OBJECTIVE:Obesity contributes substantially to cardiometabolic and overall morbidity and mortality, yet remains underdiagnosed in clinical practice. We aimed to assess discharge documentation rates of obesity among hospitalized patients with elevated body mass index (BMI) and compare these with coding rates of other cardiometabolic risk factors. METHODS:We conducted a cross-sectional analysis of adults hospitalized between 2013 and 2023 with BMI ≥ 30 kg/m² and no prior coded obesity or bariatric surgery. Obesity and metabolic comorbidities were identified via ICD-9 codes. RESULTS:Among 42,243 eligible adults (mean age 60.9 ± 16.9 years; 49.7% women; mean BMI 33.9 ± 3.9 kg/m²), only 10.6% had obesity documented at discharge. The likelihood of coding increased by 17% for each additional BMI unit (OR 1.17, 95% CI 1.16-1.18). Documentation was associated with higher utilization of obesity-related care, including metabolic clinic attendance (OR 2.26, 95% CI 2.05-2.49), bariatric surgery (OR 3.51, 95% CI 2.74-4.51), and GLP-1 receptor agonist prescriptions (OR 3.44, 95% CI 2.76-4.28). In comparison, diabetes was documented in 59.7% of patients with HbA1c ≥ 6.5%, and severe dyslipidemia in 39.0% of those with LDL-C ≥ 190 mg/dL. CONCLUSIONS:Despite being objectively measurable, obesity remains substantially underdocumented compared with other cardiometabolic risk factors. Documentation was associated with greater uptake of metabolic clinic visits, bariatric surgery, and GLP-1 receptor agonist therapy. As effective obesity treatments become routine practice, closing this documentation gap is a prerequisite for translating measured BMI into actionable care.
BACKGROUND/OBJECTIVES:Obesity is a chronic, relapsing disease associated with multiple serious comorbidities. Semaglutide has emerged as an effective pharmacological option for obesity management, owing to its substantial effects on weight loss, cardiometabolic risk factors, and patient-reported outcomes. This systematic review and meta-analysis evaluated the efficacy and safety of subcutaneous semaglutide for weight management in adults with overweight or obesity without diabetes. METHODS:Randomized controlled trials comparing subcutaneous semaglutide with placebo in adults with overweight or obesity without diabetes were identified through systematic searches of PubMed, the Cochrane Library, and ClinicalTrials.gov. Outcomes included changes in body weight, waist circumference, C-reactive protein (CRP) and serious adverse events (SAEs). A quality assessment and meta-analysis were performed using REVMAN 10.1.1 software. RESULTS:Across nine trials including 6 239 participants, subcutaneous semaglutide significantly reduced percentage body weight from baseline (mean difference [MD] -12.04%, 95% CI -13.08 to -11.00), waist circumference (MD -9.36 cm, 95% CI -10.27 to -8.45), and CRP (MD -40.90%, 95% CI -46.37 to -35.42) versus placebo (all p < 0.00001). The risk of SAEs did not differ significantly between semaglutide and placebo (risk ratio [RR] 1.12, 95% CI 0.76 to 1.65; p = 0.55). CONCLUSIONS:Subcutaneous semaglutide is effective for weight management in adults with overweight or obesity without diabetes. The recently published STEP UP trial evaluating semaglutide 7.2 mg provides additional evidence on higher-dose regimens and showed greater weight reduction compared with previously available data, representing a meaningful new contribution to the literature. Longer-term studies are needed to better define the long-term efficacy and safety profile of semaglutide across clinical populations.
