Obesity

Background and aimsThe optimal eating window for time-restricted eating (TRE) remains unclear. We investigated the effects of 8-hour TRE combined with usual care (UC, a Mediterranean diet-based education program), versus UC alone over 12 weeks on hepatic fat fraction, liver health markers, and fecal microbiota in adults with overweight or obesity. MethodsIn this multicenter randomized trial, participants (50% women) were assigned to UC (n=49), early TRE (n=49), late TRE (n=52), or self-selected TRE (n=47). Hepatic fat fraction was assessed by MRI; liver markers included elastography-based parameters, liver enzymes, and circulating biomarkers. Fecal microbiota was analyzed by 16S rRNA gene sequencing. ResultsHepatic fat fraction decreased significantly within the three TRE groups (all P[&le;]0.02), but no between-group differences were observed when comparing early TRE (mean difference [MD]: -0.4%; P=0.95), late TRE (MD: -1.5%; P=0.15), and self-selected TRE groups (MD: -0.7%; P=0.77) with the UC group, or among the TRE groups themselves (all P[&ge;]0.41). Similarly, no between-group differences were found in liver health markers and fecal microbiota. Participants with metabolic dysfunction-associated steatotic liver disease at baseline as well as those achieving [&ge;]5% weight loss had greater reductions in hepatic fat fraction than those who did not (MD: -2.7 and -2.6%; respectively, both P<0.001). A higher proportion of participants in the TRE groups achieved [&ge;]5% weight loss compared with UC (41-44% vs 16%; P=0.001). ConclusionThese findings suggest that the timing of the eating window in TRE may not impact liver fat or microbiota composition beyond the effects of weight loss, though the study was not powered for secondary outcomes. The study was registered on ClinicalTrials.gov (identifier: NCT05310721)

GLP-1 receptor agonist (GLP-1RA) discontinuation has been associated with weight regain. However, the real-world association between discontinuation of GLP-1RA prescriptions and weight change has not been explored. We assessed weight trajectories of 4,182 patients in the six months following their last GLP-1RA prescription. Approximately two-thirds of patients showed stable weight or continued weight loss during this period post the last known GLP-1RA prescription. In a representative subset of patients with clinician-documented discontinuation near the last prescription (N=300), a similar distribution of weight regain in a minority of patients was observed vs no regain in the majority of patients during the six-month post-GLP-1RA prescription period. To mirror clinical trial-style discontinuation definitions, we also evaluated cohorts with no subsequent GLP-1RA prescription for 1 year after the last prescription (semaglutide N=1,755; tirzepatide N=1,312), observing weight regain in a minority of patients (39.3% semaglutide; 26.6% tirzepatide) and no weight regain in the majority (60.7% semaglutide; 73.4% tirzepatide) in the year following the last known GLP-1RA prescription. Exercise counseling was documented more frequently among patients with durable weight loss post-last GLP1 prescription compared with those with weight regain (26.2% vs. 14.7%; p=0.04). Further studies are warranted to infer the mechanisms underlying these real-world patterns.

ObjectivesTo investigate clinical characteristics of users of weight loss drugs in Norway. DesignNested population-based case control study SettingNationwide healthcare registers in Norway with information on all dispensed medications linked to contacts with primary and specialist healthcare services. ParticipantsAll individuals aged 18-74 years with first dispensing of a weight loss drug (WLD) in 2023-2024, classified as initiators of 1) semaglutide (only Wegovy), 2) liraglutide (only Saxenda), 3) tirzepatide, 4) bupropion-naltrexone, or 5) orlistat. We matched each WLD user by sex and age to five controls randomly selected from the general Norwegian population. Main outcome measuresType and count of number of comorbidities diagnosed in the two years preceding initiation of WLD use, comedications dispensed in the preceding year, and any previous bariatric surgery. Differences between WLD users and population controls were estimated using conditional logistic regression adjusted for country of birth and education level. ResultsDuring 2023-24, 150,036 individuals initiated semaglutide, 4,603 liraglutide, 3,596 tirzepatide, 31,172 bupropion-naltrexone, and 1,411 orlistat. Among WLD users, 22-29% were registered without any of the pre-defined comorbidities, compared to around half of population controls. Comorbidities and comedications were generally observed at similar proportions in the different WLD user groups, but at much lower proportion for controls: hypertension: 32-38% of WLD users vs. 17-20% of controls; hyperlipidaemias: 20-24% vs. 12-15%; sleep apnoea: 7-11% vs. 2-3%; back pain: 15-20% vs. 10-11%; opioids: 24-30%vs. 13-15%; antidepressants: 20-24%vs. 10-11%. ConclusionsLike other countries, Norway faces the challenge of costly pharmacological obesity treatment, and the need for measures to mitigate increasing socioeconomic health disparities to ensure access to obesity treatment for those most likely to benefit including persons with multimorbidity. What is already known on this topicO_LIObesity is increasing worldwide and is associated with increased risk of multimorbidity. C_LIO_LIThe available treatment options for obesity have been rapidly and substantially transformed by the availability of new weight loss drugs. C_LI What this study addsO_LIThis nested case-control study within the Norwegian population examined clinical characteristics of new users of five weight loss drugs: semaglutide, liraglutide, tirzepatide, bupropion-naltrexone, and orlistat. The study identified a higher proportion of weight loss drugs users with cardiovascular, endocrine, mental, and other health conditions, as well as increased usage of cardiovascular, nervous system, and chronic pain medications, compared to the general population. C_LIO_LIThe majority of WLD users had high levels of multimorbidity and medication use compared to controls. Approximately 1 in 5 WLD users had no registered comorbidity in either primary or specialist health care systems. C_LIO_LIAdditionally, we noted differences in sociodemographic factors between users and population controls, such as lower education levels among WLD users. C_LIO_LIThe rapidly expanding use of weight loss drugs necessitates close attention from public health authorities. C_LI

