Obesity

Preconception weight loss by metabolic-bariatric surgery (MBS) improves maternal-fetal outcomes, but little is known about its impact on offspring growth and health. The preconception bariatric surgery and child health outcomes (POSIT) study aims to estimate the effects of maternal MBS-induced preconception weight loss on infant and childhood body size, growth, and related outcomes. This report presents the methods used to construct the POSIT cohort and its baseline characteristics. This retrospective cohort study sampled members from a United States healthcare system aged 18 and older with a singleton, live birth to create three study groups: 1) a treatment group including women who underwent preconception MBS and subsequently became pregnant (n=1,374); 2) a control group matched to the MBS pre-surgery body mass index (BMI) (pre-surgery controls, n=13,740); and 3) a second control group matched to the MBS post-surgical, pre-pregnancy BMI (pre-pregnancy controls, n=13,740). MBS and pre-surgery BMI controls showed slight imbalances in that pre-surgery BMI controls were on average [~]6 months younger, had 0.6 lower BMI (44.5 kg/m2) at the time of their pregnancy and were more likely to have become pregnant in earlier years than the MBS group prior to surgery. MBS and pre-pregnancy controls had comparable age (mean {+/-} SD 33 {+/-} 5 years), pre-pregnancy BMI (33 {+/-} 6 kg/m2), and year of delivery. Following matching, the MBS group had similar socioeconomic and health disparities as the pre-surgery control group, and both were worse than pre-pregnancy control group. Pregestational maternal comorbidity index improved after MBS and matched the pre-pregnancy controls. Upon extraction of offspring growth patterns and mediation analyses of maternal weight loss and metabolic responses to MBS, study findings will investigate effects of preconception weight loss by MBS on short- and long-term child health outcomes. Results will guide future studies focusing on improving maternal preconception weight and maternal-fetal outcomes.

ObjectiveBMI 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 assessed whether both frameworks identify overlapping phenotypes and how they classify obesity severity. MethodsA modified EOSS and DMO were applied to the UK Biobank (N {approx} 411,000). Stage distributions, cross-classification, and the impact of combining BMI with fat distribution on obesity categorization were analyzed. ResultsAbout 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 established disease with prognostic relevance. Discrepancies reflected differences in operationalization of e.g. metabolic, cardiovascular, and mental health. Obesity thresholds influenced classification, with [~]50% reclassified when BMI was combined with different fat distribution parameters, highlighting sensitivity of early-stage assignment. ConclusionEOSS and DMO provide complementary perspectives on obesity severity. Integrating EOSSs prognostic granularity with DMOs multidimensional approach may improve risk stratification and identify individuals most suitable for intensive interventions. STUDY IMPORTANCEO_ST_ABSWhat is already known?C_ST_ABSO_LIBMI alone poorly reflects obesity-related health risk; comorbidities, organ dysfunction, and functional impairments are crucial for precise staging. C_LIO_LITwo major frameworks exist: EOSS focuses on prognostic severity, while DMO identifies early/preclinical obesity--but their agreement and clinical implications were unclear. C_LI What does this study add?O_LIDemonstrates that EOSS emphasizes established disease and prognostic severity, whereas DMO captures a broader spectrum of early or subclinical organ dysfunction, revealing distinct phenotypes within the same BMI-defined population. C_LIO_LIHighlights that combining BMI with anthropometric measures can reclassify up to [~]50% of individuals, illustrating the sensitivity of early-stage assignment to diagnostic thresholds. C_LI How might these results change the direction of research or the focus of clinical practice?O_LIIntegrating EOSSs prognostic detail with DMOs broad, multidimensional approach enables targeted intervention, helping clinicians prioritize patients for intensive obesity management or treatment. C_LIO_LIProvides evidence for harmonizing obesity classification beyond BMI, emphasizing the need for multidimensional assessment in both research cohorts and routine clinical practice. C_LI

