International Journal of Obesity

Background: Ethnic 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. Methods: This cohort sampled 10,350 White and South Asian children born in Leicestershire, 1985-1997. We included 5,571 participants with [≥]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. Results: We 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], [≥]4 vs 0-3 hours/week) and adolescent onset overweight (0.75 [0.59-0.94]). Conclusion: BMI 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.

Background: The 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. Objective: We 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. Methods: We 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. Results: The 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. Conclusions: Distinct multidimensional meal timing patterns emerged in early adolescence, with the delayed start, condensed eating period pattern potentially associated with higher adiposity.

Flavor-nutrient learning (FNL) refers to learning associations between a foods flavor and the rewarding appetition signals that arise from post-oral nutrient sensing during or after a meal. In rodent models FNL reliably produces strong flavor preferences and increased intake of nutrient-paired flavors, implicating FNL as a presumptive obesogenic influence in the modern environment. However, evidence that FNL plays a causal role in diet-induced obesity is ambiguous. We have previously shown that degree of weight gain on a high-fat/sugar diet is associated with stronger FNL responses, but direction of causation was unclear. This paper reports three experiments investigating whether individual differences in FNL conditionability are linked to obesity proneness prior to obesity onset. Two experiments comparing selectively-bred obesity-prone vs resistant strains found no strain differences in FNL. A third study in lean, outbred rats evaluated whether baseline individual differences in FNL prospectively predict weight gain on a cafeteria diet. Unexpectedly, rats who showed the strongest learned increase in intake of a nutrient-paired flavor subsequently gained the least weight when switched to cafeteria diet, suggesting FNL protects against weight gain. In fact, individual differences in FNL explained a portion of variance in cafeteria weight gain over and above measured kcal intake, implying a function for FNL in adaptively modulating metabolic responses to energy intake. Collectively, several studies have now shown individual differences in obesity proneness to be either positively correlated, uncorrelated, or negatively correlated with FNL, calling for a more nuanced view of how appetition influences intake and energy balance.

Background Diverse epigenetic clocks are known to capture health risks associated with increased adiposity, but their estimates have never been combined to represent a holistic estimate of biological age acceleration (BAA). There is also a gap in research using epigenetic clocks to study adiposity in lower-middle income Asian countries. Methods and Findings Data from 1,745 participants (21.7{+/-}0.3 years old, 45% female) of the Cebu (Philippines) Longitudinal Health and Nutrition Survey were analyzed. BAA was calculated using PCHorvath 2, PCHannum, PCPhenoAge, PCGrimAge, PCDNAmTL, and DunedinPACE. After ascertaining suitability for factor analysis (Kaiser-Meyer-Olkin 0.81), factor analysis was used to create PCFactorAge. Analogously, FactorAge was created using Horvath, Hannum, PhenoAge, GrimAge, DNAmTL, and DunedinPACE. BMI, waist circumference (WC), and waist-to-height ratio (WHtR) were used to represent adiposity. Linear regression was used to test the association of each adiposity measure with each BAA measure. BMI, WC, and WHtR were positively associated with both BAA combinations: 5 kg/m2 higher BMI corresponded to 0.097 (p=0.015) standard deviation (SD) increase in FactorAge and 0.099 (p=0.004) SD increase in PCFactorAge; 10 cm increase in WC--with 0.091 (p=0.005) SD increase in FactorAge and 0.094 (p<0.001) SD increase in PCFactorAge; 0.1 increase in WHtR--with 0.164 (p=0.001) SD increase in FactorAge and 0.163 (p<0.001) SD increase in PCFactorAge. Additionally, WHtR was associated with meaningful increases in PhenoAge, PCPhenoAge, PCHorvath 2, PCHannum, PCGrimAge, and DunedinPACE. WC was positively associated with PCHorvath 2, PCHannum, PCPhenoAge, and DunedinPACE. BMI was positively associated with PCHannum, PCPhenoAge, and DunedinPACE. Conclusions Our study presents a novel approach to creating a BAA estimate using multiple epigenetic clocks and shows that adiposity measures predict this factor in a young Filipino cohort.

