Obesity

Current recommendations suggest that women achieve a healthy weight before becoming pregnant, but evidence supporting the benefits of preconception weight loss are limited and inconsistent, with some evidence of risks. The Maternal Preconception Weight Trajectory (MatTrack) study will evaluate the impact of preconception weight change on maternal, pregnancy, and child outcomes. In this paper, we present methods used to construct the cohort and evaluate baseline characteristics. The MatTrack cohort was derived from electronic health record data from four Kaiser Permanente regions. Inclusion criteria addressed data quality, availability, and enrollment; maternal age ([≥]18 years); and date (pregnancy onset date in 2006-2020, delivery [≤]12/31/2020). Starting body mass index (BMI) was calculated using weight closest to 24 months prior to pregnancy onset date and adult height. Preconception weight change rates from 24 months prior to and through pregnancy onset date were estimated using linear mixed effects models. Descriptive analyses characterized the baseline characteristics of the cohort. The cohort includes 297,592 pregnancies with the full spectrum of starting BMI: underweight (2.3%), normal weight (41.8%), overweight (28.4%); and obesity class I (15.3%), II (7.4%), and III (5.0%). The cohort is demographically diverse, with 8.3% covered by Medicaid; and 44.5%, 9.2%, and 10.9% Hispanic, non-Hispanic Black, or non-Hispanic Asian, respectively. Preconception weight change rates (kg/year) span weight loss to gain, with the greatest loss in those with obesity class III [median (10th, 90th percentile): -0.8 (-9.5, 4.9)] and the greatest gain in those with underweight [median (10th, 90th percentile): 1.1 (-0.7, 3.6)]. Longitudinal data from this cohort of nearly 300,000 linked maternal-child dyads will enable examination of associations between preconception weight loss and pregnancy, maternal, and child health outcomes. Findings will strengthen the evidence base for preconception weight management guidelines.

Background Lifestyle interventions are central to obesity prevention and management, yet interindividual variability in response remains incompletely understood. Here, we leveraged genetically defined, distinct obesity endotypes to examine lifestyle-body mass index (BMI) associations across biological pathways. Methods In the UK Biobank, we analyzed 305,713 participants with partitioned polygenic scores (pPSs) representing 10 obesity endotypes. We evaluated interactions between endotype-specific genetic susceptibility and physical activity, diet, sedentary behavior, and sleep on BMI using multivariable linear regression. Primary findings were externally evaluated in the All of Us Research Program using Fitbit-derived lifestyle measures. Results Favorable lifestyle behaviors were associated with lower BMI for all obesity endotypes, but the magnitude of these associations varied significantly across endotypes. Higher endotype-specific pPSs strengthened the benefits of physical activity (7 endotypes), healthy diet (3 endotypes), nonsedentary behavior (5 endotypes), and adequate sleep (7 endotypes) on BMI. Distinct endotypes demonstrated the greatest responsiveness to different lifestyle domains, with the metabolically unhealthy endotype showing the strongest interaction with physical activity, metabolically healthy endotype with sedentary behavior, hypothalamic dysregulation endotype with diet, and hypoinsulin 2 endotype with sleep, corresponding to differences in BMI of 0.22-0.49 kg/m2 between the highest and lowest pPS deciles. These interaction patterns were consistent in the All of Us cohort. Conclusions Obesity endotypes modify the association between lifestyle behaviors and BMI, demonstrating that responsiveness to lifestyle behaviors is heterogeneous and pathway dependent. These findings provide a framework for precision obesity prevention by identifying individuals who may derive greater benefit from specific lifestyle interventions.

Body mass index (BMI) alone may underestimate clinically relevant obesity because it does not capture central fat distribution. We compared obesity prevalence in Mexico using BMI-only criteria, adiposity-confirmed criteria, and the clinical obesity definition proposed by the Lancet Diabetes and Endocrinology Commission. We conducted a population-based, cross-sectional study of 13,160 adults aged 18 years or older who participated in the 2018-2019 Mexican National Health and Nutrition Survey (ENSANUT). Obesity prevalence was estimated through survey-weighted analyses that accounted for the complex sampling design. The weighted prevalence of obesity based on BMI was 34.5% (95% CI, 33.1-35.9), while 30.9% (95% CI, 29.6-32.2) met criteria for clinical obesity. One quarter of individuals with clinical obesity had a BMI under 30 kg/m2, a phenotype more common among older adults. Half of adults with a BMI under 30 kg/m2 showed elevated central adiposity. BMI alone underestimates clinically relevant obesity in Mexican adults. Adding waist-based measurements could improve the identification of individuals with excess fat and metabolic risk, both in clinical settings and population monitoring.