Obesity and metabolic dysfunction are among the strongest risk factors for poor brain and mental health, yet the neural mechanisms linking metabolism, brain, and behaviour remains poorly understood. Here, we provide the first evidence for two distinct large-scale brain network configurations--one associated with metabolic health and another with obesity-- identified using resting-state fMRI data and metabolic phenotypes from a large community cohort (N = 564). While obesity was linked to enhanced coupling between subcortical reward and higher-order cortical networks, metabolic health was characterized by functional integration among default mode, salience, and frontoparietal control regions (metabolic health functional connectivity; MHFC). The MHFC network mediated the relationship between eating restraint and metabolic health, independent on individuals body weight and metabolic status, and it was replicated with data from a different time point. Longitudinal analysis showed that change of MHFC strength predicted metabolic indicators over time, suggesting a role for this network as a potential marker of metabolic resilience. These findings reveal a neurobiological pathway through which executive and interoceptive regulatory systems contribute to metabolic health, offering new insights into the brain mechanisms linking eating behaviour, metabolism, and brain function.

BackgroundThe role of adipokines in childhood glycemia is poorly understood. We investigate the longitudinal association between adipokines and glycemia in a cohort of children in Mexico City. MethodsChildren from the Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) cohort (948 children, 52% male) were followed longitudinally from birth. Leptin, adiponectin, glucose, and HbA1c were measured at four, six, and eight years, and fasting insulin at eight years. Adiponectin to leptin ratio (ALR) and HOMA2 indices were computed. Longitudinal associations were examined by linear mixed models and cross-sectional associations were examined by multivariable linear regression. All models were adjusted for maternal and child covariates. FindingsBetween ages four and eight years, average levels of leptin increased from 3{middle dot}2 to 10{middle dot}8 ug/mL; adiponectin dropped from 15{middle dot}7 to 13{middle dot}7 ng/mL; and ALR dropped from 9{middle dot}1 to 3{middle dot}1 ug/ng. Longitudinally, across timepoints four, six, and eight years after birth, there was no association between adipokines and glycemia. However, the cross-sectional analysis at age 8 years found an association between leptin and insulin (1{middle dot}0, 95% CI: 1{middle dot}0; 1{middle dot}1), HOMA2-B (1{middle dot}0, 95% CI: 1{middle dot}0; 1{middle dot}0), HOMA2-IR (1{middle dot}0, 95% CI: 1{middle dot}0; 1{middle dot}1), and HOMA2-S (0{middle dot}9, 95% CI: 0{middle dot}9; 0{middle dot}9). InterpretationFurther investigation is needed to understand the role of adipokines in the development of T2DM in children and the factors that may alter adipokine metabolism.