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.

Introduction: Eating behaviors are consistently associated with weight-related traits, yet the biological factors contributing to individual differences in these behaviors remain poorly characterized. Plasma proteomics offers an opportunity to investigate the biological processes underlying eating behaviors. Methods: Participants were 730 young adult twins from the FinnTwin12 cohort. Eating behaviors were measured through self-report questionnaires, including the Three-Factor Eating Questionnaire-R18 and four additional items on eating styles. Associations between plasma proteins and eating behaviors were examined using generalized estimating equation models adjusted for age and sex, with additional analyses adjusting for body mass index (BMI). Within-pair analyses were conducted in both monozygotic (MZ) and dizygotic twin pairs to assess whether associations were influenced by genetic or environmental factors. Results: We identified 51 significant protein-eating behavior associations involving 35 unique proteins (FDR <0.05). We observed 19 associations for the item "overeating when feeling down" and 12 for the TFEQ factor of emotional eating. The identified proteins were predominantly enriched in immune system pathways, including the complement cascade and adaptive immune signaling. After further adjustment for BMI, 12 associations persisted, most of which were associated with eating-style items, suggesting that BMI had a substantial influence on protein-eating behavior associations. Within-pair analyses of MZ pairs indicated that several associations persist after accounting for genetic effects. Conclusion: Our study identifies plasma proteins associated with eating behaviors, largely involving immune-related pathways. While some associations attenuated in twin analyses, several persisted, suggesting environmental influences. These results highlight potential biomarker candidates and indicate that modifiable environmental factors may contribute to the proteomic profiles associated with eating behaviors, with possible implications for weight-related traits.

Background and aims: Direct evidence to connect early life metabolism with cardiometabolic diseases in old age is limited due to the rarity of multi-decadal biochemical follow-up studies. To gain deeper insight into metabolic ageing, we conducted a longitudinal study that integrates serial data on clinical biomarkers, metabolomics and clinical events across the human life course. Methods: Children born in 1962-1992 were included from four European cohorts. Time-series of clinical biomarkers and metabolomics data were available for 8,653 participants (ages 0-49 years, 142 molecular and four physiological variables). Comparable data for 13,795 UK Biobank participants at two visits (ages 40-79 years) were linked with retrospective and prospective records of diabetes and cardiovascular disease. Lifetime metabolic trajectories were reconstructed by unsupervised machine learning and local polynomial regression. Results: A stable stratification in metabolic health emerged in children between ages 3 and 12 years and persisted to old age. We summarized this population pattern by assigning each participant into one of seven metabolic subgroups with characteristic biomarker trajectories. Two subgroups (MetDys TG+ and MetDys TG-) featured increased waist-height ratio from childhood, persistently higher C-reactive protein throughout life and rapidly increasing fasting insulin between 30 and 49 years of age. Both subgroups exhibited high risk for diabetes (HR > 13) and ischemic heart disease (HR > 2.5) when compared against the lowest risk subgroup (High HDL ApoB-). Conclusions: This life-course analysis shows that metabolic dysfunction associated with excess weight gain begins in early childhood and is associated with cardiometabolic morbidity in later life.