Background: Poor prenatal sleep health is associated with greater gestational weight gain, but the contributions to longer-term maternal weight retention remain unclear. Purpose: To examine associations between prenatal sleep health across multiple domains and maternal weight retention 2 to 7 years after a first birth. Methods: Participants were from the nuMoM2b-Heart Health Study. Self-reported sleep was assessed during early (6 to 13 6/7 weeks) and mid-pregnancy (22 to 28 6/7 weeks) across six domains: regularity, quality, sleepiness, timing, efficiency, and duration. A multidimensional sleep health (MSH) score reflected the number of domains meeting healthy thresholds. Outcomes included maternal weight retention, total and substantial (>11 lbs.), from pre-pregnancy to 2 to 7 years after a first birth. Associations were estimated using adjusted linear regression for total weight retention and Poisson regression with robust variance for substantial weight retention. Results: The sample included 3,661 individuals with data in early (n = 2,962) and mid-pregnancy (n = 3,210). In early pregnancy, healthy sleep duration was associated with lower total weight retention, whereas healthy sleep regularity was unexpectedly associated with greater retention. In contrast, during mid-pregnancy, a higher MSH score was associated with a lower risk of substantial weight retention (RR = 0.96, 95% CI: 0.93 to 0.99). Healthy sleep duration and quality were the two individual domains associated with lower weight retention (2 to 3 lbs.). Conclusions: In a prospective cohort of pregnant nulliparous individuals, healthy prenatal sleep, particularly during mid-pregnancy, was associated with less maternal weight retention 2 to 7 years after delivery. Future studies should estimate the causal effects of sleep health on long-term maternal weight retention.

Background Glucagon-like peptide-1 receptor agonists (GLP1 RAs) are first-line pharmacotherapy for obesity and metabolic dysfunction-associated steatotic liver disease (MASLD); however, 20% to 35% of patients fail to achieve clinically meaningful weight loss despite guideline-directed therapy. Whether this GLP1 refractory obesity (GRO) phenotype is associated with distinct hepatic molecular abnormalities or influences bariatric surgical outcomes remains unknown. Objectives To characterize the hepatic histological, ultrastructural, and molecular phenotype of GRO at bariatric surgery, determine its recovery following surgery, and identify preoperative hepatic biomarkers associated with postoperative weight loss. Setting Academic tertiary referral bariatric surgery center. Methods Intraoperative liver biopsies were obtained from lean controls (n=3), GLP1 naive obese patients (GNO; n=10), and GLP1-refractory obese patients (GRO; n=10) undergoing Roux-en-Y gastric bypass. GRO was defined as <5% total weight loss after 12 months of guideline-directed GLP1 RA therapy. Paired liver biopsies were obtained six months postoperatively from subsets of GNO (n=5) and GRO (n=5). Histological, ultrastructural, and molecular analyses were performed, and preoperative hepatic protein expression was correlated with postoperative total weight loss. Results Compared with GNO, GRO patients exhibited more advanced hepatic steatosis, fibrosis, lipid accumulation, and mitochondrial ultrastructural disruption at surgery (all P<0.05). Despite equivalent Body mass index, GNO patients maintained lean-equivalent hepatic pCREB, pAMPK, pACC, and oxidative phosphorylation (OXPHOS) protein expression, whereas GRO patients demonstrated marked suppression of GLP1R downstream signaling (75 to 85%) and OXPHOS complex subunits (38 to 55%; all P<0.001). Six months after surgery, histological and molecular recovery remained significantly attenuated in GRO. GRO patients achieved less postoperative weight loss than GNO patients (25.2% vs. 29.51% total weight loss; P<0.001). Across the pooled cohort, several hepatic molecular markers correlated with postoperative weight loss; however, no individual biomarker independently predicted postoperative weight loss within the GRO subgroup. Conclusions GLP1 refractory obesity is associated with a distinct hepatic phenotype characterized by impaired GLP1R signaling, mitochondrial dysfunction, and attenuated hepatic recovery following bariatric surgery. The coordinated suppression of hepatic energy-sensing, mitochondrial biogenesis, and oxidative phosphorylation pathways supports the concept that GLP1 refractory obesity represents a biologically distinct metabolic phenotype. Larger prospective studies are required to determine the prognostic utility of hepatic molecular profiling for postoperative outcomes. Keywords: GLP1 receptor agonist refractoriness; bariatric surgery; hepatic steatosis; MASLD; AMPK; pCREB; mitochondrial dysfunction; OXPHOS; weight loss outcomes; biomarker