ObjectiveTo investigate the effects of breaking up prolonged sedentary behavior (SB) on daily movement behavior and energy balance in adults with overweight/obesity. MethodsThirty participants (16F/14M; 34.2{+/-}7.3y; 29.5{+/-}3.2kg/m2) were randomized to either BREAK (nine hourly 5-min brisk walking bouts) or a duration-matched intervention, ONE (45-min brisk walking), both performed 5 days/week for 6 weeks. Pre- and post-intervention, daily SB and physical activity (PA; accelerometry), body composition (doubly labeled water [DLW]), total daily energy expenditure (TDEE; DLW), appetite, and fasting leptin were measured. Linear-mixed effects models tested time effects and time-by-group interactions. ResultsOnly BREAK reduced prolonged SB (-8%; interaction: p=0.043). Both groups shifted SB-PA composition toward greater moderate-to-vigorous PA with proportional reductions in SB and light PA (time: all p[≤]0.011), which were associated with increases in TDEE (+0.67 MJ/d; time: p=0.040). Body and fat mass increased in ONE only (interaction: p=0.061 and p=0.055). No differences were noted in energy intake, appetite, or leptin levels. ConclusionsSpreading short PA bouts throughout the day increases MVPA and TDEE to the same extent as a traditional continuous PA bout. Future studies should investigate whether minor differences in body composition are driven by distinct behavioral/physiological compensations influenced by the daily pattern of PA/SB. STUDY IMPORTANCE QUESTIONSO_LIWhat is already known about this subject? O_LIAcutely, breaking up prolonged sedentary behavior (SB) with short bouts of physical activity (PA) increases energy expenditure and reduces food cravings compared to a single continuous PA bout. C_LIO_LISingle continuous PA bouts have been associated with compensatory reductions in non-exercise activities (daily living activities) in some studies, which may attenuate increases in total daily energy expenditure (TDEE) and limit effects on body mass and adiposity. C_LI C_LIO_LIWhat are the new findings in your manuscript? O_LIPerforming brisk walking either through frequent, short bouts spread across the day or as a single continuous bout over 6 weeks increases moderate-to-vigorous PA (MVPA) at the expense of SB and light PA and increases TDEE to a similar extent in adults with overweight or obesity. C_LIO_LIHowever, only the frequent, short active breaks reduced time spent in prolonged SB (>60 min), an independent cardiometabolic health risk factor. C_LIO_LIDespite no differences in energy intake, appetite, or plasma leptin concentration, the single continuous bouts were associated with a small, non-robust increase in body and fat mass, whereas these remained stable in the active breaks group, suggesting differential compensatory adaptations. C_LI C_LIO_LIHow might your results change the direction of research or the focus of clinical practice? O_LIPromoting frequent, short bouts of PA throughout the day can improve daily movement and help meet current PA/SB guidelines to a similar extent as traditional PA strategies, while also reducing prolonged sedentary time. C_LIO_LIThis strategy may help limit compensatory responses sometimes observed in response to continuous MVPA bouts, offering a new tool to manage body weight. C_LIO_LIHowever, differences in body composition outcomes were small and not robust, and future studies are needed to determine whether these patterns translate into meaningful long-term effects on energy balance and weight regulation. C_LI C_LI

BackgroundThe timing of energy intake could be important in the development of obesity. However, most observational evidence stems from adults, anthropometric defined obesity outcomes, single meal timing phenotyping, and traditional regression modeling. ObjectiveWe aimed to describe meal timing patterns in adolescents and determine if they associated with fat mass by modeling the median and all other percentiles of the frequency distribution. MethodsWe analyzed data from the Sleep and Growth Study 2 (S-Grow2, N=286, 12-13y). Participants completed 3-day 24-hour dietary recalls and time stamped eating occasions were used to define 8 meal timing traits, with aide from self-reported wake and bed timing. Principal component analysis (PCA) identified multi-dimensional meal timing patterns. Fat mass index (FMI) was estimated using dual energy X-ray absorptiometry. Quantile regression assessed if there were associations between meal timing traits and FMI across the entire FMI frequency distribution. ResultsThe typical first and last eating occasions were 8:00am (40 minutes after waking) and 8:00pm (2.7 hours before sleep), respectively, thus the eating period typically lasted 11.5 hours per day. The typical eating period midpoint was 2:15pm, and the timing when 50% of energy intake was consumed typically occurred at 3:15pm. PCA revealed three meal timing patterns: 1) "Delayed Start, Condensed Eating Period" (43% of variance; shorter eating period and delayed timing of first eating); 2) "Late, Sleep Proximal Eating" (30% of variance; later timing of last eating and extended eating period), and 3) "Later Energy Intake" (10% of variance; delayed energy intake midpoint). Higher scores for the "Delayed Start, Condensed Eating Period" pattern associated with higher body mass index and FMI at the upper tails of their distributions. ConclusionsDistinct multidimensional meal timing patterns emerged in early adolescence, with the delayed start, condensed eating period pattern potentially associated with higher adiposity. Clinical Trials Registry Site and NumberN/A

Background: C-terminal binding protein 2 (CtBP2) has been implicated in metabolic regulation, but its association with specific measures of adiposity and lipid profiles in humans remains unclear. This study examined the relationship between circulating CtBP2 levels and key components of metabolic syndrome, focusing on body fat distribution and lipid markers. Methods: Data from 508 participants (259 men, 249 women) from a publicly available dataset were analyzed. Serum CtBP2 concentrations were measured using ELISA. Associations with obesity markers (BMI, waist circumference, waist-to-hip ratio) and lipid profiles (triglycerides, HDL cholesterol) were assessed using Spearman correlation and linear regression, adjusting for age and sex. Results: CtBP2 levels showed weak but statistically significant positive correlations with all measures of adiposity, with the strongest association observed for waist circumference ({rho} = 0.150, p < 0.001), followed by BMI ({rho} = 0.120, p = 0.007) and waist-to-hip ratio ({rho} = 0.098, p = 0.027). No significant correlations were found with triglycerides or HDL cholesterol. In the regression model predicting BMI, age, and sex were significant predictors, while CtBP2 demonstrated a trend toward association ({beta} = 0.080, p = 0.052). Conclusion: Circulating CtBP2 appears to be modestly associated with measures of adiposity, particularly abdominal fat, but not with lipid abnormalities. These findings suggest a potential role for CtBP2 in obesity-related metabolic dysregulation and underscore the need for further mechanistic studies to clarify its clinical relevance.