Individuals vary widely in their response to behavioral weight-loss interventions, suggesting that neurocognitive differences may influence treatment success. We examined whether baseline cognitive performance predicted percent change in body weight over 8 months in a behavioral weight-loss trial. This secondary analysis used data from the Dietary Adaptation for Weight-loss maintenance at Yale (DAWLY) trial, a randomized, double-blind, placebo-controlled study of oleoylethanolamide (OEA) in adults with overweight or obesity. All participants completed a structured lifestyle behavioral weight-loss program (LEARN®) for four months (including dietary and physical activity guidance and behavioral strategies to achieve the lifestyle changes), followed by a four-month maintenance phase. Thirty-one participants completed the 8-month follow-up and a comprehensive neurocognitive battery. Cognitive variables were z-standardized and entered into principal component analysis; component scores were then used in regression models predicting percent weight change, adjusting for baseline weight, age, education, days tracked, sex, and treatment group. The first six components explained 73.8% of the variance in baseline cognition. Sex and PC5, characterized by strong loadings on probabilistic reinforcement learning and spatial working-memory tasks, were significantly associated with percent weight change. Individuals with higher PC5 scores and women showed greater 8-month weight loss. These results suggest that the ability to learn and update value contingencies and to use effective working-memory strategies may contribute to successful weight-loss during behavioral interventions. Clinical trial registration: www.ClinicalTrials.gov , identifier: NCT04614233.
PURPOSE:The downregulation of the cystic fibrosis transmembrane conductance regulator (CFTR) reduces lipogenesis and alters lipid metabolism. However, the role of CFTR in inflammation regulation in adipose tissue has been unknown. This study aims to explore the role of CFTR in adipose inflammation and lipid metabolism and the underlying mechanism using both in vivo and in vitro models. METHODS:We observed the changes in CFTR levels in human adipose tissue, a diet-induced obesity (DIO) mouse model, and 3T3-L1 cells and explored the relationship between CFTR and adipose inflammation. RESULTS:The mRNA expression of CFTR in human omental adipose tissue firstly rose with the BMI and WHR increasing, reached the peak at a BMI of 25-27 kg/m2 and a WHR of 0.8-0.9, and then declined, closely correlated with the serum hs-CRP level. A high-fat diet (HFD) inhibited CFTR expression in adipose tissue and caused the phenotypic transition of M1 to M2-type macrophages. Down-regulation of CFTR led to palmitate-induced adipose inflammation by increasing nuclear factor κB (NF-κB) phosphorylation through GTP-RhoA activation, IKKβ phosphorylation, and the Toll-like receptor 4 (TLR-4)/MyD88/IRAK4 pathway. CONCLUSIONS:CFTR plays a critical role in adipose inflammation regulation and it also represents a potential therapeutic target for the regulation of adipose inflammation and obesity.
BACKGROUND:Early life represents a critical period for shaping long-term health outcomes, with early interventions playing a significant role in promoting well-being. This study aimed to investigate whether infant weight status could predict concerns of development and well-being in the first years of school using health nurse data. METHODS:Data from the Danish Child Health Database collaboration included 54 917 children and families who received home visits at 8-10 months and school examinations by health nurses during the children's first years of school. Weight status was measured using BMI z-scores and tested categorical, linear and using restricted cubic splines to explore predictive performance. Well-being was assessed by health nurses using seven indicators, including language skills, motor development, emotional well-being, and peer relationship problems. Model performance was evaluated through visualization of restricted cubic splines and by Area Under the Curve (AUC). RESULTS:Infant weight status at 8-10 months showed poor predictive performance (AUC < = 0.533) across all indicators of well-being in the first years of school. While certain weight categories-especially severe thinness, overweight, and obesity-were linked to specific concerns such as language skills and motor development, these associations had wide confidence intervals. CONCLUSION:Although infant weight status may indicate later health concerns, it was not a reliable predictor of health nurses' well-being concerns in the early school years. The findings demonstrated that predictive performance remained poor across several models, suggesting that infant weight alone may not capture the complexity of factors influencing later well-being as recorded by health nurses.