Objective: To examine changes in the neural valuation of high- versus low-calorie stimuli following bariatric surgery and determine whether these changes relate to weight loss at 24 months. Methods: Adults undergoing bariatric surgery completed fMRI scans before surgery and at 4, 12 and 24 months post-surgery while performing the Becker-DeGroot-Marschak auction task to assess willingness-to-pay (WTP) for food stimuli. Linear mixed-effect models tested longitudinal changes in WTP-related blood oxygen level-dependent (BOLD) associations and their interactions with total weight loss at 24 months. Results: WTP for high-calorie foods decreased significantly after surgery, whereas valuation of low-calorie foods remained stable. At 4 months, WTP-BOLD associations for high- versus low-calorie stimuli were enhanced within the frontoparietal control network and right lateral orbitofrontal cortex relative to pre-surgery. These early postoperative changes did not correlate with 24-month weight loss. Instead, greater 24-month weight loss correlated with both pre-surgical and long-term changes (24 months versus pre-surgery) in WTP-BOLD associations within the precuneus, inferior parietal cortex and visual cortex. Conclusion: Bariatric surgery induces early reductions in the valuation of high-calorie foods, potentially through enhanced cognitive control and aversive processing. However, long-term weight-loss success appears more strongly related to trait-like neural differences in self-referential and attentional processing.

Obesity is a growing public health challenge, with body mass index (BMI) influenced by both genetic and environmental factors. While the role of direct genetic transmission is well established, evidence for genetic nurture effects, in which parental genotypes impact offspring through the environment, has remained mixed. This study investigates direct genetic transmission and genetic nurture effects on BMI across ages, using parent-offspring trios and pairs from the Dutch Lifelines cohort study (N = 18,897 offspring, aged 8 to 67 years). We leveraged the latest multi-ancestry BMI polygenic score (PGS) to construct transmitted (PGS-T) and non-transmitted (PGS-NT) polygenic scores, where PGS-NT consists of parental alleles not passed on to offspring and serves as a proxy for genetic nurture. Linear mixed models showed a large effect of PGS-T on offspring BMI (Beta = 0.416, p < 0.001), corresponding to a 1.85 kg/m2 increase per SD increase in PGS-T. PGS-NT had a small but significant effect (Beta = 0.026, p = 0.013), consistent with a genetic nurture effect accounting for approximately 6.6% of the effect of direct transmission. Parent-of-origin analyses showed that maternal PGS-NT effects were larger than paternal effects. PGS-T interactions with age indicated that direct transmission effects increased in childhood and stabilized in adulthood, while PGS-NT effects remained stable across age. Our findings suggest that direct genetic transmission is the dominant influence on BMI, while results are consistent with small genetic nurture effects that are driven by the maternal side.