Background and AimsThe glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide has demonstrated efficacy for the secondary prevention of cardiovascular disease among patients with overweight/obesity without diabetes mellitus. However, the comparative effectiveness of GLP-1 RA versus other antiobesity medications (e.g. phentermine-topiramate) not been evaluated. MethodsThis was a retrospective, observational, cohort study using target trial emulation methodology using the Truveta electronic health record database of more than 120 million patients. Adult patients with a body mass index (BMI) >=27 kg/m2, a history of cardiovascular disease (prior ischemic stroke, transient ischemic attack, or myocardial infarction, or known coronary artery disease, heart failure, or peripheral artery disease) without diabetes mellitus were included in the study. The primary endpoint was time to first major adverse cardiovascular or cerebrovascular event (MACCE, defined as stroke or myocardial infarction). ResultsIn total, 35,240 were included in the bupropion-naltrexone versus GLP-1 RA comparison, and 27,051 were included in the phentermine-topiramate versus GLP-1 RA comparison. In the pre-weighting cohort, GLP-1 RA use was associated with decreased hazard of MACCE compared to bupropion-naltrexone (HR 0.50 [95% confidence interval (CI) 0.36-0.69]) and phentermine-topiramate (HR 0.43 [95% CI 0.30-0.60]). In the propensity score-overlap weighted cohort, GLP-1 RA prescription was not associated with a lower hazard of MACCE than bupropion-naltrexone (aHR 0.69 [95% CI 0.47-1.00]) but was associated with a lower hazard compared to phentermine-topiramate (aHR 0.61 [95% CI 0.41-0.91]; adjusted absolute rate difference 0.98 per 1000 person-years). ConclusionsPrescription of a GLP-1 RA was associated with a lower risk of subsequent MACCE than phentermine-topiramate.

BackgroundFat distribution patterns, rather than total adiposity alone, critically influence the risk of obesity-related diseases. However, due to correlations between fat accumulation in different regions, the contribution of regional fat to metabolic and non-metabolic diseases remains unclear. MethodsUsing UK Biobank MRI data (N = 23,548) and a Japanese cohort (N = 642), we used archetype analysis to identify patterns of predominantly isolated fat accumulation in the liver, pancreas, visceral adipose tissue, and thigh muscle. We then characterized the type 2 diabetes (T2D) risk, biomarker profiles, and broad health burden associated with isolated fat accumulation. FindingsWe identified four distinct patterns of isolated fat accumulation in the liver, thigh muscle, pancreas, and visceral adipose tissue and replicated these patterns in the Japanese cohort. Organ-specific fat accumulation was associated with an equal or greater T2D burden than isolated visceral adiposity, despite lower BMI and visceral fat amount. Moreover, specific fat depots were linked to distinct comorbidities not observed with visceral fat alone, including knee osteoarthritis (thigh myosteatosis), COPD (pancreatic steatosis) and breast cancer (hepatic steatosis). In contrast, total and visceral fat alone were not significantly associated with many of these complications. InterpretationThese findings highlight the central role of organ-specific fat accumulation beyond general adiposity in obesity-related diseases, offering new insight into the heterogeneity of obesity. FundingEuropean Research Council, European Union, and the Japanese Society for the Promotion of Science.

BackgroundVisceral adiposity is widely regarded as the pathogenic component of central obesity in cardiometabolic disease. However, emerging evidence suggests that abdominal subcutaneous adiposity may also confer metabolic risk in South Asian populations, although data in young, lean individuals are scarce. We investigated associations of MRI-measured abdominal subcutaneous adipose tissue (ASAT) and visceral adipose tissue (VAT) with cardiometabolic risk markers in young rural Indian adults. MethodsWe quantified ASAT and VAT using MRI in 590 participants (310 men) aged 18 years from the Pune Maternal Nutrition Study cohort. Sex-specific multiple regression models were used to examine associations with glucose-insulin indices, blood pressure, lipids, adipokines, and inflammatory markers. ResultsASAT showed broad and consistent associations with adverse cardiometabolic profiles, including higher 120-min glucose, dyslipidaemia, elevated blood pressure, leptin, CRP and leukocyte count, and lower insulin sensitivity and adiponectin, particularly in men; in women, ASAT was associated with most cardiometabolic risk markers except HDL-cholesterol. In contrast, VAT was associated with fewer risk markers and exhibited weaker, sex-specific patterns of association. Across outcomes, associations with ASAT were generally stronger than those observed for VAT. ConclusionsIn young, lean Indians, abdominal subcutaneous adiposity exhibits stronger associations with insulin resistance, dyslipidaemia and inflammation than visceral adiposity, challenging the prevailing VAT-centric paradigm derived largely from Western populations. These findings provide human evidence that the hierarchy of metabolic risk across abdominal fat depots is population-specific. This suggests genetic and early-life risk stratification, and supports early targeted preventive strategies. Research InsightsWhat is currently known about this topic? (max. 3 highlights, each < 100 characters) Indians have higher central obesity-adiposity than Europeans at similar BMI. Western data links VAT with cardiometabolic risk, while ASAT is protective. VAT & ASAT risk patterns vary across native and migrant South Asians. What is the key research question? (formatted as a question, < 100 characters) How do VAT and ASAT associate with cardiometabolic risk in lean rural Indian youth? What is new? (max. 3 highlights, each < 100 characters) ASAT shows stronger links with cardiometabolic risk than VAT in rural Indian youth. ASAT may contribute to high diabetes and CVD risk at low BMI in young Indians. How might this study influence clinical practice? (max. 1 highlight, < 100 characters) Early-life ASAT accumulation may raise later cardiometabolic risk, supporting early prevention strategies.