BACKGROUND:Standard body fat metrics fail to capture the unique biological characteristics of subcutaneous (SAF) and visceral (VAF) abdominal fat. We characterized computed tomography (CT) radiomic profiles of SAF and VAF, identified sex-specific and pro-atherogenic signatures, and assessed their incremental value in cardiovascular risk assessment. METHODS:In 1736 adults without known coronary artery disease, we extracted size, first- and second-order (texture) features of SAF, VAF, and total abdominal fat (TAF) from non-contrast CT. Partial least squares discriminant analysis and XGBoost models were developed to differentiate abdominal fat depots, biological sex, and coronary calcification (defined as coronary calcium score, CCS > 0). RESULTS:SAF and VAF exhibited distinct radiomic profiles. SAF was characterized by lower attenuation and greater high-density structural continuity. Sexual dimorphism was evident in both depots, but was particularly pronounced in SAF; males displayed greater textural heterogeneity and radiodensity compared to females. Pro-atherogenic signatures exhibited increased textural heterogeneity in both depots. However, coronary calcification was associated with higher radiodensity in SAF (metabolic densification) and lower radiodensity in VAF (pathological hypertrophy). TAF radiomics significantly enhanced the performance of the TAF area to detect CCS > 0, and its accuracy was comparable to more complex models combining the best-performing pro-atherogenic SAF and VAF radiomic features. CONCLUSION:CT radiomics identified texture heterogeneity as a key feature of male, visceral, and pro-atherogenic adipose tissue phenotypes, while further supporting the protective characteristics of SAF compared with VAF. Unlike conventional TAF area measurements, radiomic analysis of TAF captures underlying tissue complexity and heterogeneity, providing a robust alternative to separate abdominal fat depot assessments for individualized obesity risk stratification. These findings highlight the potential of CT radiomics to differentiate biologically distinct abdominal fat phenotypes and enhance obesity-related cardiometabolic risk profiling.
BACKGROUND:Although discrimination against individuals with higher body weights is prevalent both within and outside the United States, research has largely overlooked how cultural norms and gender shape the experiences of those individuals. While cross-cultural work on anti-fat attitudes has examined variations in the Negative Cultural Value of Fat (NCF), how perceptions of NCF and Perceived Weight Discrimination (PWD) jointly affect well-being among individuals with higher weights across different countries has not been examined. The present study focused on participants who self-identified as overweight, hypothesizing larger gender disparities in well-being in Portugal and Mexico than in the United States, partly due to higher PWD and NCF among women. METHODS:1865 participants from the United States (n = 676), Portugal (n = 616), and Mexico (n = 573) who self-identified as overweight completed an online survey lasting approximately 12 min (50% Women; Age: M = 34.6, SD = 12.44). The cross-sectional survey assessed PWD, NCF, Psychological Distress, and Difficulties in Emotion Regulation. RESULTS:Mediational models for Psychological Distress (F(8,1856) = 83.96, p < 0.001, R² = 0.27) and Difficulties in Emotion Regulation (F(8,1856) = 82.51, p < 0.001, R² = 0.26) were significant. Gender had indirect effects on well-being via PWD and NCF, with stronger effects of NCF observed in Portugal and Mexico than in the United States. This indicates that cultural context moderates the association between gender, NCF, weight stigma, and mental health outcomes. CONCLUSIONS:Findings underscore NCF as a distinct and important construct in understanding the cultural dimensions of weight stigma and highlight the necessity of cross-cultural approaches to studying the mental health impacts of weight stigma.
