Obesity

ObjectiveDespite the obesity crisis in the United States, the underlying genetics are poorly understood. Our lab previously identified Keratinocyte-associated protein 3, Krtcap3, as a candidate gene for adiposity where increased expression of Krtcap3 correlated with decreased fat mass. Here we seek to confirm that Krtcap3 expression affects adiposity traits. MethodsWe developed an in vivo whole-body Krtcap3 knock-out (KO) rat model. Wild-type (WT) and KO rats were placed onto a high-fat or low-fat diet at six weeks of age and were maintained on diet for 13 weeks, followed by assessments of metabolic health. We hypothesized that Krtcap3-KO rats will have increased adiposity and a worsened metabolic phenotype relative to WT. ResultsWe found that KO male and female rats have significantly increased body weight versus WT. KO females ate more, had more fat mass, but were also more insulin sensitive than WT. Alternatively, KO males weighed more and were more insulin resistant than WT, with no differences in eating or fat mass. ConclusionsThis study validates Krtcap3 in body weight regulation and demonstrates sex-specific effects on food intake, adiposity, and insulin sensitivity. Future studies will investigate how Krtcap3 is acting and seek to better understand these sex differences. Study Importance QuestionsWhat is already known about this subject? O_LIOver 900 low-risk, common genetic variants for BMI have been identified, but these still only explain a fraction of the heritability and many of the underlying causal genes remain unknown C_LIO_LIKrtcap3 has been identified as a candidate gene for obesity in both rats and humans, but no verification or functional studies have been done C_LI What are the new findings in your manuscript? O_LIIdentified Krtcap3 as a novel gene that impacts feeding behavior and adiposity in female rats C_LIO_LIDetermined that Krtcap3 impacts insulin sensitivity differentially in male and female rats C_LI How might your results change the direction of research or the focus of clinical practice? O_LIThis work may lead to identification of new pathways that contribute to obesity without metabolic complications, which will advance understanding of the biology of obesity and potentially identify novel drug targets C_LIO_LIThis work highlights the need to investigate sex differences in the genetics of obesity C_LI

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.

ObjectiveCold exposure is one of the most powerful physiological stimuli for thermogenic adipose tissue activity and may positively impact metabolic homeostasis. An important gap in knowledge is whether mice with diet-induced obesity respond to cold similarly to their lean counterparts. The goal of the present study was to compare the response to cold exposure between mice fed a standard (normal-fat) diet and a higher-fat diet. MethodsMale C56BL/6J mice fed a standard diet (13.1% fat) or a higher-fat diet (21.6% fat) during adulthood and exposed to cold (4-6{degrees}C) following different approaches. Body weight, body composition, food intake, rectal temperature, energy expenditure, and respiratory exchange ratio were assessed. ResultsCold exposure significantly increased energy expenditure and limited weight gain despite elevated food intake in mice fed either a standard or a higher-fat diet, while body composition, body temperature, and respiratory exchange ratio remained stable across both dietary groups. Moreover, energy expenditure measured at 4-6 {degrees}C was comparable between mice fed standard and higher-fat diets, demonstrating that cold-induced thermogenesis may elicit a consistent metabolic response independent of dietary fat content. ConclusionsOur results demonstrated that cold exposure increased energy expenditure in both lean and obese animals, highlighting thermogenesis as a promising target for obesity treatment beyond current approaches focusing on appetite suppression. HighlightsO_LICold exposure increases energy expenditure and limits weight gain in both control diet and higher-fat diet-fed mice, despite increased food intake. C_LIO_LICore body temperature and body composition remain stable during cold exposure, regardless of dietary fat content. C_LIO_LICold-induced thermogenesis elicits a comparable metabolic response in control diet and higher-fat diet-fed mice, supporting its potential as a therapeutic strategy for obesity. C_LI

IntroductionSemaglutide is an effective intervention for weight loss, but the relative contributions of fat and fat-free mass (FFM) to total weight loss remain unclear. MethodsThis was a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating semaglutide use in adults living with overweight or obesity. Searches were performed in PubMed, Web of Science, Embase, and Scopus through April 2025. Eligible trials reported baseline and post-treatment measures of body mass, fat mass, and FFM. Data extraction followed PRISMA guidelines, and risk of bias and certainty of evidence were assessed. Random-effects models were applied, with linear or quadratic functions fitted as appropriate. ResultsSeven RCTs involving 452 participants (259 semaglutide, 193 placebo) met the inclusion criteria. Semaglutide produced significant non-linear weight loss (0.04 kg/day; 95% CI 0.03-0.05; p<0.0001), primarily due to fat mass reduction (0.03 kg/day; 95% CI 0.01-0.05; p=0.007). FFM declined linearly at a smaller rate (0.007 kg/day; 95% CI 0.003-0.010; p=0.0001). Certainty of evidence was moderate. ConclusionSemaglutide induces substantial reductions in body and fat mass, with modest FFM loss. Clinical strategies combining semaglutide with resistance exercise and nutritional support may help preserve lean mass and optimize long-term outcomes.