Introduction and ObjectivesMetabolic dysfunction-associated steatotic liver disease (MASLD) affects about one-quarter of adults worldwide, and liver fibrosis is its strongest predictor of liver-related morbidity and mortality. Using combined in-silico screening and clinical validation, we aimed to identify circulating biomarkers associated with fibrosis progression. Fibulin-3 was identified, and its diagnostic performance was evaluated in biopsy-proven MASLD cohorts. Materials and MethodsThe GSE125251 RNA-seq dataset was reanalyzed to compare liver transcriptomes from MASLD subjects with minimal (F0-F1) versus moderate to advanced fibrosis (F2/F3-F4). Differentially expressed genes (DEGs) were filtered to retain plasma-secreted, protein-coding candidates. Top-ranked genes were evaluated in liver biopsies from a morbidly obese cohort (n = 65) stratified by fibrosis stage, and their plasma levels were measured via ELISA in an independent bariatric cohort (n = 225). ResultsAmong 106 DEGs, 22 encoded plasma-circulating proteins. Six top candidates (EFEMP1, LTBP2, LUM, DPT, CHI3L1, CCL20) were prioritized. EFEMP1 (Fibulin-3) showed the strongest association with fibrosis, with significantly higher hepatic mRNA and protein expression in F2/F3-F4 versus F0-F1 (p < 0.005). Plasma Fibulin-3 levels correlated with fibrosis stage ({rho} = 0.40, p < 0.0001), increasing from 9.4 ng/mL in F0-F1 to 21.7 ng/mL in F2/F3-F4. Its diagnostic performance for F [&ge;] 2 (AUROC = 0.78) exceeded that of APRI, FIB-4, NFS, and HSI. A combined index including Fibulin-3, HSI, platelets, and GGT increased the AUROC to 0.87 (CI: 0.79-0.92). ConclusionsPlasma Fibulin-3 is notably higher in individuals with advanced MASLD and represents a promising non-invasive biomarker for liver fibrosis stratification in metabolically unhealthy obese populations.

BackgroundThe pancreas is essential for metabolic homeostasis. Alterations in morphology and parenchymal integrity may impact proper function but are not routinely used for risk stratification. Here, we propose an AI-pipeline to quantify pancreas volume and fat content from MRI to identify individuals at high-risk for cardiometabolic disease in the general population. MethodsWe quantified pancreas volume (milliliters, mL) and intrapancreatic fat content (defined as fat fraction; FF, %) from MRI of UK Biobank (UKB) and German National Cohort (NAKO) participants using deep learning. We 1) analyzed differences in volume and FF across age and sex, 2) computed percentile-curves and z-scores adjusted for age and sex to identify high-risk volumes/FF, and 3) conducted Cox regression to assess associations between z-score categories (volume: reference, z=-1 to 1; low, z=<-1; high, z>1; FF: low, z<1; moderate, z=0-1; high, z>1) and incident outcomes (diabetes, major adverse cardiovascular events (MACE), all-cause mortality) after adjustment for risk factors. ResultsAmong 63,548 UKB and NAKO-participants (57.7{+/-}12.8 years; BMI: 26.3{+/-}4.4 kg/m2, 46.9% female), automated pancreas analysis revealed a positive association between both volume and FF and age. In 33,099 UKB-participants (median 4.8 years follow-up), z-score categories were associated with incident diabetes (low volume, aHR:1.59, 95%CI[1.20-2.11]; high FF, aHR:1.70, 95%CI[1.31-2.19]), MACE (high volume, aHR: 0.79, 95%CI[0.61-1.01]; high FF, aHR: 1.32, 95%CI[1.01-1.73]), and all-cause mortality (low volume, aHR: 1.48, 95%CI[1.16-1.90]) beyond risk factors. Adding z-score categories to a baseline model including risk factors improved discrimination of future diabetes (volume:0.781 to 0.784, p=0.004; FF:0.781 to 0.787, p<0.001) and mortality (volume:0.781 to 0.787, p<0.001) ConclusionsDeviations from normalized pancreas volume and FF predicted cardiometabolic outcomes beyond known risk factors and alcohol intake. This automated approach identifies high-risk individuals who may benefit from cardiometabolic/endocrinology referral.