BACKGROUND:The popularity of GLP-1 receptor agonists (GLP-1 RAs) for weight loss has increased significantly in recent years, raising concerns about self-medication with these medications. OBJECTIVE:To assess the proportion and identify factors associated with GLP-1 RA use without medical prescription among GLP-1 RA users in Brazil. METHODS:This cross-sectional study was conducted through a self-administered online questionnaire including adults aged 18 years or older residing in Brazil who reported current or past use of GLP-1 RAs for weight loss. We reported the proportion of self-medication and explored associated factors using Poisson regression with robust variance, adjusting for potential confounders. RESULTS:A total of 860 participants were included (mean age: 39.46 ± 10.61 years; 82.0% female; 47.1% with obesity). The proportion of self-medication with GLP-1 RA was 23.8% (95% CI: 21.1-26.8%). Predictors of self-medication included not having obesity (PR = 1.45; 95% CI: 1.13-1.89), not attending physical training centers (PR = 1.55; 95% CI: 1.23-1.96), and working in healthcare-related professions (PR = 1.45; 95% CI: 1.14-1.84). Conversely, being married (PR = 0.73; 95% CI: 0.57-0.94), having diabetes (PR = 0.35; 95% CI: 0.18-0.70), or having eating disorders (PR = 0.72; 95% CI, 0.34-0.97) were associated with lower self-medication rates. CONCLUSION:Almost one in four users reported using GLP-1 RAs without medical prescription. This practice was more frequent among individuals without obesity, those not attending physical training centers, and healthcare professionals.
BACKGROUND/OBJECTIVES:Dopamine plays a key role in motivation and behavioral regulation and may influence eating behavior in obesity. Previous studies indicate altered dopamine receptor availability in obesity, but the role of presynaptic dopaminergic function remains unclear. This study employed [18F]FDOPA PET imaging to evaluate presynaptic dopamine function in a large cohort of individuals with obesity compared with individuals with normal weight. SUBJECTS AND METHODS:Routine [18F]FDOPA PET/CT scans performed for the detection and follow-up of neuroendocrine tumors were reviewed. Striatal-to-occipital uptake ratios were used as an index of presynaptic dopaminergic tracer uptake after six hours of fasting. Individuals with normal weight (BMI ≤ 25) were compared with individuals with obesity (BMI ≥ 30) using multivariable regression analysis adjusted for age and sex. Sensitivity analyses included BMI modeled continuously and exploratory analyses of non-linear associations. A sensitivity analysis was performed in individuals with obesity class II (BMI 35-40). RESULTS:Median striatal SUV ratios were 2.2 (IQR 0.4, n = 67) in participants with obesity and 2.3 (IQR 0.4, n = 67) in participants with normal weight. No significant differences were observed between groups in the striatum (p = 0.07), putamen (p = 0.17), or caudate nucleus (p = 0.14), including among individuals with BMI ≥ 35 kg/m². Continuous and multivariable analyses yielded consistent results. CONCLUSION:This study did not demonstrate significant differences in striatal [18F]FDOPA uptake ratios between individuals with normal weight and individuals with obesity in the fasting state. Further research is warranted to clarify the role of the reward system in the development and management of obesity.
Although GLP-1 medications have transformed obesity treatment, their rapid expansion has occurred alongside moral narratives emphasizing discipline, willpower, and personal responsibility in weight management. These narratives often portray GLP-1-assisted weight loss as a “shortcut” or as “taking the easy way out” compared to lifestyle-based approaches such as diet and exercise. Such perceptions reflect broader weight stigmatizing attitudes; however, GLP-1-related stigma represents an emerging and distinct form of weight stigma in which judgments extend beyond body size to include the perceived legitimacy and moral worthiness of pharmacologic weight management. This compounded form of stigma may exacerbate negative physical and mental health impacts and GLP-1 treatment engagement beyond those associated with weight stigma alone, potentially creating new barriers to effective obesity care. Researchers across obesity, behavioral medicine, and psychosocial health are uniquely positioned to investigate the conceptual and psychometric similarities and differences between weight-based and GLP-1-related stigma. Such efforts will advance the understanding of this emerging phenomenon and improve the health and well-being of individuals with obesity using or considering GLP-1 therapies.