Background: Repeated metabolic-bariatric surgery (MBS, r-BS) represents 10-25% of all MBS procedures and is commonly performed for recurrent weight gain after initial weight loss. How weight loss followed by regain reshapes adipose tissue biology remains unclear. We hypothesized that women undergoing r-BS exhibit a distinct adipose tissue signature compared with those undergoing primary bariatric surgery (p-BS). Methods: We analyzed subcutaneous and visceral adipose tissues (SAT, VAT, respectively) from women undergoing either p-BS, or r-BS with documented >15% weight loss after prior MBS. Tissues were assessed histologically, molecularly, and functionally (activation of human microglia cells (HMC3) by SAT secretome). Results: Consistent with other cohorts, women undergoing r-BS (n=21) trended to be older (47.2 vs. 40.5 y, p=0.06) than those undergoing p-BS (n=35), with a lower BMI (42.3 vs. 45.6 kg/m2, respectively, p=0.103), and a trend for improved cardiometabolic risk parameters such as fasting insulin, CRP and HDL-c. Adipose tissue histological features (adipocyte size, fibrosis, macrophage and crown-like structure abundance) were similar, while adipose mast cells were slightly (though insignificantly) more prevalent in r-BS. A single-nucleus RNA-seq-based deconvolution algorithm applied to bulk RNA-seq confirmed the absence of a major shift in adipose tissue cell-type composition. Yet, it uncovered a unique SAT transcriptome, with activation of inflammatory pathways in r-BS. Consistently, SAT explants from r-BS secreted higher protein concentrations of NFkB-regulated cytokines IL6 and IL8. Biological impact of the more inflammatory secretome was demonstrated by its increased ability to activate human microglia cells. Conclusions: Prior BS with significant weight loss-regain in women is associated with an inflammatory SAT transcriptome and secretome, possibly reflecting altered adipose-brain endocrine communication.

BackgroundObesity is a chronic multifactorial disease characterized by substantial interindividual variability in weight loss after lifestyle intervention and bariatric surgery. Thyroid hormones play a key role in energy homeostasis, but their influence on postoperative weight outcomes remains insufficiently studied. ObjectiveTo evaluate the association between preoperative thyroid status and changes in body mass index (BMI) after lifestyle intervention and bariatric surgery over a five-year follow-up. MethodsWe conducted a retrospective cohort study including adults with class II or III obesity enrolled in the Obesite Severe et Epigenetique (OBESEPI) study. All participants underwent preoperative lifestyle intervention followed by bariatric surgery. Thyroid status was classified as euthyroid or hypothyroid based on clinical and biochemical criteria. BMI was assessed at baseline and at nine postoperative time points over five years. ResultsAmong 435 included patients, 71 (16.8%) had hypothyroidism. Baseline BMI was similar between groups, whereas diabetes was more frequent in hypothyroid patients (52.1% vs 37.7%; p = 0.022). Hypothyroid patients had significantly higher BMI at 6-24 months after surgery, but differences were no longer significant beyond three years. BMI trajectories and magnitude of weight regain were comparable between groups. Higher preoperative TSH levels were independently associated with BMI regain (OR 1.32, 95% CI 1.00-1.72; p = 0.047). Higher baseline BMI, younger age, and female sex were also associated with greater BMI regain. ConclusionsHypothyroidism was associated with lower early postoperative weight loss but did not influence long-term BMI trajectories. Higher preoperative TSH levels were independently associated with BMI regain. KEYPOINTSO_LIPreoperative hypothyroidism is associated with reduced early weight loss during the first two years after bariatric surgery. C_LIO_LILong-term BMI trajectories and weight regain patterns are similar between hypothyroid and euthyroid patients beyond three years of follow-up. C_LIO_LIHigher preoperative TSH levels independently predict BMI regain. C_LIO_LIBaseline BMI, younger age, and female sex remain key determinants of the magnitude of BMI regain after bariatric surgery. C_LI