Cushings disease is caused by the overproduction of cortisol. The effects of this disease are well known in a general population, including high blood pressure, diabetes, and weight gain. Cushings disease causes both obesity and metabolic related symptoms, and it can be difficult to discern the obesity-dependent from the obesity-independent mechanisms of Cushings disease. To identify patients with Cushings disease, we identified 476 Michigan Medicine patients between January 1st 2000-2025 along with propensity-matched control cases. We stratified our participants by obesity status and into a Cushings disease group and a control group. As expected, the Cushings group had an elevated BMI compared to the control group (34 kg/m2 vs 29 kg/m2). We found a higher proportion of females diagnosed with Cushings compared to males (287 vs 72). Cushings disease was associated with an increase in the fasting glucose levels in both non-obese and obese patients. In both the obese, and non-obese patients, there was an increase in ALT and AST levels regardless of Cushings disease status, but the increase due to Cushings disease was much greater in the patients with obesity (73.4 vs 35.1 mg/dL). Cushings disease also had a moderating effect on blood pressure, with participants a BMI under 30 kg/m2 increasing by 12.6 mmHg and participants with obesity increasing by only 7.9 mmHg. These findings highlight the need to consider obesity status when evaluating the effects of Cushings disease.

BackgroundMetabolic dysfunction-associated steatohepatitis (MASH) is a prevalent and progressive liver disease with limited pharmacologic treatment options. Pemvidutide, a GLP-1-glucagon dual receptor agonist, has shown promise in targeting both hepatic steatosis and fibrosis. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of pemvidutide in adults with MASH. MethodsWe systematically searched PubMed, Scopus, Web of Science, and Cochrane CENTRAL through December 15, 2025, for randomized controlled trials (RCTs) comparing once-weekly subcutaneous pemvidutide (1.2 mg, 1.8 mg, or 2.4 mg) with placebo in adult MASH patients. Primary outcomes were changes in liver fat content (LFC, % via MRI-PDFF) and Enhanced Liver Fibrosis (ELF) score. Secondary outcomes included body weight, glycemic and lipid parameters, blood pressure, heart rate, and adverse gastrointestinal events. Dose-specific pairwise meta-analyses were performed using a random-effects model. ResultsThree RCTs encompassing 370 participants (195 pemvidutide, 175 placebo) were included. Pemvidutide significantly reduced LFC at all doses, with the greatest effect at 1.8 mg (MD = -21.63%, 95% CI: -27.23 to -16.02; p<0.0001). ELF score improvement was significant at 1.2 mg and 1.8 mg doses but not at 2.4 mg. Across all doses, body weight decreased significantly, while HbA1c remained unchanged. Pemvidutide also reduced systolic blood pressure and total cholesterol (1.8 mg and 2.4 mg), with modest HDL reduction at 2.4 mg. Mild-to-moderate gastrointestinal adverse events were observed, with nausea more frequent at 1.8 mg. ConclusionsPemvidutide is effective in reducing liver fat and improving cardiometabolic parameters in MASH, with a favorable safety profile. Dose-specific effects on fibrosis suggest potential early antifibrotic activity, highlighting its promise as a dual-targeted therapy for MASH. Further long-term studies are warranted to confirm sustained hepatic and metabolic benefits.

ImportanceInfants born small or large for gestational age exhibit different growth patterns compared with appropriate-for-gestational age counterparts. Evidence is lacking on how birth weight centiles beyond conventional thresholds predict early life growth. ObjectiveQuantify association of birth weight centile range with infant and child growth. DesignProspective cohort study. SettingFrance, Netherlands, Portugal, Singapore, United Kingdom, United States. ParticipantsSingletons from seven birth cohort studies with repeated growth measurements from age one week to 10 years. Five European cohorts were used for discovery analysis, and remaining cohorts for replication. ExposuresBirth weight centiles standardised for sex and gestational age using the INTERGROWTH-21st standards and classified into deciles. Main Outcomes and MeasuresInfant height (cm/month) and weight (g/month) velocity at 1, 6, 12, 24 months, body mass index (BMI: kg/m2) and age (months or years) at infancy BMI peak and childhood BMI rebound, and overweight/obesity at age 10 years. ResultsThe discovery analysis included 36,018 children (48% girls, birth years: 1991-2011). Growth velocity, peak BMI (mean: 17.7 vs. 17.3 kg/m2), age at peak BMI (10.2 vs. 10.4 months), rebound BMI (15.6 vs. 15.5 kg/m2), age at rebound BMI (5.3 vs. 5.0 years), and overweight/obesity prevalence were broadly similar in boys and girls. Compared with lowest birth weight decile (<10th centile), all higher decile groups had an initially lower height velocity that reversed by 24 months, an increasingly higher weight velocity through infancy, a higher and earlier peak BMI, higher rebound BMI, and a higher probability of overweight/obesity at age 10 years. For example, mean differences in BMI and age at peak BMI, and probability of overweight/obesity at age 10 years for the 7th (vs. 1st) birth weight decile were 0.77 kg/m2 (0.72 to 0.82), -0.58 months (-0.69 to -0.46), and 34% (18 to 49). Birth weight was not associated with age at rebound BMI. Replication analyses (n=2,517) supported findings. Associations were typically linear and consistent for boys and girls. Deciles provided only modest predictive gains over conventional categories. Conclusions and RelevanceBirth weight centiles may identify high-risk children missed by traditional thresholds, although predictive benefit over conventional groups was modest.