BACKGROUND:Obesity is associated with adverse alterations in lipoprotein profiles and increased cardiometabolic risk, yet standard clinical lipid measures provide limited resolution of the underlying lipoprotein structure. Here, we perform a population-level characterisation of the impact of obesity on the high-resolution blood lipoprotein subfraction profile. METHODS:Lipoprotein profiles were investigated in an Australian cohort (n = 1806) stratified by Body Mass Index (BMI) (healthy weight, overweight, obese). The composition and particle number of lipoproteins and their subfractions were quantified (n = 112 parameters) using 1H NMR spectroscopy. Associations between BMI, lipoprotein subfractions, and particle number ratios were evaluated. Key BMI-associated ratios were validated in a second Australian cohort (n = 1313) RESULTS: Participants with obesity had significantly higher particle concentrations of VLDL and IDL and lower HDLs, while total LDL concentration was similar between the BMI categories. Notably, obesity was associated with a marked redistribution of LDL subfractions, with a shift from larger, buoyant LDL1-3 particles to smaller, dense LDL4-6 particles, accompanied by a similar shift in HDL subfractions, with proportionally lower concentrations of HDL1-3 particles in the high BMI group. An inverse association between BMI was found for two LDL particle number ratios (LDL1-3:LDL4-6 and LDL2:LDL5) and one HDL ratio (HDL1:HDL4), which demonstrated good discriminatory power for obesity status (AUROCs 0.70-0.74). CONCLUSIONS:The pattern of lipoprotein subfraction redistribution in participants with obesity was consistent across cohorts. These subfractional changes offer enhanced resolution compared with conventional lipid and lipoprotein measures and may contribute to improved cardiovascular risk stratification in individuals with obesity.
Obesity has become a major global health problem. It is characterized by increased body fat storage and is associated with excessive food intake. Although obesity is often thought of as a simple problem involving fat accumulation in the body, it is a complex disease that alters cellular defense systems and causes low-grade chronic inflammation, which can contribute metabolic syndrome. Even though obesity is an inflammatory disease, an increase in the formation of reactive oxygen species (ROS) is also observed due to excess nutrition. Excessive ROS production contributes to obesity progression and endoplasmic reticulum (ER) stress. In response to oxidative stress, cells activate antioxidant defense mechanisms either through unfolded protein response (UPR) pathways or via UPR-independent signaling pathways. Nuclear factor-erythroid 2-related factor-2 (NRF2) controls the transcription of multiple genes encoding antioxidant and cytoprotective proteins. NRF2 is of interest in obesity research as it can be activated with or without UPR elements and plays a role in the regulation of antioxidant response. Targeting NRF2 through multiple approaches has been shown to reduce or prevent obesity and obesity associated metabolic complications. This review examines the molecular mechanisms of NRF2 activation in obesity, with particular focus on its bidirectional crosstalk with the UPR and discusses the therapeutic implications of targeting this axis in obesity and its related metabolic dysfunction.
BACKGROUND:Hepatic insulin resistance (HIR), an early feature of prediabetic, plays a pivotal role in disrupting glucose homeostasis. Clarifying the mechanisms underlying HIR is critical for diabetes prevention. Our previous study has discovered the positive correlations between plasma cathepsin D (CTSD) activity and the degree of HIR in people with obesity. Accordingly, this study investigates the roles of CTSD in the underlying mechanisms involving HIR and impaired glucose homeostasis. METHODS:The samples from people/mice with obesity/MASLD (metabolic dysfunction- associated steatotic liver disease) and HIR cellular models were used for assessing mRNA expression/protein expressions/activity of CTSD. RNA sequencing data from hepatocytes were then performed to disclose the potential mechanism of CTSD-induced HIR. Next, the plasmids of CTSD overexpression and CTSD knockdown were constructed to verify the effects and mechanisms of CTSD in HIR. Lastly, the CTSD inhibitor Pepstatin A (PepA) was administrated to mice with obesity/MASLD to explore the preventive effect of targeting CTSD on prediabetes. RESULTS:Significant increases in mRNA expression, protein levels, and activity of CTSD were observed in individuals and mice with obesity/MASLD, as well as in HIR cell models, compared with controls. Furthermore, we found that increased CTSD or overexpressing CTSD could trigger HIR mediated by the IL2RG-JAK2 axis, thus disturbing hepatic insulin signaling transduction. Inhibiting CTSD with PepA or knocking down CTSD markedly improved HIR and rebalanced glucose metabolism in mice with obesity/MASLD and HIR cell models. CONCLUSION:Altogether, these current findings implicate that increased CTSD suppresses hepatic insulin sensitivity via activating the IL2RG-JAK2-STAT3 axis, highlighting CTSD inhibition as an attractive preventative strategy for prediabetes. CTSD-centered IL2RG-JAK2 axis interruption as a precision strategy to rescue hepatic insulin signaling and halt prediabetes progression.