IP3R-Grp75-VDAC1 protein complex at the mitochondria-ER contact sites (MERCS) is involved in response to nutrients and control of glucose and energy metabolism, however, early alterations of the complex and MERCS in response to increased fat intake remain inconclusive. We investigated early effects of high-fat diet (HFD) on IP3R-Grp75-VDAC1 protein expression in correlation with ER-mitochondrial interaction in the liver of mice. Five-week-old mice were fed an HFD or a standard diet (SD) for 2 weeks (2W) or 8 weeks (8W). MERCS fractionation by a gradient ultracentrifugation, Western blot, transmission electron microscopy (TEM), Oroboros high-resolution respirometry were used to analyse liver tissues, while real-time PCR was used to profile genes responsive to HFD. No macroscopic morphological or functional alterations were observed in mice at 2W, while, expectedly, at 8W of HFD mice gained weight and glucose intolerance. Total IP3R protein was reduced at both 2W and 8W points by a post-transcriptional mechanism, while in MERCS, IP3R, VDAC1 and Grp75 were reduced at 8W time-point. TEM analysis revealed a significant reduction of mitochondrial coverage by MERCS, mitochondrial fragmentation and shortening of ER-mitochondria distance already at 2W time-point. Mitochondrial function and metabolism were largely spared. Markers of altered protein homeostasis such as Lmp2, Mecl-1 and Lmp7 showed an early upregulation. In conclusion, HFD induces early alterations in liver MERCS that precede gain of weight and glucose intolerance, suggesting their primary role in obesity and metabolic diseases and as potential therapeutic target.

Background: This prospective cohort analysis investigated how age, sex, and body morphology modify associations of physical activity (PA) intensity, duration, and volume with cardiovascular disease (CVD) mortality. Methods: We analysed wrist-worn accelerometer data from 8,661 adults (51.9% women) in the National Health and Nutrition Examination Survey. The outcome was CVD mortality. PA intensity and volume were quantified using the intensity gradient and average acceleration, respectively. Survey-weighted Cox proportional hazards models were used to estimate associations, including interaction terms with age, sex, or body morphology (waist-to-height ratio as indicator of adiposity). Results: Median (interquartile range) follow-up was 81 (69, 94) months. All hazard ratios (HR) compare 50th with 25th percentile. Beneficial associations between CVD mortality and PA were stronger in younger than older adults for intensity (e.g., 45-year-olds: HR=0.47, 95%CI:0.29-0.75 vs 75-year-olds: HR=0.75, 95%CI:0.54-1.06), and volume (e.g., HR=0.18, 95%CI:0.07-0.71 vs 0.29, 95%CI:0.16-0.51). In women, intensity-related association were stronger than in men (HR=0.45, 95%CI:0.31-0.65 vs HR=0.79, 95%CI:0.50-1.24). Volume-related associations were stronger in men (HR=0.37, 95%CI:0.22-0.60 vs HR=0.24, 95%CI:0.11-0.51), though with earlier plateauing and greater uncertainty. Associations were observed across waist-to-height ratio levels but attenuated at higher values (intensity: waist-to-height ratio 0.5, HR=0.45, 95%CI:0.29-0.69 vs 0.6, HR=0.69, 95%CI:0.49-0.97; volume: 0.5, HR=0.07, 95%CI:0.03-0.17 vs 0.6, HR=0.28, 95%CI:0.17-0.45). Conclusion: Older adults and men may benefit more from increasing PA volume than intensity, whereas younger adults and women may benefit more from higher-intensity PA. Although benefits were observed across adiposity levels, associations were attenuated as adiposity increased, suggesting stronger benefits in individuals with low-to-moderate adiposity.

{beta}2-Adrenergic receptor (Adr{beta}2) is the most abundant form of adrenergic receptors in skeletal muscle. Our previous studies have shown that the ventromedial hypothalamic nucleus (VMH) regulates metabolic benefits of exercise, potentially by skeletal muscle Adr{beta}2. Although a large body of literature has shown the importance of Adr{beta}2 on skeletal muscle physiology, it remains unexplored whether skeletal muscle Adr{beta}2 contributes to metabolic benefits of exercise, such as prevention of diet-induced obesity (DIO). Here, we generated mice lacking Adr{beta}2 in skeletal muscle cells (SKMAdr{beta}2) and tested whether SKMAdr{beta}2 is required for metabolic benefits of exercise on DIO. Deletion of SKMAdr{beta}2 completely abolished the induction of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1) in skeletal muscle by {beta}2-agonist, which is a potent activator of Pgc-1. Exercise upregulates Pgc-1, which regulates a broad range of skeletal muscle physiology, including hypertrophy and mitochondrial function. Deletion of SKMAdr{beta}2 hampers augmented Pgc-1 in skeletal muscle by a single bout of exercise. Intriguingly, we found that deletion of SKMAdr{beta}2 increased endurance capacity. Further, our data showed that body weight in DIO mice lacking SKMAdr{beta}2 is comparable to that of control DIO mice during exercise training, suggesting that deletion of SKMAdr{beta}2 did not affect the metabolic benefits of exercise in DIO. Collectively, our data indicate that SKMAdr{beta}2 contributes to exercise-induced transcriptional changes and endurance capacity, however, it is not required for exercise benefits on bodyweight in DIO mice.