BackgroundDigital health self-monitoring tools are widely used to support weight management and metabolic health. Higher engagement with these tools is often associated with better clinical outcomes; however, real-world engagement-outcome relationships for consumer metabolic monitoring devices remain incompletely characterized, particularly in heterogeneous user populations. ObjectiveTo evaluate whether engagement with a portable breath-based metabolic device (Lumen; Metaflow Ltd.) is associated with greater weight loss and reduction in body fat among real-world glucagon-like peptide-1 receptor agonist (GLP-1RA) users. The study also explores correlations between engagement and a device-specific measure of metabolic flexibility (FLEX score). MethodsWe retrospectively analyzed 2,296 adult Lumen users who self-reported GLP-1RA use over 24 weeks. Engagement was quantified as total engagement days over a 24-week period and ordered engagement consistency groups defined by weekly use frequency thresholds. Weight and body fat percentage data were collected by a combination of connected devices and manual user input in the Lumen smartphone application. Associations with weight loss and reduction in body fat percentage were evaluated using linear regression and ANCOVA adjusted for age, baseline BMI, and sex, with HC3 robust standard errors. Body fat percentage data were available for only 490 of the 2,296 subjects. In addition, similar associations were evaluated for FLEX score. GLP-1RA exposure was self-reported at onboarding and not verified longitudinally. ResultsAt 24 weeks, low/medium/high engagement users lost 3.2%, 4.6%, and 5.2% of body weight (trend p=2.36x10-11). Engagement days were associated with percent weight change (slope -0.0214% per day; P(HC3)=7.9x10- 18). Engagement days showed modest association with body fat percentage change (n=490; slope -0.0105% per day; P(HC3)=.010). The adjusted ANCOVA trend across engagement groups was not significant (P=.19). Engagement days and consistency both showed a highly significant trend in increase in FLEX score (slope +0.0185 per day; P(HC3)=2.0x10- 36). ConclusionsIn a real-world digital health dataset, higher engagement with a breath-based metabolic monitoring device and its smartphone application was associated with greater 24-week weight loss after adjustment for age, baseline BMI, and sex. The absolute difference between low and high engagement (2.0% body weight) is modest but clinically meaningful in real-world settings after 24 weeks of tracking. Associations with body fat percentage change were smaller and not consistently significant in adjusted analyses. Associations with metabolic flexibility were highly significant, but it remains unknown whether this parameter is predictive or reflective. Prospective controlled studies are needed to test causality and determine whether device-driven biofeedback and sustained engagement independently improve outcomes because GLP-1RA use was self-reported and unverified, and the present analysis was observational. These findings should be interpreted as engagement-outcome associations and reflect behavioral motivation and adherence rather than evidence of device efficacy.