BACKGROUND/OBJECTIVE:Clinical guidelines suggest body mass index (BMI) thresholds of ≥25 kg/m² to identify individuals at elevated risk of type 2 diabetes and (T2D) hypertension, however, growing evidence suggests that higher BMI values within the normal weight range may also be associated with increased risks. METHODS:A systematic search was conducted in PubMed and Scopus, with an updated PubMed search through October 2025, to identify cohort studies from the US and Europe that reported risk estimates of T2D or hypertension for higher normal weight BMI values (e.g., 22.5-24.9 kg/m²) compared with lower normal weight BMI values. Asian studies were excluded because of lower BMI thresholds in Asian populations. Random-effects meta-analysis was performed to estimate summary relative risks (RRs) and 95%CIs. RESULTS:Eleven cohort studies were included, with 23% of participants and 17% of cases being classified as having high normal weight BMI values (22.5-24.9 kg/m²). Compared with lower BMI values within the normal weight range, high normal weight BMI values were associated with a greater risk of T2D (RR = 1.78, 95% CI: 1.30-2.45, I² = 98%; n = 10 studies with 1,818,036 participants and 84,414 cases; moderate certainty evidence). Evidence for hypertension was limited, based on three US cohort studies (RR = 1.42, 95% CI: 1.33-1.51, I2 = 0; n = 3 studies with 129,046 participants and 22,254 cases; low certainty evidence). CONCLUSIONS:Compared with lower normal weight BMI values, higher BMI within the normal range was associated with a higher risk of T2D and hypertension, suggesting that current BMI classifications may not fully capture the increased risk among individuals at the upper end of the normal weight spectrum. If replicated, the findings may justify reconsideration of BMI thresholds to better reflect the higher cardiometabolic risk observed among individuals with high normal weight BMI.
INTRODUCTION:We tested the bidirectional association between epigenetic age acceleration (EAA), a marker of biological aging, and metabolic syndrome (MetS), a cluster of conditions that together increase the risk of type 2 diabetes, cardiovascular disease, and other chronic conditions, at different time points. METHODS:A random sample of 962 Hispanic/Latino adults participating in the Hispanic Community Health Study/Study of Latinos were included in the analyses. At baseline, the mean age was 44.8 years, 61.5% of participants were female, and prevalence of MetS was 35.4%. DNA methylation was measured from whole blood, at two different time points six years apart, using the Illumina EPIC BeadChip and epigenetic age and EAA were calculated using the PhenoAge, GrimAge, and DunedinPACE algorithms. MetS was defined using the National Cholesterol Education Program Adult Treatment Panel III guidelines, in which a diagnosis is met when participants meet at least 3 of the 5 conditions: elevated waistline/abdominal obesity, high blood pressure, high blood sugar levels, high blood triglycerides, and low high-density lipoprotein (HDL) cholesterol. RESULTS:In cross-sectional analyses, higher PhenoAA (PR, 95% CI: 1.03, 1.01, 1.05), GrimAA (PR, 95% CI: 1.05, 1.01, 1.09), and DunedinPACE values (PR, 95% CI: 1.03, 1.02, 1.04) were associated with higher MetS prevalence. Over an average follow-up of six years, higher DunedinPACE values at baseline were associated with higher risk of incident MetS (Risk Ratio (RR), 95% CI: 1.04, 1.02, 1.05). Faster DunedinPACE rates (vs. average) were associated with higher risk of incident MetS (RR, 95% CI: 1.44, 1.07, 1.94), whereas slower DunedinPACE rates (vs. average) were associated with lower risk (RR, 95% CI: 0.44, 0.23, 0.87). CONCLUSION:The study suggests EAA is a potential indicator of both prevalent and incident MetS among Hispanic/Latino adults.
