high-risk population. However, external validation is required before clinical application.
OBJECTIVE:A global multidisciplinary consensus initiative identified eight patient-reported outcome domains important in obesity care: self-esteem; physical, mental, and social health; eating; stigma; body image; and excess skin. Several of these domains are not represented in generic preference-based measures typically used in weight loss research. We developed the BODY-Q-7 Dimensions (BODY-Q-7D) to provide a valuation-ready framework for a preference-based instrument. METHODS:Concepts from the BODY-Q were used to inform the development of items that covered the eight consensus initiative domains. Psychometric performance of the BODY-Q-7D was examined using an online international sample (i.e., Prolific). RESULTS:Content validity was established with 123 participants. The field test included 770 participants, of whom 269 completed a test-retest, and 599 completed a 3-month follow-up. Rasch Measurement Theory analysis reduced the BODY-Q-7D to 7 items. Items fit the Rasch model with ordered thresholds and structural independence. Reliability was > 0.80 across three reliability coefficients. Hypothesis-based tests of construct validity and responsiveness were supported with 22/28 (79%) and 12/16 (75%) tests accepted. CONCLUSIONS:The BODY-Q-7D demonstrated strong psychometric performance in a weight loss sample. The next phase of development is to elicit and model preference weights to assign utility values to each defined health state.
OBJECTIVE:Obesity is associated with chronic low-grade inflammation. Whether within-day organization of concurrent training influences inflammatory adaptation remains unclear. METHODS:Sixty-four young adults with obesity were randomized to continuous training (CT; high-intensity functional training immediately followed by aerobic training) or separated training (ST; the same exercise volume divided into two sessions ~6 h apart). Both groups completed an 8-week intervention. Body composition and inflammatory markers were assessed before and after training using repeated-measures ANOVA. RESULTS:Both groups showed significant reductions in body mass, BMI, body fat mass, and BF% over time (all p < 0.05). Significant time × group interactions were observed for body mass, BMI, and body fat mass, with the CT group showing greater reductions than the ST group. IL-6 was the only inflammatory marker showing a significant interaction effect (p < 0.001), decreasing in CT while remaining unchanged in ST. TNF-α decreased significantly over time in both groups, whereas IL-10 and IL-1β showed no significant interaction effects. CONCLUSIONS:Within-day continuity of concurrent training reduced fat mass more than temporally separated training in young adults with obesity. An exploratory association with reduced IL-6 was observed but requires confirmation. Trial RegistrationChinese Clinical Trial Registry identifier: ChiCTR2500108145.
OBJECTIVE:Fibroblast growth factor 21 (FGF21) is a stress-induced hormone secreted by the liver. It has a beneficial role in the regulation of glucose and energy metabolism. Herein, we identify apoptosis signal regulating kinase 1 (ASK1) as an inducer of hepatic FGF21 synthesis. METHODS:Glucose and energy metabolism were assessed in liver-specific ASK1 overexpressing (ASK1+hep) and control littermate (ASK1f/f) mice fed a regular chow or high fat diet (HFD) for 20 weeks. Liver and fat depots were analyzed using RNA sequencing. Hepatic Fgf21 expression was downregulated using adeno-associated virus (AAV) expressing short-hairpin RNA sequences. ASK1 and FGF21 expression was determined in human liver samples. RESULTS:HFD-fed ASK1+hep mice exhibited improved glucose metabolism, elevated energy expenditure, and reduced body weight. FGF21 plasma levels were increased in HFD-fed ASK1+hep mice, and its reduction in vivo blunted beneficial effects on obesity. Mechanistically, ASK1 promoted hepatic Fgf21 gene expression via the transcription factor ATF4. In humans, hepatic ASK1 expression correlated positively with FGF21 and negatively with BMI and visceral fat area. CONCLUSIONS:We describe a novel role of hepatic ASK1 in the synthesis of FGF21. Hence, increasing hepatic ASK1 expression might be a novel strategy to combat obesity-associated metabolic complications.
OBJECTIVE:Increasing evidence links ultra-processed food (UPF) intake to obesity and related diseases; however, little is known about the role of UPF in behavioral weight-loss interventions (BWLIs). Thus, the current study investigated whether UPF intake changes during a BWLI and whether these changes are associated with weight-loss outcomes. METHODS:A total of 449 adults with obesity (mean ± SD age = 49.5 ± 11.4 years, BMI = 35.7 ± 4.0 kg/m2, 83.5% female, 23.4% Black/African American, 9.8% Hispanic) completed a 16-week BWLI. Using dietary intake data collected via the Automated Self-Administered 24-Hour Dietary Assessment Tool (ASA24), we examined (1) changes in caloric intake and the proportion of calories from UPFs from baseline to post-intervention and (2) associations between these changes and weight loss, overall and adjusting for caloric intake. RESULTS:Participants demonstrated reductions in calorie intake (-461 ± 931 kcal/day), UPF intake (-3.0% ± 2.8% of total energy), and body weight (-7.2 ± 7.6 kg) over the BWLI, ps < 0.001. Greater reductions in UPFs were associated with greater decreases in caloric intake (r = 0.10) and greater weight loss (r = 0.08, ps < 0.001), even after adjusting for changes in caloric intake (p = 0.005); however, effect sizes were small. CONCLUSION:UPF intake decreased during the BWLI, and greater reductions were associated with greater weight loss, independent of caloric changes, though small effect sizes warrant cautious interpretation. Future research should examine whether targeting UPF reduction in a BWLI enhances weight outcomes. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT04116853.