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

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 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.

Excess body weight has been associated with increased cancer risk, but the role of weight change across adulthood remains unclear. We examined body weight trajectories from ages 17 to 60 and their associations with site-specific cancer incidence. Data were based on the ODDS study, a pooled, nationwide cohort study in Sweden, with data on weight spanning 1911 to 2020, and cancer follow-up through 2023. Weight trajectories were estimated with linear mixed effects models in individuals with at least three weight measurements. Cox regressions estimated hazard ratios for associations between weight trajectories and established and potentially obesity-related cancers. Fifth versus first quintile of weight change was associated with many cancers, most strongly with esophageal adenocarcinoma in men (HR 2.25; 95% CI 1.66-3.04), liver cancer in men (HR 2.67; 95% CI 2.15-3.33), endometrial cancer in women (HR 3.78; 95% CI 3.09-4.61), and pituitary tumors in both sexes (men: HR 3.13 [95% CI 2.13-4.61]; women: HR 2.13 [95% CI 1.41-3.22]). Associations varied by sex and age. Heavier weight at age 17 years and earlier obesity onset were also associated with higher cancer incidence. These findings highlight the importance of a life-course approach to weight management and support sex- and age-targeted cancer prevention strategies.

Obesity affects millions of people worldwide and has serious complications such as cardiovascular disease and diabetes. Current treatments for obesity target proteins such as the receptors for glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP) and/or glucagon (GCG). These interventions have revolutionized the treatment of obesity and represent first-line pharmacotherapeutic strategies. One major weakness to these strategies is that once drug treatment stops, most patients are unable to maintain the new body weight setpoint, often gaining weight back rapidly. Thus, the identification of new therapies that focus on the ability to maintain homeostatic setpoint are necessary. The glucocorticoid receptor (GR) has been implicated in several pathways including reward-seeking, inflammation, stress and energy balance. Here, we investigated the effects of 30 days treatment with PT150 (40 mg/kg), a novel GR antagonist, alone and in combination with semaglutide (30 nmol/kg) on food intake, glucose homeostasis, body weight and setpoint maintenance using a C57Bl/6 diet-induced obesity (DIO) mouse model. We monitored food intake and body weight throughout treatment and after drug washout for 20 days to evaluate defended body weight maintenance (body weight setpoint). Our results indicate that treatment with PT150 alone does not significantly alter body weight but in combination with semaglutide it shows the most promising effects in body weight reduction and homeostatic setpoint maintenance. Together, these data suggest that PT150, a GR modulator, may be effective as a homeostatic setpoint modulator when combined with semaglutide.