BackgroundThis study was designed to investigate the relationship between visceral fat metabolic score (METS-VF), lipid accumulation product (LAP), visceral adiposity index (VAI) and thyroid function. MethodsUtilizing data from the National Health and Nutrition Examination Survey (NHANES) 2007-2012, participants were excluded if they lacked data on METS-VF, LAP, VAI or thyroid function, or were under 18 years of age. Multiple linear regression, smooth curve fitting, and subgroup analyses were performed to determine the independent relationship between lipid accumulation and thyroid function. ResultsAfter full covariate adjustment, all three visceral adiposity indices showed significant positive associations with FT3 (LAP: {beta}=0.028, VAI: {beta}=0.024, METS-VF: {beta}=0.026; all P<0.001), FT3/FT4 ratio, TT3, TT4, and TgAb. LAP and VAI demonstrated inverse associations with FT4 ({beta}=-0.218 and -0.183, respectively; both P<0.001), while VAI and METS-VF were positively associated with TSH ({beta}=0.149, P=0.041; {beta}=0.167, P=0.025). Quartile analyses confirmed dose-dependent relationships, with Q4 participants showing elevated FT3, FT3/FT4, TT3, TT4, and reduced FT4 compared to Q1. RCS analyses revealed distinct non-linear patterns: LAP exhibited non-linearity with FT3, TSH, TT3, and TT4 (all P-nonlinear<0.05) but linear inverse associations with FT4. VAI displayed reverse L-shaped curves for FT3, TSH, and TT3 with plateaus at higher levels, while TT4 showed an inverted U-shape. METS-VF demonstrated non-linear increases for FT3 and TT3, linear associations with TSH and TT4, and an inverted U-curve for FT4. Stratified analyses identified age, race, and smoking as consistent modifiers of FT3/FT4 associations across all indices (interaction P<0.05), with stronger effects in younger/older adults, males, White participants, and high-income groups. TT3 and TT4 modification patterns varied by index. Thyroid autoantibodies showed minimal associations across all indices. ConclusionVisceral lipid accumulation is closely associated with thyroid dysfunction, and this association exhibits significant non-linear characteristics, which are modulated by factors such as age, race, and lifestyle habits. These findings provide new perspectives for the early identification and intervention of obesity-related thyroid dysfunction.

Objectives To estimate population-level eligibility for glucagon-like peptide-1 receptor agonist (GLP-1RA) medications among adults in Australia, according to Therapeutic Goods Administration (TGA) approved indications for chronic weight management and secondary prevention of cardiovascular disease. Design Cross-sectional analysis of data from the Australian Bureau of Statistics 2022 National Health Survey. Setting, Participants Non-pregnant adults [&ge;] aged 18 years who are usual residents of Australia and living in a private dwelling. Main outcome measures Total number of adults who are eligible for GLP-1RA medications according to TGA approved indications for chronic weight management and secondary prevention of cardiovascular disease, across subgroups defined by body mass index, weight-related comorbidities, and/or socio-demographic factors. Results In total, 39.7% (95% CI 38.4 - 41.0%) of adults in Australia are eligible for GLP-1RA use for chronic weight management, accounting for 7.8 million (95% CI, 7.6 - 8.1 million) individuals. Among those eligible under this indication, 2.9 million (95% CI 2.7 - 3.1 million) adults had no weight-related comorbidities, 3.3 million (95% CI 3.1 - 3.4 million) adults had at least 1 weight-related comorbidity, and 1.7 million (95% CI 1.6 - 1.8 million) adults had at least 2 weight-related comorbidities. The proportion of adults eligible under this indication varied across clinical and sociodemographic factors. Among those eligible under the chronic weight management indication, up to 338.9 thousand (95% CI 271.3 - 406.5 thousand) adults also meet the indication for secondary prevention of cardiovascular disease. Conclusions More than one third of Australian adults are eligible to access GLP-1RAs for chronic weight management, with 3.7-4.3% of adults also qualifying according to the indication for established cardiovascular disease. This study provides a valuable reference to allow policy makers to understand the number of adults in Australia that may benefit from access to GLP-1RA medications under a range of coverage scenarios.

Background: 39M children worldwide are overweight or have obesity, accelerating risk for adult non-communicable diseases. Presently, interventions to prevent obesity have had limited success due to poor timing and lack of personalisation. Objective: We aimed to identify early-life predictors of childhood obesity (ChOB) that could aid targeting specific population subsets for obesity prevention interventional studies. Methods: Data were from the Raine Study Gen2 participants (n=1494). Anthropometric and genetic predictors evaluated included birthweight (BW), early-life BMI (1-3 years), and three polygenic scores (PGS) [two BW-PGSs (BW-PGS2016 and BW-PGS2019) and a ChOB-PGS], developed from BW and ChOB genome-wide-association-studies, respectively. Multivariate analyses were performed to investigate associations between predictors and child-BMI (5-, 8-, 10-years). Results: BW-PGS2019 associate with child-BMI at 5-years. BW-PGS2016 was not associated with child-BMI. Remaining predictors positively associate with child-BMI at 5-, 8- and 10-years (p<0.001). Early-life BMI, ChOB-PGS and BW accounted for up to 38.7%, 5.8% and 3.4% of the variability in child-BMI, respectively. Conclusions: Our data suggest early-life BMI is a better predictor of child-BMI than ChOB-PGS, and BW, accounting for up to ten-fold more variance in child-BMI. Future interventional studies to mitigate obesity could target early-life BMI as a marker to identify children at the highest risk.