BACKGROUND:High body mass index (BMI) in adolescence is associated with accelerated biological aging, which might predict the onset of obesity-related diseases before they develop. Genetic factors may shape both adolescent BMI and weight trajectories. METHODS:Participants were from the Young Finns Study (n = 3 596, ages 3-18 at baseline), followed from 1980 to 2018-2020. Biological aging was estimated using DNA methylation based epigenetic clocks DunedinPACE (years/calendar year) and PC-GrimAge (years) at three follow-ups (ages 15-56, n = 2045). Genetic predispositions to BMI and childhood body size were quantified using polygenic risk scores (PRSs) (941 and 286 genetic variants). BMI trajectories were modelled from BMI measured at ages 9, 12, 15 and 18 using latent growth curve modelling. Path analysis was used to examine whether genetic liability to BMI is associated with biological aging and if BMI trajectories in adolescence mediate this association. The causal effect of genetically predicted adolescent BMI on biological aging in adulthood was examined with Mendelian randomisation (MR) using individual-level data. RESULTS:Higher level of adolescent BMI partly mediated the association between higher BMI-PRS and accelerated biological aging from late adolescence to middle adulthood. MR analyses supported a positive causal effect from genetically predicted adolescent BMI on biological aging, and the causal effect was more consistent when DunedinPACE was used to measure biological aging in 2011 (causal estimate = 0.020 [95% CI = 0.008, 0.031]) and 2018 (0.019 [0.003, 0.035]). CONCLUSIONS:Our findings indicate that high BMI in adolescence may accelerate biological aging, especially in individuals with a genetic predisposition to high BMI. Adolescents with a genetic susceptibility to high BMI and elevated BMI might be prone to obesity-related health risks, highlighting early prevention strategies' importance.
BACKGROUND:Prior obesity neuroimaging studies used univariate methods and small samples, limiting reproducibility. Employing a large-scale dataset and a two-stage machine learning framework, we identified neuroanatomical signatures of obesity and evaluated their population-level associations with delay discounting impulsivity. METHODS:We enrolled 243 young adults with obesity and 475 healthy-weight controls from the Human Connectome Project S1200 dataset. Cortical surface area, cortical thickness, and subcortical gray matter volume were extracted using surface-based morphometry. Support vector machine (SVM) classifiers discriminated obesity from healthy weight based on neuroanatomical features, with interpretability assessed via SHapley Additive exPlanations (SHAP). Partial correlations evaluated associations between the 15 SVM-selected features and the area under the curve (AUC) of delay discounting (DD) in the full sample. Normative modeling examined if the obesity group deviated from brain-structure-based expectations of AUC-DD. RESULTS:The neuroanatomical-only SVM achieved a receiver operating characteristic (ROC-AUC) of 0.648; adding demographic and cognitive covariates improved it to 0.740. SHAP highlighted the superior parietal, entorhinal, medial orbitofrontal, posterior cingulate, and rostral anterior cingulate cortices. Ten of the top 15 features were significantly associated with AUC-DD, and all in the expected direction. The obesity group showed systematically higher DD impulsivity than predicted impulsivity by brain structures alone. CONCLUSIONS:Distributed neuroanatomical features in prefrontal, medial temporal, cingulate, and parietal cortices discriminated obesity and showed convergent population-level associations with delay discounting impulsivity across group, correlational, and normative analyses.