ObjectivesTo estimate potential launch prices of generic semaglutide following patent expiry from 2026 and to quantify the global obesity and type 2 diabetes (T2DM) burden in countries where generic access may become possible. MethodsWe used World Bank population data and World Obesity and Diabetes Atlas prevalence estimates to calculate obesity and T2DM burden in countries where semaglutide patents expire in 2026 or were not filed. Patent status was identified using MedsPaL and cross-checked with regional databases. We updated established cost-plus pricing methodologies using 2024-2025 Indian API shipment data to estimate production costs for oral and injectable semaglutide, incorporating formulation, packaging, taxation, and profit assumptions. ResultsTen countries with 2026 patent expiry represent 44% of the global population and 48% of the global obesity burden. No patent filings were identified in 150 additional countries. By the end of 2026, generic injectable semaglutide could be distributed in 160 countries where 69% of global T2DM and 84% of clinical obesity occurs. Estimated generic injectable costs ranged from $28-140 per person-year, while oral formulations ranged from $186-380 per person-year. Injection devices contributed disproportionately to total cost. ConclusionPatent expiry could substantially expand access to semaglutide at dramatically lower prices, particularly in high-burden settings. However, device costs, secondary patents, and health system constraints may limit equitable uptake without coordinated policy action. Study ImportanceO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LISemaglutide is highly effective for obesity and cardiometabolic disease but remains unaffordable in many low- and middle-income countries due to high branded prices and patent protections. C_LIO_LIPrevious cost-plus analyses show that generic competition can substantially reduce prices of essential medicines after patent expiry. C_LI What are the new findings in your manuscript?O_LIUsing 2024-2025 API shipment data, we estimate generic injectable semaglutide could be produced for $28-140 per person-year following 2026 patent expiry. C_LIO_LIBy 2026, generic semaglutide could be available in 160 countries comprising 69% of global T2DM and 84% of clinical obesity burden. C_LI How might your results change the direction of research or the focus of clinical practice?O_LIProvides an evidence base for procurement planning and price negotiations ahead of patent expiry. C_LIO_LIHighlights the importance of addressing device costs and secondary patents to ensure equitable global access. C_LI

The melanocortin 4 receptor (MC4R) plays a critical role in the central control of energy homeostasis and its disruption causes severe early onset obesity. The MC4R agonist Imcivree has been approved for the treatment of certain genetic obesity syndromes. Here we demonstrate that the membrane-spanning protein Attractin-like protein 1 (ATRNL1) directly interacts with MC4R to amplify its signaling in cells and that expression of ATRNL1 potentiates the activation of MC4R neurons by MC4R agonists in mice. Disruption of ATRNL1 in the PVN of the hypothalamus causes increased food intake and obesity, which cannot be rescued by MC4R agonist treatment. In exomes from 927 children with severe early-onset obesity, we identified 21 rare ATRNL1 variants. Eleven of 17 variants studied in cells impaired ATRNL1-mediated regulation of MC4R signaling, including variants ultra-rare or absent from UK Biobank and other populations. Cumulatively, these findings establish ATRNL1 as an important regulator of mammalian energy homeostasis.

BackgroundThe body roundness index (BRI), calculated from height and waist circumference, is a novel obesity metric proposed as an alternative to body mass index (BMI). Although the BRI is reportedly associated with mortality risk, little is known about how the performance of the BRI and BMI compare. MethodsWe used data from the SKDB, a regional healthcare database in Shizuoka, Japan, that includes data from >2 million people from 2012 to 2022. Individuals aged 40 to 74 years who received a Specific Health Checkups in 2013 were included and followed for up to nine years. We investigated the associations of the BRI and BMI with future risk of all-cause death and compared their predictive value using the net reclassification index (NRI) and c-statistics. ResultsAmong 202,133 individuals (median age: 66 years; 64.6% female; median BMI: 22.3 kg/m{superscript 2}), 10,336 deaths (5.2%) occurred over a median follow-up of eight years. Both the BRI and BMI demonstrated J-shaped associations with mortality risk. Incorporating the BRI or BMI into age- and sex-adjusted models improved NRI and c-statistics, with NRI increases of 5.6% (95% confidence interval [CI]: 3.6 to 7.1%) for BRI and 7.8% (95% CI: 6.0 to 9.6%) for BMI. The incremental improvements in the c-statistic were 0.48% (95% CI, 0.47 to 0.48%) for the BRI and 0.65% (95% CI, 0.64 to 0.65%) for BMI, whereas the BRI performed slightly worse than BMI (difference: -0.17%; 95% CI, -0.16 to -0.18%). ConclusionsAlthough BRI was predictive of mortality risk, the BRI did not outperform BMI in our population.