We completed a video-based, four-night, in-home, level 3 sleep apnea study of healthy, low-risk pregnant participants and their bed partners in order to characterize sleep physiology in the third trimester of pregnancy. Demographic, anthropometric, and baseline sleep health characteristics were recorded, and the NightOwl home sleep apnea test device was used to measure sleep breathing, posture, and architecture parameters. Symptoms of restless legs syndrome were elicited in the exit interview. Forty-one pregnant participants and 36 bed partners completed the study. Bed partners had a significantly higher prevalence of sleep apnea than their pregnant co-sleepers (31% vs. 5.9%). Bed partners also had more severe sleep apnea than their pregnant co-sleepers, and this persisted on an adjusted analysis for baseline differences in factors known to increase risk of sleep apnea. In pregnant participants, increasing gestational age was found to be protective against mild respiratory events but not more severe events. While the correlation between STOP-Bang score and measures of sleep apnea severity was weak, an affirmative response to the "witnessed apneas" item on the STOP-Bang questionnaire was a strong predictor of more severe sleep apnea for all participants. Smoking history also increased sleep apnea risk. Pregnant participants had lower sleep efficiency and longer self-reported sleep onset latency. Restless legs syndrome was experienced by 39.5% of the pregnant participants but no bed partners. From a sleep breathing perspective, people with healthy, low-risk pregnancies have better sleep than their bed partners despite lower sleep efficiency and higher rates of restless legs syndrome. Clinical Study RegistrationSleep in Late Pregnancy - Artificial Intelligence Development for the Detection of Disturbances and Disorders (SLeeP AID4), https://clinicaltrials.gov/study/NCT05376475, registration ID NCT05376475. Statement of SignificancePregnancy negatively impacts sleep, and poor sleep in pregnancy negatively impacts maternal and fetal health. Pregnancy represents a unique challenge to sleep breathing physiology and, thus, an opportunity to test for sleep apnea. Sleep apnea however, while increased in pregnancy, is more common in males. This novel study tested healthy people with low-risk pregnancies and their bed partners for sleep apnea in the comfort of their home over four nights in late pregnancy. Sleep apnea was more common and worse in the bed partners. Advancing gestational age was protective against mild but not severe sleep apnea, and a critical remaining knowledge gap is this interplay in high-risk pregnancies. Future sleep in pregnancy research should make efforts to include high-risk pregnancies.

This updated systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and obesity-related complications. Medline and Embase were searched up to 21 November 2025 for randomized controlled trials comparing OMMs versus placebo or active comparators in adults. The primary endpoint was percentage total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and [&ge;]3 years, anthropometric, metabolic, mental health and quality-of-life outcomes, cardiovascular morbidity and mortality, remission of obesity-related complications, serious adverse events and all-cause mortality. Sixty-six RCTs (66 comparisons) were identified - orlistat (22), semaglutide (18), liraglutide (11), tirzepatide (8), naltrexone/bupropion (5) and phentermine/topiramate (2) - enrolling 63,909 patients (34,861 and 29,048 with active compound and placebo, respectively). All OMMs showed significantly greater TBWL% versus placebo; tirzepatide and semaglutide exceeded 10% TBWL and showed the most favourable glycaemic effects. Semaglutide reduced major adverse cardiovascular events and all-cause mortality. In dedicated complication-specific trials, semaglutide and tirzepatide showed benefit on heart-failure-related outcomes; tirzepatide was associated with improved obstructive sleep apnoea syndrome and semaglutide with knee osteoarthritis pain remission. Tirzepatide and semaglutide were associated with improvements in metabolic dysfunction-associated steatohepatitis remission, and semaglutide with improvement in liver fibrosis. No OMMs were associated with an increased risk of serious adverse events. These updated results reinforce the need to individualize OMMs selection according to weight-loss efficacy, complication profile and safety.

BackgroundHigher-quality diets have been associated with lower levels of ectopic fat deposited in the viscera and liver, which is hypothesized to be mediated in part by the gut microbiota. ObjectivesWe tested this hypothesis in a multi-ethnic imaging study using global (microbiome-wide) testing as well as a high-dimensional multiple-mediators regression framework to identify bacterial genera in the human gut that mediate the association between diet quality and ectopic adiposity. MethodsWe analyzed the cross-sectional data of 1,400 older adults (age 60-77) from five racial/ethnic groups in the Multiethnic Cohort Adiposity Phenotype Study (2013-2016). Overall diet quality was defined by adherence to the MIND diet. The relative abundance of 151 bacterial genera was quantified from 16S rRNA gene sequencing of the stool samples. Visceral fat, liver fat, and the presence of MASLD (metabolic dysfunction-associated steatotic liver disease) were determined based on magnetic resonance imaging (MRI). We used high-dimensional mediation analysis (HDMA) to estimate gut microbial mediation in the linear regression of visceral fat or liver fat, or in logistic regression of MASLD, on the MIND adherence score, adjusted for potential confounders. ResultsHigher diet quality was associated with lower ectopic adiposity: 12% less visceral fat area, 23% less liver fat, and a 49% less likelihood of having MASLD, comparing the highest to the lowest quartile of the MIND score. Using a distance-based global test, we confirmed overall significant microbial mediation of the inverse diet-ectopic fat association. From HDMA, four bacterial genera were identified as mediating the protective association with visceral fat, with the largest mediation conferred by Lachnospiraceae UCG.001 (12.2%). Two genera (Lachnoclostridium, Weissella) were shown to mediate the MIND association with both liver fat and MASLD. In particular, Lachnoclostridium mediated 13.6% of the liver fat association and 10.8% of the MASLD association, and Lachnospiraceae UCG.001 additionally mediated 12.1% of the liver fat association. ConclusionsOur results support the hypothesis that the gut microbiota contributes to conveying the effect of diet quality on preferred body fat distribution, e.g., involving bacteria that are known to produce short-chain fatty acids (Lachnospiraceae) or secondary bile acids (Lachnoclostridium).