Importance: Evidence on GLP-1/GIP therapies is largely derived from trials enrolling selected populations or medical records that miss utilization outside healthcare channels. No nationally representative cohort has characterized real-world uptake, indications, and access. Objective: To characterize GLP-1/GIP prevalence, indication, clinical profile, and access. Design: Prospective cohort study with three GLP-1/GIP surveillance waves (March 2024, December 2024, October 2025). Setting: The Understanding America Study, an address-based, nationally representative panel of approximately 15,000 US adults aged 18+ years initiated in 2014. Participants: UAS participants responding to at least one surveillance wave (n=9150). Exposures: GLP-1/GIP use status (never vs any use, comprising current and former use), self-reported primary indication (diabetes, weight loss, or other), and access pathway (traditional vs non-traditional). Main Outcomes and Measures: Survey-weighted prevalence of GLP-1/GIP use, overall and by indication and access pathway; sociodemographic, cardiometabolic, treatment, and access characteristics; and smartwatch-derived resting heart rate, heart rate variability, maximum activity heart rate, step count, and sleep duration and variability. Results: Among n=9150 adults (1274 with any use; 60.9% female; median age 53 years), weighted prevalence increased 46%, from 8.2% (March 2024) to 12.0% (October 2025) representing 32 million. Weight-loss indications grew, reaching nearly half of use (4.1% to 5.6%); diabetes-indicated use was stable (5.3% to 5.4%). Users carried high cardiometabolic burden (obesity, 68.2%; diabetes, 53.6%) but diverged by indication: diabetes-indicated users were older (median, 59 vs 49 years), whereas weight-loss-indicated users were more often female (69.9% vs 51.3%) and healthier. One in three users (~9 million) had non-traditional access, especially in weight-loss-indicated users, of whom 33% had no conventional prescription; 41% used compounding, online, or foreign pharmacies; and, 43% lacked coverage. Non-traditional users were five times as likely to report an unlisted, likely compounded formulation (19.8% vs 4.1%). All p<0.05. Conclusions and Relevance: Real-world GLP-1/GIP use has grown rapidly and diversified substantially in indication, access, and population profile. One in 3 users obtained treatment through nontraditional channels largely invisible to claims data, raising long-term safety, efficacy, and coverage questions. GLIMMER provides a public, nationally representative longitudinal evidence base for future payer and provider decisions.

Background: Cardiometabolic health typically declines with age and is worse among individuals living with obesity. Weight loss medications have modified the potential for weight loss across the life course, but it remains unclear whether weight reduction in later midlife contributes to improved cardiometabolic health, or if continuing to gain weight may continue to worsen cardiometabolic health. Methods: Using the nationally representative 1958 National Child Development Study (NCDS), a British birth cohort, associations were examined using lagged linear regression between weight change between ages 50-55 and health outcomes at age 62 (n=6,309 high-density lipoprotein (HDLc) and low-density lipoprotein (LDLc) cholesterol, systolic and diastolic blood pressure (SBP and DBP), heart rate, triglycerides, C-reactive protein (CRP), and glycated haemoglobin (HbA1c). Models accounted for prior biomarker levels at age 44. We also explored impacts of weight change on subsequent body composition. Results: Those who gained weight into or within obesity had less favourable cardiometabolic profiles and experienced faster deterioration of cardiometabolic markers between the ages of 44 and 62 than those remaining in healthy weight (e.g. SBP: 5.726, 95% CI: 2.660 to 8.793, p < 0.001; CRP: 0.802, 95% CI: 0.409 to 1.196, p < 0.001). Those who lost weight from obesity had similar rates of cardiometabolic biomarker deterioration to the healthy weight group (SBP: 0.947, 95%CI: -6.605 to 8.499, p=0.806; CRP: 0.140, 95% CI: -0.774 to 1.055, p= 0.764). Conclusion: Weight change in midlife tends towards increasing obesity and associated adverse cardiometabolic risk. Those who lose weight experienced improved cardiometabolic profiles. By viewing midlife as a modifiable stage of the life course, this study highlights opportunities to promote cardiometabolic health, and limit the speed of health decline.