ObjectiveTo introduce and evaluate the clinical utility of the "adipo-B index" as a novel metric of the adipose tissue-pancreatic beta cell axis. To our knowledge, no prior clinical metric has integrated adipose tissue insulin resistance and pancreatic beta-cell function into a single index applicable across therapeutic classes. MethodsTreatment-naive subjects with T2DM received monotherapy with modified traditional diet for diabetes (MJDD, n=61), canagliflozin (n=67), pioglitazone (n=54), or sitagliptin (n=63). Correlations between the baseline and changes in adipo-IR or adipo-B and clinical parameters were analyzed. This is a prospective, non-randomized observational study. ResultsAt baseline, among all the subjects, adipo-B significantly correlated with FBG, HbA1c, non-HDL-C and BMI, while adipo-IR did not. At 3 months, across all therapeutic strategies, significant negative correlations were observed between the changes in ({Delta})adipo-B and baseline adipo-B. By contrast, in MJDD, canagliflozin and pioglitazone, significant negative correlations were seen between {Delta}adipo-IR and baseline adipo-IR, while with sitagliptin, no correlations were noted. {Delta}adipo-B, but not {Delta}adipo-IR, correlated with the improvements of glycemic (FBG, HbA1c) and lipid (non-HDL-C) parameters across all these therapies. While significant correlations were seen between {Delta}adipo-B and {Delta}adipo-IR with MJDD, pioglitazone and sitagliptin, canagliflozin uniquely "decoupled" this axis. With sitagliptin and pioglitazone, adipo-B improved despite weight gain. ConclusionThe adipo-B index is a superior indicator of systemic metabolic status and therapeutic response and could serve as a useful tool for precision therapy for diabetes.

Obesity-driven type 2 diabetes (T2D) is characterized by pathological alterations in visceral white adipose tissue (vWAT). While microRNAs (miRNAs) are key post-transcriptional regulators, comprehensive human vWAT profiling across metabolic states remains limited. This study characterized vWAT miRNA expression in lean, obese, and obese+T2D individuals to identify regulatory networks associated with metabolic failure. Deep miRNA sequencing was performed on vWAT samples from a discovery cohort, followed by validation via qPCR in an independent replication cohort. Differentially expressed miRNAs across the three groups were bioinformatically integrated with matched mRNA transcriptomic data to construct functional regulatory modules and identify enriched pathways underlying metabolic impairment. Several miRNAs exhibited robust and reproducible differential expression between obesity and obesity with T2D. Integrated miRNA-mRNA analyses revealed coherent regulatory modules involving inflammation, lipid metabolism, insulin signaling, and iron homeostasis. Specifically, miR-141-3p, miR-200b-3p, miR-15b-3p, miR-12136, and miR-585-3p showed consistent differential expression. Notably, miR-141-3p and miR-200b-3p were markedly upregulated and inversely associated with metabolic stress-related genes, including TF and FBXO32. Several miRNAs correlated with clinical markers of metabolic dysfunction, supporting their biomarker potential. By comparing lean, obese, and diabetic populations, this study provides a comprehensive characterization of the vWAT miRNA landscape and identifies specific miRNA-mRNA regulatory circuits that orchestrate the transition from healthy adiposity to pathological adipose tissue dysfunction. These findings pinpoint novel molecular drivers of type 2 diabetes progression and offer potential targets for therapeutic intervention in metabolic endocrine disorders.

BackgroundDysbiosis of gut microbiota plays a key role in type 1 diabetes mellitus (T1DM). Fecal microbiota transplantation represents a novel therapeutic avenue. We hypothesize that youth-derived fecal microbiota transplantation (yFMT) can remodel the gut microecosystem and improve clinical outcomes. This study aims to investigate the efficacy and safety of orally administered yFMT capsules in adults with T1DM. Methods and analysisThis single-center, randomized, double-blind, placebo-controlled pilot study will enroll adults with T1DM who have suboptimal glycemic outcomes (glycated hemoglobin[HbA1c] of 7-14% and time in range [TIR] <70%). Following a 17-day run-in period for insulin optimization, continuous glucose monitoring(CGM) wearing, baseline assessments and bowel preparation, participants will be randomly allocated (1:1) to take yFMT or placebo capsules for consecutive 6 days, alongside their standard insulin therapy, and then complete a 12-week follow-up. The primary efficacy endpoint is the change from baseline in the rate of achieving the composite target of TIR>70% and time below range<4% at 4 and 12 weeks post-randomization. Secondary efficacy endpoints comprise changes from baseline at weeks 4 and 12 in other glycemic metrics (including HbA1c, fasting glucose, 2-hour postprandial glucose, and additional CGM metrics), C-peptide, immune responses, infection markers, and gut microbiota composition. Changes from baseline at week 12 in serum metabolomic profiles will also be assessed, encompassing bile acids, short-chain fatty acids, and other related metabolites. Safety endpoints include the incidence of adverse events and serious adverse events. DiscussionOur findings will offer new insight into the feasibility and effects of oral yFMT in adult with T1DM and provide the necessary evidence to power a subsequent multicenter large-scale study. Exploratory biomarker analyses conducted within this study may further pave the way for future individualized microbiome-based therapeutics. Trial registrationChinese Clinical Trial Registry identifier: ChiCTR2500111955 (November 7, 2025).