Background Higher levels of sedentary behaviour, such as leisure screen time (LST), and lower levels of physical activity are associated with diseases across multiple body systems which contribute to a large global health burden. Whether these associations are causal is unclear. The primary aim of this study is to investigate the causal effects of higher LST (given greater power) and, secondarily, lower moderate-to-vigorous intensity physical activity (MVPA), on a wide range of diseases in a hypothesis-free approach. Methods A two-sample Mendelian randomisation phenome-wide association study was conducted for the main analyses. Genetic single nucleotide polymorphisms (SNPs) were first selected as exposure genetic instruments for LST (hours of television watched per day; 117 SNPs) and MVPA (higher vs. lower; 18 SNPs) based on the genome-wide significant threshold (p < 5*10-8) from the largest relevant genome-wide association study (GWAS). For disease outcomes, we used summary results from FinnGen GWAS, including 1,719 diseases defined by hospital discharge International Classification of Diseases (ICD) codes in 453,733 European participants. For the main analyses, we used the inverse-variance weighting method with a Bonferroni corrected p-value of p [&le;] 3.47*10-4. Sensitivity analyses included Steiger filtering, MR-Egger and weighted median analyses, and data from UK Biobank were used to explore replication. Findings Genetically predicted higher LST was associated with increased risk of 87 (5.1% of the 1,719) diseases. Most of these diseases were in musculoskeletal and connective tissue (n=37), genitourinary (n=12) and respiratory (n=8) systems. Genetic liability to lower MVPA was associated with six diseases: three in musculoskeletal and connective tissue and genitourinary systems (with greater risk of these diseases also identified with higher LST), and three in respiratory and genitourinary systems. Sensitivity analyses largely supported the main analyses. Results replicated in UK Biobank, where data available. Conclusions Higher levels of sedentary behaviour, and lower levels of physical activity, causally increase the risk of diseases across multiple body systems, making them promising targets for reducing multimorbidity.

Childhood obesity remains a pressing global health challenge, yet the impact of dynamic adiposity changes during active developmental window retains poorly understood. Leveraging longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study (N=8519 at baseline; N=1873 at 4-year follow-up), our study reveals distinct neurodevelopmental implications of central fat dynamics during adolescence. At baseline, central fat indices (body roundness index, BRI / waist-to-height ratio, WHtR) outperformed BMI in predicting cognitive deficits, showing robust associations with impaired inhibitory control and episodic memory. The prediction effect was partially mediated by cortical changes in prefrontal and temporal regions. Longitudinally, the rate of fat accumulation ({Delta}) emerged as a critical predictor: faster adiposity accrual predicted attenuated cortical thinning (i.e., slower development) in parietal lobes and poorer executive function at follow-up, while baseline adiposity showed no significant effects on the follow-up brain morphology or cognitive development. Notably, subgroup analyses uncovered that obese adolescents with central fat reduction exhibited accelerated cortical thinning in posterior cingulate (change difference p=0.006-0.029) alongside rapid improvement in inhibitory control (Flanker slope difference p<0.05), whereas those with persistent adiposity showed delayed thinning in the postcentral gyrus. The study reveals that central fat (BRI/WHtR) is closely linked to neurocognitive risks, and longitudinal fat accumulation?rather than baseline adiposity?drives cortical alteration. Notably, fat reduction activated adaptive neural change in obese adolescents, underscoring the importance of weigh regulation during neurodevelopment.

Body fat distribution is a strong predictor of cardiometabolic disease risk. Gene-environment and gene-gene interactions can affect body fat distribution, resulting in differential phenotypic variance across genotype groups that can be detected through variance quantitative trait loci (vQTLs). Using UK Biobank MRI data in conjunction with genetic data, we explored evidence for vQTLs for body fat distribution phenotypes aiming to uncover potential genetic interactions. We identified three vQTLs for liver fat distribution, including rs738408 (PNPLA3), rs4293458 (APOE), and rs58542926 (TM6SF2), and one vQTL region (FTO) for abdominal subcutaneous adipose tissue. To dissect putative gene-environment and gene-gene interactions underlying these signals, we identified multiple vQTL-environment interactions and one epistatic effect (rs58542926*rs429358) for liver fat. The vQTLs and interaction results were validated in multiple UK Biobank and external replication cohort datasets (Framingham Heart Study, All of Us, and TwinsUK), showing replication of the three liver vQTLs with the greatest reproducibility for vQTL rs738408. Our findings uncover vQTLs and underlying interaction effects on body fat distribution, especially liver fat, that may be useful for the development of precision medicine approaches.