Introduction: Research has documented that obesity and morbidity are associated. Black persons in the United States (U.S.) incur higher financial costs of obesity-related multimorbidity (ORM). However, lifetime healthcare costs (LHCs) remain underexamined for these populations. Objective: We quantified racial differences in 1) LHCs and 2) lifetime healthcare cost differential (LCD) associated with ORM for ages > 40 years. Methods: We used the 2008- 2012 Medical Expenditure Panel Survey Household Component to examine unique obesity-related diseases (ORDs): high blood sugar, hypertension, coronary heart disease, and stroke. We used a prior published Markov model to simulate a person's life history of ORDs and compute LHCs among ages > 40 years. We computed LCD-associated ORM as the difference in LHC for those with ORM and LHC for members without ORDs. We quantified differences in race as the difference between LHC or LCD among White and Black men and women. Results: Our analytic sample included 53,035 Black and White persons representing 97,229,611 (S.E., 2,104,365), 12.4% as Black and 87.6% as White persons. ORM was more prevalent in the Black (21.2%) than the White group (13.4%). LHCs by race (Black/White) for women/men with ORM and LCDs associated with ORM (2012$) were $3 1,035/43,595 and $11,350/26,948 for age 40-49, $2 1,567/25,6 115 and $3,846/9,808 for 50-59, $9,863/18,515 and -$2,566/7,426 for 60-69, -$8,220/16,285 and -$11,524/3,865 for 70-79. Conclusions: Racial Differences in LHCs and LCDs related to ORM persist and vary across subpopulations. Future interventions designed to prevent/manage ORM are crucial for prioritizing populations with high LHCs and advancing health equity.

Paternal obesity increases metabolic risk in offspring, but whether this risk can be reduced by restoring paternal health before conception remains unresolved. We developed a within-sire induction-and-reversal model in outbred CD1 mice in which high-fat diet (HFD)-exposed males generated offspring before and after transition to an ingredient-matched control diet with voluntary exercise. HFD caused obesity, glucose intolerance, insulin resistance, and extensive remodeling of sperm mRNA, lncRNA, and sncRNA profiles, together with transcriptomic changes in metabolic tissues. Diet and exercise reversal normalized paternal metabolic indices and broadly restored tissue RNA profiles, although sperm retained a limited transcriptional memory of prior HFD exposure. Offspring sired before reversal developed sex-dependent metabolic dysfunction despite control-diet rearing, whereas offspring sired after reversal showed substantial improvement. These findings show that paternal metabolic risk is modifiable before conception and that this reversibility is linked to remodeling of sperm RNA. (140 words) HighlightsO_LIPaternal HFD-Ex induces obesity, glucose intolerance and insulin resistance in CD1 males C_LIO_LISperm shows much stronger RNA response than four metabolic organs profiled C_LIO_LIDiet and exercise reversal restores metabolism and RNA profiles in sperm and four metabolic organs analyzed C_LIO_LIOffspring metabolic risk is reduced when sires conceive after reversal through diet and exercise intervention C_LI eTOC BlurbChen, Magalhaes, et al. show that paternal metabolic recovery before conception remodels sperm RNA and reduces transmission of HFD-associated metabolic risk to offspring in a within-sire mouse model.

Background: Self reported height and weight are prone to misreporting, which can bias BMI estimates. This study identifies misreporting determinants, develops calibration equations and examines how measured, self-reported, and calibrated BMI affect estimates of obesity prevalence and socioeconomic inequalities. Methods: We analysed survey-weighted, sex stratified data from 3,404 adults (18-64 years) in the Portuguese National Food, Nutrition and Physical Activity Survey (IAN-AF 2015-2016), including self reported and measured anthropometry. Misreporting determinants were assessed using multinomial logistic regression. Calibration equations for height and weight were estimated using measured values, self-reports, age, region of residence and education level. Calibrated BMI was derived from predicted values. Obesity prevalence was estimated for each BMI assessment method (30 kg/m^2). Education, income and employment inequalities in obesity were compared across BMI methods using prevalence difference and ratio, slope index and relative indexes of inequality. Results: Height is systematically overreported and weight underreported, with misreporting increasing with age and BMI. Calibration eliminates underestimation of obesity prevalence from self-reported BMI, bringing calibrated estimates close to measured values. Regarding education-related inequalities in obesity, calibration widen disparities among women, whereas among men corrects the overestimation observed from self-reported BMI. Income and employment-inequality patterns are similar across BMI methods. Conclusions: Among Portuguese adults, the systematic and socially patterned misreport of self-reported anthropometry affects obesity prevalence and inequality estimates. Calibration based on simple sociodemographic models improves validity and equity of obesity surveillance and could be routinely integrated into national surveys to strengthen monitoring of obesity and its socioeconomic distribution.