BackgroundEthnic minorities and socioeconomically disadvantaged populations in the UK are at increased risk of obesity. We modelled longitudinal body mass index (BMI) trajectories through infancy, childhood, and adolescence to identify at-risk groups and modifiable risk factors. MethodsThis cohort sampled 10,350 White and South Asian children born in Leicestershire, 1985-1997. We included 5,571 participants with [&ge;]3 BMI measurements between 0-18 years collected from healthcare records, questionnaires, and study visits. We used Group-Based Trajectory Modelling of BMI, separately by sex and ethnicity, and combined. We identified at-risk groups and modifiable risk factors using multinomial logistic regression, with inverse probability weighting to reduce selection bias. ResultsWe identified similar five BMI trajectories across sex and ethnicity: stable normal BMI (47%); persistent low BMI (30%); early overweight resolving (8%); childhood onset obesity (4%); and adolescent onset overweight (11%). Childhood onset obesity deviated from stable normal BMI at 2-4 years of age, adolescent onset overweight at 4-6 years. South Asians were at higher risk of childhood onset obesity (aOR: 1.66 [95%CI 1.08-2.53]) and adolescent onset overweight (1.29 [0.98-1.71]) than Whites. Children from deprived backgrounds (1.66 [0.92-2.82], most vs least deprived quintile) and those with less educated parents (1.67 [1.08-2.63], compulsory vs higher education) were at increased risk of childhood onset obesity. Smoking during pregnancy (1.50 [0.88-2.54]) and absence of breastfeeding (1.56 [1.07-2.29]) increased risk of childhood onset obesity. Physical activity decreased risk of childhood onset obesity (0.64 [0.44-0.93], [&ge;]4 vs 0-3 hours/week) and adolescent onset overweight (0.75 [0.59-0.94]). ConclusionBMI trajectories diverge as early as age 2 years, revealing ethnic and social inequalities. Obesity strategies in the UK should intervene during critical windows in early life and prioritise South Asian children and those from socioeconomically deprived backgrounds.

Obesity is considered a risk factor for metabolic diseases, including type 2 diabetes, and results from an imbalance between energy intake and energy expenditure. While pharmacological approaches such as tirzepatide, a dual GIP/GLP-1 receptor agonist, effectively reduce food intake and body weight, strategies that enhance energy expenditure (EE) may provide complementary metabolic benefits. Intermittent cold exposure (ICE) is one such approach that enhances EE and improves glucose homeostasis independent of weight loss. However, the combined effects of these interventions remain unexplored. In this study, we investigated the individual and combined effects of tirzepatide and ICE on body composition, energy metabolism, and glucose homeostasis in diet-induced obese (DIO) male and female mice housed at thermoneutrality. After 8 weeks of 45% high-fat diet feeding, mice received tirzepatide (10 nmol/kg) or vehicle and were exposed to ICE (4{degrees}C, 1 h/day, 5 days/week) or remained at thermoneutrality for 3 weeks. Energy expenditure and substrate utilization were assessed using indirect calorimetry at thermoneutrality and during an acute 1 h cold challenge. Tirzepatide reduced body weight, food intake, and adiposity in both sexes, with a greater reduction in lean mass in males. ICE did not affect body weight but improved glucose homeostasis. At thermoneutrality, tirzepatide did not alter total EE but lowered respiratory exchange ratio (RER), indicating a shift toward lipid utilization. In contrast, ICE increased energy expenditure and fat oxidation, with no additive effects observed when combined with tirzepatide. Together, these findings highlight that targeting both energy intake and expenditure represents complementary, but not necessarily additive approaches to improving metabolic health.