Background/ObjectivesIndividuals with Down syndrome (DS) are at increased risk of obesity and metabolic comorbidities, yet the mechanisms underlying these conditions remain unclear. Here we investigated how DS-associated genetic condition interacts with diet and metabolic pathways in the Dp(16)1Yey mouse model of DS. MethodsUntargeted plasma metabolomics was performed in Dp(16)1Yey and control mice, subjected to either control or high-fat diet (HFD). Raw data were processed, and features were annotated. Statistical analyses were conducted in R, and pathway analysis was performed with MetaboAnalyst v5.0. Fecal microbiome was obtained using 16SrRNAseq and analyzed using phyloseq in R. ResultsDiet exerted the strongest effect on mice plasma metabolome, followed by sex and genotype. Seventy-five diet-responsive metabolites were enriched in amino acid and nucleotide metabolism. Genotype-driven changes affected 34 metabolites, notably impacting amino acid and taurine-hypotaurine metabolism. Fifty-six sex-associated metabolites highlighted disruptions in aromatic amino acid biosynthesis and pyrimidine metabolism. A significant Diet*Genotype interaction was observed for five metabolites, including a marked reduction in the microbiota-derived metabolite 3-indolepropionic acid (IPA) in Dp(16)1Yey mice on HFD. Both genotype and diet exerted pronounced effects on fecal microbiome with selective depletion of the IPA-producing Clostridia in Dp1Yey mice under HFD. ConclusionSegmental trisomy in Dp(16)1Yey mice modulates the host metabolic response to dietary fat, partly through microbiota-derived metabolites such as IPA. These findings highlight the importance of genotype, diet, and microbiome interactions in shaping metabolic disease risk in DS and point toward microbiota-targeted dietary interventions.

Childhood socioeconomic position (SEP) can have lifelong effects on health. Many studies have used adult height as a surrogate marker for early-life conditions. In this study, we derived the non-genetic component of height, calculated as the residual from sex-specific standardized height regressed on genetically predicted height, as a surrogate for childhood SEP, using data from the Hispanic Community Healthy Study/Study of Latinos (2008-2011). A positive residual would indicate favorable early-life conditions promoting growth, while a negative residual indicates early-life adversity that may stunt the development. The height residual was associated with early-life variables such as parental education, year of birth, US nativity and age at first migration to the US (50 states/DC), supporting the validity of height residual as a surrogate for early-life conditions. Furthermore, a height residual was positively associated with better cardiovascular health (CVH) and cognitive function among middle-aged and older adults. Interestingly, among <35 years old, the height residual was negatively associated with the "Lifes Essential 8" clinical CVH scores. These results suggest the non-genetic component of height as a surrogate for childhood environment, with predictive value for CVH and cognitive function.

Loneliness--the perceived discrepancy between desired and actual social connection--is a common and aversive psychological state associated with a range of adverse health outcomes. Several theoretical models suggest that these associations may operate partly through health behaviors. In this preregistered study, we used data from the All of Us Research Program to evaluate associations of loneliness and functional rurality (FR), a study-specific contextual index of reduced neighborhood accessibility, with Fitbit-derived physical activity and sleep outcomes. Final samples included 16,912 participants for physical activity analyses and 13,937 for sleep analyses. In adjusted models, higher FR was associated with greater loneliness ({beta} = 0.061, 95% CI [0.045, 0.077], p = 9.63 x 10-14). FR and loneliness were independently associated with fewer daily steps and lower moderate-to-vigorous physical activity. Loneliness was also associated with shorter sleep duration, greater sleep duration variability, higher odds of short sleep, and higher odds of low sleep efficiency. FR was not associated with sleep duration or sleep duration variability but showed a small positive association with mean sleep efficiency and lower odds of low sleep efficiency. Interaction analyses provided little evidence that FR modified the associations of loneliness with most outcomes, although the FR x loneliness interaction was significant for sleep duration variability, indicating that loneliness was more strongly associated with irregular sleep duration in higher-FR contexts. Sensitivity analyses using stricter valid-day thresholds, winsorization, quartile-based exposure coding, and a backward 30-day window yielded directionally similar findings. These results suggest that FR and loneliness are independently associated with lower physical activity, whereas loneliness shows a more consistent relationship with adverse sleep patterns.