Background: The retail food environment is a widely used exposure in behavioural-nutrition and obesity research, on the premise that nearby food retailers shape diet and obesity risk. Over the past quarter-century, grocery stores have declined across rural and small-town America while limited-assortment discount ("dollar") stores have proliferated. Standard food-environment indices classify retailers as healthy or less-healthy but typically exclude dollar stores, now the fastest-growing food-retail format. As a result, a single classification decision may alter how the food environment is measured and the conclusions drawn from it. We develop a dollar-aware index, quantify how counting dollar stores changes the measured exposure, and derive a longitudinal trajectory typology. Methods: Using establishment-level data from Data Axle for all 878 Mississippi census tracts (1997-2024), we classified food retailers into five mutually exclusive categories using a previously validated approach and calculated the modified Retail Food Environment Index (mRFEI) in both its standard and dollar-aware forms, with the latter counting dollar stores as less-healthy outlets. We fitted Nagin-style group-based trajectory models to the tract-level dollar-aware index, related class membership to the Social Vulnerability Index (SVI) and urbanicity with multinomial regression, and characterised spatial clustering (Getis-Ord Gi*, join-counts) and grocery access. Results: Grocery stores fell from 1,616 to 716 while dollar stores rose from 315 to 1,005, intersecting in 2018. Counting dollar stores lowered the index by a margin that widened over time, and a growing number of tracts had only dollar-store retail, undefined under the standard index. Six trajectory classes emerged: stable adequate (5.6% of tracts), steady decline (13.1%), early collapse (11.1%), late collapse (6.7%), persistently constrained (34.1%) and chronic desert (29.3%); only the stable-adequate class (5.2% of children) stayed adequate throughout. Constrained and steady-decline membership rose steeply with vulnerability (RRR 11.7 and 9.9); chronic desert was urban (RRR 5.2, a food-swamp pattern); collapse classes had no cross-sectional social signature. Conclusions: In the US state with the highest adult obesity prevalence, a single retailer-classification decision substantially changes the measured food environment. The dollar-aware index and trajectory typology offer a transferable, time-varying exposure for behavioural-nutrition and obesity research and establish a foundation for future childhood-obesity studies.

Objective Women with a history of Pelvic Inflammatory Disease (PID) face elevated risks of health complications and mortality. This study examined the association between cardiovascular health (CVH) and PID among U.S. women. Methods We conducted a cross-sectional analysis of NHANES 2013-2023 (n=6,382). The LE8 scores were categorized into four groups based on quartiles: Q1 (<25), Q2 (25-49), Q3 (50-74) and Q4 ([&ge;]75). We calculated adjusted ORs (95% CIs) via logistic regression to evaluate LE8-PID associations. Results Compared to the highest LE8 quartile ([&ge;]75), adjusted ORs for PID were 1.66 (95%CI:1.03-2.67) for Q3, 1.71(1.10-2.67) for Q2, and 1.99(1.13-3.50) for Q1. The inverse association was consistent across health behavior and health factor components, with sleep, smoking, blood pressure, and BMI showing the strongest effects, particularly among younger women. Conclusions Higher LE8 scores are inversely associated with PID prevalence, particularly in younger women. Promoting cardiovascular health may help reduce PID burden.

The GLP-1-based obesity drug semaglutide lowers bodyweight primarily by increasing satiation and satiety, whilst also reducing food reward and commonly causing nausea. The brainstem dorsal vagal complex (DVC) has been identified as a key site of action for these phenotypic components of semaglutides anorectic effect. However, which GLP-1 receptor (GLP-1R) populations within the DVC are recruited to mediate these phenotypic components, and whether they are dissociable, are translationally important but unresolved questions. We addressed these using metabolic and behavioural phenotyping, combined with activity-dependent genetic labelling ( Sema-TRAP) and chemogenetic manipulation of semaglutide-recruited brainstem circuits. Semaglutide potentiated satiation and satiety, caused behavioural proxies of nausea, and suppressed motivation for Western diet, in a largely sex-independent manner. It activated a substantial proportion of GLP-1R-expressing neurons in the brainstem area postrema (AP), but surprisingly most semaglutide-activated neurons in the nucleus tractus solitarius (NTS) did not express GLP-1R. Chemogenetic reactivation of Sema-TRAP neurons in the NTS alone was sufficient to recapitulate the acute effects of semaglutide on satiation, nausea, food reward, and bodyweight. Knockdown of GLP-1R expression in the AP before Sema-TRAPing abolished the recruitment of Sema-TRAPNTS neurons which elicited all these effects, while leaving the effects of semaglutide on satiety and bodyweight intact. These data demonstrate that semaglutide recruits dissociable anorectic circuits to suppress eating via distinct behavioural mechanisms, with non-GLP-1R NTS neurons downstream of GLP-1RAP representing potential therapeutic targets to tune GLP-1-based obesity drugs towards a better-tolerated effect profile.