BackgroundObesity disrupts type 2 immune cell populations in white adipose tissue, replacing the homeostatic network of group 2 innate lymphoid cells (ILC2s), eosinophils, T helper 2 (Th2) cells, and alternatively activated macrophages (AAMs) with pro-inflammatory type 1 populations. Whether this remodelling reflects permanent immune impairment or a reversible shift in cellular equilibrium, and to what extent bariatric surgery restores type 2 immunity, remain incompletely understood. MethodsWe performed comprehensive immunophenotyping of visceral white adipose tissue (WAT) and peripheral blood from persons with severe obesity (people with obesity, PWO) scheduled for or having undergone bariatric surgery (sleeve gastrectomy, gastric bypass), combined with lean controls. Using flow cytometry, quantitative PCR, and in vitro polarization assays, we assessed immune cell frequencies, transcription factor expression, cytokine profiles, and functional polarization capacity across lean, pre-operative, and post-operative states. ResultsObesity was associated with decreased eosinophil and CD8+ T cells frequencies in WAT, accompanied by an increase in CD4+ frequency and a shift from Th2 toward Th1 predominance, as well as elevated PD-1 expression on T cell subsets. Bariatric surgery partially normalised peripheral immune cell composition, reducing CD8+ T cell frequencies while increasing CD4+ T cells. Macrophage polarization capacity, dampened in pre-operative PWO, recovered after surgery. Conversely, Th2 polarization capacity and IL-13 production were reduced in post-operative T cells despite preserved function pre-operatively, indicating divergent trajectories of innate and adaptive immune reconstitution. ConclusionType 2 immune cells retain functional plasticity in human obesity despite reduced frequency. Bariatric surgery differentially reconstitutes immune function, restoring macrophage plasticity while paradoxically reducing Th2 polarization capacity, arguing against uniform immune normalisation after weight loss. FundingGerman Federal Ministry of Research, Technology and Space (BMFTR, FKZ 01KI2109), Interdisciplinary Center for Clinical Research (IZKF, Faculty of Medicine, Friedrich-Alexander Universitat (FAU) Erlangen-Nurnberg).

BackgroundPsychiatric conditions, eating disorders (EDs), and exposure to violence are highly prevalent in patients with severe obesity. However, their association with postoperative weight trajectories following bariatric surgery remains unclear. ObjectiveTo assess the associations between eating disorders, psychiatric conditions, and history of violence with multiple dimensions of weight trajectory after bariatric surgery. MethodsThis retrospective study included 414 patients with severe obesity from the OBESEPI cohort who underwent bariatric surgery at Nancy University Hospital (France). Psychological factors were assessed using a standardized preoperative psychiatric interview. Weight outcomes included preoperative BMI change, maximal BMI loss ({Delta}BMImax), final BMI change (dBMIdf), weight regain (BMIR), and magnitude of weight regain (dBMIR). Multivariable linear and logistic regression models were adjusted for age and sex. ResultsPsychological factors were not associated with baseline BMI or preoperative BMI variation. A history of violence was significantly associated with greater maximal BMI loss ({beta} = 1.99, 95% CI [0.73-3.26]; p = 0.002) and greater final BMI reduction ({beta} = 1.81, 95% CI [0.47- 3.14]; p = 0.009). Eating disorders and psychiatric conditions were not associated with weight loss outcomes. No association was observed between overall exposure to violence and weight regain. However, subtype analyses showed that physical violence was associated with a higher risk of weight regain, whereas psychological violence was associated with a lower risk. No significant associations were found for the magnitude of weight regain. ConclusionsEating disorders and psychiatric conditions were not associated with postoperative weight outcomes in this cohort. In contrast, exposure to violence--particularly when differentiated by subtype--was associated with distinct patterns of weight loss and regain. These findings highlight the relevance of trauma-informed assessment in bariatric care and support a more individualized approach to obesity management.

Importance: Glucagon like peptide 1 receptor agonists (GLP 1 RAs) and dual glucose dependent insulinotropic polypeptide/glucagon like peptide 1 receptor agonists have demonstrated what may be considered transformative efficacy in recent randomized clinical trials for the treatment of obesity, yielding substantial weight loss in a majority of participants. However, the extent to which these trial results translate into routine clinical practice particularly within the rapidly expanding direct to consumer (DTC) telehealth sector serving self pay populations remains insufficiently characterized. As access to and affordability of these therapies broaden beyond traditional insurance based care models, evaluating real world effectiveness, safety, and patient engagement among individuals shouldering the full financial cost of treatment is essential for informing future models of obesity care delivery. Objective:To assess long term medication specific weight loss outcomes, including gender specific responses and discrepancies, and explore usage trends in a real world, self pay telehealth cohort receiving GLP 1 RA therapy, using an Observational study design (Retrospective data analysis). Setting and Participants:Retrospective data of patients enrolled in electronic health records (EHR) from Carevalidate, a national US telehealth platform provider for Online TeleHealth companies. The data collected ranged for a total of 703 days from January 12, 2024, to December 15, 2025. The analysis included 572 adults with overweight or obesity diagnosis who initiated treatment with semaglutide or tirzepatide and completed a minimum of 9 months of active follow up. Patients with insufficient follow up or those utilizing insurance coverage were excluded to isolate the self pay phenotype. Exposures: Prescription of semaglutide or tirzepatide (injectable or oral formulations) via synchronous or asynchronous telehealth consultations, titrated according to standard clinical protocols adapted for patient tolerance and financial sustainability. Main Outcomes and Measures: The primary outcome was percentage total body weight loss (%TBWL) from baseline to the last recorded encounter. Secondary outcomes included categorical responder rates (5%, 10%, 15%, >20% weight loss), weight loss velocity analysis, and telehealth utilization metrics (frequency of encounters and visit intervals) including gender differences in approaching the telehealth program. Results: The final analytical cohort included 572 patients (79.2% female; 20.8% male). Overall, 95.8% (548/572) achieved weight loss, while 3.7% experienced weight gain. At 12 months, the mean %TBWL was 13.8% for the semaglutide cohort (n=450) and 12.5% for the tirzepatide cohort (n=122), with no statistically significant difference between the two medications (P >.05), contrary to standard clinical trial data suggesting tirzepatide superiority. A significant gender difference was observed: females were significantly more in number comprising 80% of the cohort and were likely to be "major responders" (>20% weight loss) compared to males (29.8% vs 5.9%; P <.001). Conversely, males demonstrated significantly higher utilisation rates, attending more frequent encounters (mean 13.5 vs 12.7; P =.028) with shorter intervals between visits (35.6 vs 44.1 days; P =.009) compared to females. Weight loss velocity for both medications peaked during months 1 to 3 (~1.07 lbs/week) and declined substantially by months 12 to 15, indicating a plateau effect independent of the specific agent used. Conclusions and Relevance: Telehealth-managed GLP 1 treatment in a self pay population demonstrates high efficacy comparable to clinical trials for semaglutide. However, tirzepatide outcomes fell short of trial benchmarks, likely due to economic barriers preventing optimal dose titration and lower sample size. The study identifies a discrepancy where females approach the telehealth based self pay system more but males engage more frequently with the digital platform which could be due to inferior physiological outcomes ( less weight loss and more non responders) compared to females.This suggests that while telehealth is a viable model for long term obesity care, the "one size fits all" approach may be insufficient for under responders, who may require distinct titration strategies or tailored behavioral interventions to overcome baseline genetic and biological resistance.