Obesity is a growing epidemic associated with a range of comorbidities, including anxiety and depression. Genetics and environmental factors such as diet contribute to both adiposity and anxiety/depression. Heterogeneous stock (HS) rats are an outbred colony and useful for genetic mapping of complex traits. We have previously shown that HS male rats exhibit worsened metabolic and behavioral health in response to high fat diet (HFD). This study aims to determine if females have similar response to diet and if response to diet interacts with genetic background. We measured multiple metabolic (body weight, fat pad weight, glucose tolerance, fasting glucose and insulin) and behavioral (elevated plus maze, open field test, and forced swim test) outcomes in a large cohort of male and female rats on either HFD or low fat diet (LFD). We estimated overall heritability as well as heritability of response to diet for each outcome. Both sexes showed worsened metabolic measures when fed HFD compared to LFD. In contrast, only males exhibited altered behavioral responses to HFD relative to LFD, with no effect in females. Most metabolic and behavioral measures showed overall heritability in both sexes. In contrast, although there was some evidence for gene by diet (GxD) interactions for behavioral measures in males, GxD interactions were generally not found for the metabolic measures. These data demonstrate an important role of diet, sex and genetics in metabolic and behavioral phenotypes in HS rats, with a potential role of gene by diet interactions for behavioral outcomes only in males.

BackgroundObesity is associated with increased risk of morbidity, reduced quality of life, and pervasive weight stigma. For patients with severe obesity and multimorbidity who are ineligible for bariatric surgery, effective treatment options remain limited. Recently, glucagon-like peptide 1 receptor agonist-based weight loss medications have shown promise in weight management, but their effects in highly complex patient populations are not well described. ObjectiveThis protocol outlines a prospective observational study designed to explore and describe changes in cardiometabolic health, physical activity, physical capacity, and wellbeing among patients with obesity and multimorbidity enrolled in a two-year intensive weight loss program with GLP-1RA medication. MethodsThe study uses an exploratory prospective longitudinal cohort design and is based on an intensive weight loss program for patients with obesity and multimorbidity at Copenhagen University Hospital - Hvidovre. Approximately 35 patients will be enrolled over a six-month period. Data are collected at baseline, four months, and 24 months. Key outcomes include objectively measured physical activity, health-related quality of life, and 10-year cardiovascular risk. Additional outcomes include anthropometrics, mental health-related quality of life, weight bias internalization, cardiorespiratory fitness, lower body strength, and walking capacity. Data will be analyzed descriptively, and changes will be reported as mean differences with 95% confidence intervals. The study was registered at clinicaltrials.gov prior to recruitment (NCT06234111). PerspectiveThis study will provide novel insights into the health effects of intensive GLP-1RA-based weight loss program for patients with severe obesity and multimorbidity ineligible for bariatric surgery, thereby addressing an important knowledge gap in obesity management. Trial RegistrationThe study has been pre-registered with clinicaltrials.gov prior to inclusion of the first participant (NCT06234111). Project groupO_ST_ABSSemPAct project groupC_ST_ABSRasmus H. Brodsgaard (principal investigator), Thomas Bandholm, Kirstine N. Bojsen-Moller, Carsten Dirksen, Jeanette W. Kirk, Mette M. Pedersen, Sara O. Hofmann, Emilie S. Larsen, Minna Titika Finken, and Olivia M. Duun.

ObjectiveThis study sought to determine whether the drive to regain weight following weight loss was truly long-lived in mice. MethodsWe generated a model of reduced dietary obesity (ReDO) whereby male mice with diet-induced obesity (DIO) mice were calorically restricted until weight matched to control mice, and then after a 24-hour food assessment period were pair-fed relative to control mice. We subsequently generated ReDO mice that, after CR were pair-fed relative to control mice for 0, 8, or 28 days, or chronically. Body weight, food intake, and select metabolic parameters were measured, along with whole hypothalamic Pomc gene expression. ResultsReDO mice in both experiments exhibited hyperphagia following CR, while a persistent form of hyperphagia was detected in ReDO_8d and ReDO_28d mice relative to control and chronically pair-fed mice. 4-week initial weight gain was predictive of the degree of weight regain across ReDO_8 and ReDO_28 mice. ConclusionsReDO mice exhibit a long-lived form of hyperphagia and an apparent drive to reclaim an upwardly shifted body weight set point. There was considerable variability with regard to ReDO_8 and ReDO_28 body weight regain which was correlated with the of initial degree of 4-week body-weight gain when first exposed to a high-fat diet. This study showcases the perdurance of weight loss-associated hyperphagia and introduces a prognostic tool for identifying mice that are prone towards weight regain, while setting the stage for future inquiries into the neurobiological basis of persistent hunger following weight loss owed to a dietary intervention in mice.