The analysis uses a global 2010-2023 panel comprising 3,038 economy-years across 217 economies. It explicitly separates between-economy and within-economy estimands and tests the longitudinal interpretation using an identical-sample temporal analysis with cluster-aware coefficient contrasts, a formal isometric log-ratio sensitivity analysis, independent fixed-effects replication, and wild-cluster-bootstrap inference. The central finding is deliberately calibrated: cross-economy agreement cannot validate national sugar availability for longitudinal obesity surveillance. The study identifies temporal and construct instability without claiming that sugar is protective or that the mechanisms producing the instability have been identified. The manuscript aligns well with PLOS ONEs emphasis on technically sound, transparent and reproducible research of broad relevance. All data required to reproduce the findings, complete metadata, executable code, full-precision results, diagnostic outputs and a completed STROBE checklist are provided as S1-S5. Figures are provided separately as compliant 350-dpi TIFF files. The study used only publicly available, aggregated economy-year statistics and involved no individual participants, identifiable information or biological specimens; institutional ethics review and consent were therefore not required. This is original work; it is not under consideration elsewhere, and the sole author has approved the submission and accepts responsibility for its content. Funding and competing-interest declarations will be entered accurately in the submission portal. An Academic Editor with expertise in nutritional epidemiology, global health metrics, longitudinal panel methods, or food-system surveillance would be well placed to assess the work.

Abstract Background The gut microbiome has been widely studied in the context of obesity, and yet the reported associations vary widely across populations and analytical approaches. In Asian populations where the prevalence of obesity is rapidly rising, the extent to which gut microbiome features could associate with adiposity in a robust and generalizable manner remains unclear. Methods Population-scale shotgun metagenomic data was generated for adults (n=871) from the Health for Life in Singapore (HELIOS) cohort, comprising ethnic Chinese, Malay, and Indian participants. Integrated taxonomic, functional, and machine-learning-based analyses were used to assess associations between gut microbiome features and obesity, adjusting for demographic covariates and evaluating for robustness across multiple statistical frameworks. Results Global microbiome structure exhibited weak separation by body mass index (BMI), with enterotype-like clustering providing limited discriminatory power for obesity status. Differential abundance analyses identified a small number of method-dependent taxa and pathways, with only limited recurrence across methods. Supervised machine learning models trained on taxonomic profiles achieved modest predictive performance, particularly for intermediate BMI classes, and did not reveal robust microbial signatures beyond those detected by univariate analyses. Conclusions Our study highlights the importance of large-scale, multi-framework analyses for distinguishing robust microbiome-phenotype associations from weak, method-dependent signals. Together, our findings emphasize that obesity-associated microbiome signatures may be too weak, diffuse, and insufficient to explain adiposity in Asian populations.

Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely prescribed for type 2 diabetes and obesity, yet their neuropsychiatric safety profile remains incompletely characterized. We aimed to systematically evaluate neuro-adverse event (AE) signals for six GLP-1RAs and to validate key findings using population-based data. Methods We conducted disproportionality analysis of FAERS data for semaglutide, liraglutide, dulaglutide, tirzepatide, exenatide, and lixisenatide. RORs were calculated for 93 predefined neuro-AE MedDRA PTs across 11 neurological categories. External validation used NHANES 2013-2018 (n=17,057; 70 GLP-1RA users) with survey-weighted regression. Results We identified 41 significant neuro-AE signals. Semaglutide showed the strongest neuromuscular signal, muscle atrophy (ROR 3.94; 95%CI 3.42-4.54), corroborated by tirzepatide (ROR 2.35; 95%CI 2.04-2.71). Exenatide generated the highest psychiatric signal: nervousness (ROR 4.03; 95%CI 3.70-4.40). NHANES confirmed higher depression odds (OR 2.05; 95%CI 1.32-3.19; P=0.001) and reduced sleep hours (beta -0.35; P=0.033). Conclusions GLP-1RAs carry multiple neuropsychiatric safety signals, including muscle atrophy as a potential class effect and depression risk corroborated by population-level data. These findings support heightened clinical monitoring.