Selectively bred diet-induced obesity-prone (DIO-P) rats have defective nutrient sensing prior to obesity onset. We hypothesized that glial inflammation in the arcuate nucleus (ARC) impairs hypothalamic responses to dietary clues, thereby promoting obesity development in genetically susceptible animals. This study established a timeline of inflammatory events in male and female DIO-P and diet-resistant (DR) rats fed either a low fat chow or exposed to a high energy diet (HED; 32% fat, 25% sucrose) for three days or four weeks. On chow diet, DIO-P rats of both sexes displayed elevated astrocyte density and increased expression of pro-inflammatory markers in the ARC, alongside reduced microglial content, compared to DR rats. Three days of HED transiently amplified most MBH pro-inflammatory markers in DIO-P rats. Four weeks of HED decreased GFAP expression in DIO-P rats while Iba1 density remained unchanged, whereas, DR rats showed a reduction in Iba1with no change in GFAP or cytokine expression. To determine whether mediobasal hypothalamus (MBH) astrocyte inflammation contributes to the development and maintenance of an obesity, astrocytic IKK{beta} was depleted before or after HED exposure. Prophylactic MBH astrocyte-specific IKK{beta} knockdown prevented subsequent body weight gain, improved glucose tolerance and decreased leptin levels in DIO-P rats to levels comparable to DR rats, with no effect in the latter. In contrast, MBH IKK{beta} astrocytic depletion in already obese DIO-P rats had no effect on energy homeostasis. Together, these findings validate the DIO-P rat as a polygenic model of obesity predisposition and demonstrate that preventing ARC astrogliosis is sufficient to HED-induced body weight gain and obesity development in genetically susceptible animals, highlighting MBH inflammation as a marker and driver of obesity predisposition. HighlightsO_LIChow-fed DIO-P rats present heightened ARC astrogliosis and cytokine expression preceding HED-induced obesity. C_LIO_LIInhibition of IKK{beta} in MBH astrocytes prevents DIO-P rats from becoming obese. C_LIO_LIOnce obese, inhibition of IKK{beta} in MBH astrocytes is not sufficient to reverse the obese phenotype. C_LI

Oxytocin is a hypothalamic hormone and neuromodulator that has been linked to a variety of different functions, including parturition, social behavior, and cognitive processing. More recently, oxytocin has also been associated with metabolism and energy balance. However, evidence to date in this field has been inconsistent, especially in human research. To address this, we performed a preregistered systematic review and meta-analysis, which synthesized existing literature on the effect of exogenous oxytocin administration compared to a placebo on caloric intake and appetite in humans, using a living meta-analysis approach. Results indicated a significant, reductive effect of oxytocin administration on appetite in participants belonging to certain patient groups (e.g., obesity or type II diabetes; Hedges' g = -0.21). A separate moderator analysis evaluating oxytocin's effect on caloric intake revealed a conditional effect depending on the patient group, with the obesity group showing a significant effect. We did not find any statistically significant effects in healthy participants. However, further analyses revealed that these effects were also not equivalent, indicating that the data are currently too insensitive to draw clear conclusions. Taken together, the results provide some evidence for the role of oxytocin in regulating appetite in an anorexigenic, possibly homeostatic fashion. Future updates in this living meta-analysis may lead to more definitive conclusions.