Angiotensinogen (AGT) deletion in hepatocytes reduces Western diet-induced adiposity and hepatic steatosis in mice maintained under conventional room-temperature (RT) housing. Given the high metabolic activity of mice, this temperature imposes adaptive metabolic responses in this species. Whether this metabolic protection persists independent of increased thermogenic demand remains unclear. In this study, we first determined whether thermoneutral housing (TN, 30 {degrees}C) alters Western diet-induced metabolic phenotypes compared with RT housing (20 {degrees}C) in wild-type mice. Although body weight did not differ significantly between housing conditions, Western diet-fed mice housed at TN exhibited brown adipose tissue whitening and more pronounced hepatic steatosis than mice housed at RT, confirming that thermoneutrality exacerbated diet-induced metabolic dysfunction. We then housed hepatocyte Agt deficient (hepAGT-/-) mice and wild-type (hepAGT+/+) littermates at TN and fed them Western diet for 12 weeks. Despite enhanced metabolic dysfunction under TN, hepatocyte AGT deletion resulted in reductions in diet-induced body weight gain, fat mass, liver weight, and hepatic triglyceride accumulation. Bulk RNA sequencing of liver revealed hepatocyte AGT deficiency-dependent alterations in lipid-metabolic pathways. Cross-temperature analysis of RT and TN housing identified 35 shared differentially expressed genes, including 27 concordantly downregulated genes enriched in lipid metabolism and transport. Extended Western diet feeding for 24 weeks confirmed sustained reductions in body weight gain, liver weight, and hepatic lipid accumulation in hepAGT-/- mice. These findings demonstrate that hepatocyte AGT deletion provides sustained protection against Western diet-induced metabolic dysfunction under thermoneutral housing, a condition that more closely recapitulates human basal metabolism. NEW & NOTEWORTHYThis study investigated hepatocyte angiotensinogen (AGT) biology during Western diet feeding in mice under thermoneutral housing, a condition relevant to human metabolism. By minimizing adaptive thermogenesis induced by standard room temperature housing, thermoneutrality more closely recapitulates human basal metabolic conditions. Under this condition, hepatocyte AGT deletion remains protective against adipo and hepatic lipid accumulation, despite exacerbated Western diet-induced metabolic dysfunction in wild-type mice, demonstrating that this protection persists in a human-relevant thermal environment. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/742617v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1ac7094org.highwire.dtl.DTLVardef@131cfforg.highwire.dtl.DTLVardef@d4dba6org.highwire.dtl.DTLVardef@a09acc_HPS_FORMAT_FIGEXP M_FIG C_FIG

Resolving the inner conflict between improving eating habits (change talk) and sticking to unhealthy ones (sustain talk) is a key target in communication-based behavioral change interventions such as motivational interviewing (MI). Recent work has shown that this inner conflict affects how tastiness and healthiness are traded off in dietary decision-making. The effect varied with body mass index (BMI). Here we aimed to identify why participants with higher BMI shifted toward healthier food choices after listening to change talk. An evidence accumulation model found that BMI affected health evidence sampling when listening to change talk, and taste evidence sampling when listening to sustain talk. A serial mediation analysis showed that the effect of BMI on change-talk-induced health evidence sampling was explained by stronger resting-state connectivity in the ventromedial prefrontal cortex within the default mode network (DMN), which in turn predicted greater motivation to change eating habits. These cross-sectional findings indicate that the intrinsic functional organization of valuation-related regions within the DMN is associated with motivation to change. They provide evidence that these neural and behavioral factors need to align with contextual cues, such as weight status (as reflected by BMI), and with reasons for behavioral change to promote healthier decision-making.