ImportanceChildhood obesity is a risk factor for type 2 diabetes (T2D), cardiovascular disease, and mental disorders later in life. To investigate the parallel effects on cardiometabolic and mental health in children with overweight or obesity will provide new insights on the benefits of exercise on overall health. ObjectiveThis study aimed to investigate the effects of a 20-week exercise program on cardiometabolic and mental health in children with overweight or obesity. DesignParallel-group randomized clinical trial (RCT) conducted in Granada (Spain) from November 2014 to June 2016. SettingClinical setting. ParticipantsEligibility criteria included children with overweight or obesity aged 8 to 11.9 years from Granada (Spain) and surrounding areas. InterventionThe exercise program included 3-5 sessions/week (90 min/session) of aerobic plus resistance training for 20-weeks. The wait-list control group continued with their usual routines. Main Outcomes and MeasuresCardiometabolic outcomes included body composition (fat mass, fat-free mass, and visceral adipose tissue), physical fitness (cardiorespiratory, speed-agility, and muscular), and traditional risk factors (waist circumference, blood lipids biomarkers, glucose, insulin, and blood pressure). Cardiometabolic risk score (z-score) was calculated based on age and sex reference values for triglycerides, inverted high-density lipoprotein cholesterol, glucose, the average of systolic and diastolic blood pressure, and waist circumference. An additional cardiometabolic risk score also included cardiorespiratory fitness. Mental health outcomes included an array of psychological well-being and ill-being indicators. ResultsThe ActiveBrains exercise program reduced the cardiometabolic risk score by [~]0.4 (95% confidence interval [CI95%]: -0.75, -0.03) standard deviations (SD). The exercise program had a positive effect on low-density lipoprotein cholesterol (-7.40 [CI95%: -14.82, 0.016] mg/dL), body mass index (-0.60 [CI95%: -1.07, -0.13] kg/m2), fat mass index (-0.70 [CI95%: -1.03 to -0.36] kg/m2), visceral adipose tissue (-34.05 [CI95%: -61.38, -6.73] g), and cardiorespiratory fitness (+3.07 [CI95%: 0.68, 5.45] laps) in the exercise group compared to controls. No effects were observed on mental health outcomes. Conclusions and RelevanceThe ActiveBrains exercise program improved cardiometabolic health in children with overweight or obesity, yet it had no effect on mental health. These findings support public health initiatives promoting exercise programs in children with excess body weight to prevent future cardiovascular comorbidities. Trial RegistrationClinicalTrials.gov Identifier: NCT02295072. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the parallel effects of exercise on cardiometabolic and mental health in children with excess of adiposity? FindingsIn this parallel-group randomized clinical trial of 109 children with overweight or obesity, a 20-week exercise program including aerobic plus resistance training improved body composition, cardiorespiratory fitness, and cardiometabolic risk factors. No effects on mental health were observed. MeaningExercise programs should be promoted in children with excess adiposity to improve their cardiometabolic health.

BackgroundOverweight and obesity are widespread among children and adolescents. We aimed to summarize the evidence for the pharmacotherapy as an adjunct to lifestyle interventions in overweight or obese children and adolescents by comparing the benefits and harms. MethodsRCTs (randomized controlled trials) were sourced from PubMed, Embase (using the OVID platform), the Cochrane Library (CENTRAL), as well as the trial registers ICTRP (WHO) and ClinicalTrials.gov. Searches were undertaken from inception to April 25, 2023. A network meta-analysis was performed using the frequentists framework based on random-effects model. We used GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach to evaluate the overall certainty of evidence and categorized the interventions. ResultsIn total, 42 RCTs (n=3883) comparing 8 different pharmacotherapy strategies were included in this study. Evidence strongly suggested that phentermine-topiramate reduced BMI the most (the mean difference (MD) -4.83 [95% CI, -7.46 to -2.20] kg/m2) and weight (MD, -14.59 [95% CI, -19.37, -9.81] kg) in children and adolescents with overweight or obesity. Compared to lifestyle intervention alone, phentermine-topiramate was associated with an additional 557 events per 1000 person-years in terms of the proportion of participants achieving a BMI reduction of [&ge;]5%, but there was no increased harm in total gastrointestinal adverse effects and discontinuation due to adverse events. ConclusionsPhentermine-topiramate was closely related to weight loss and showed a good tolerability, proving to be the optimal treatment strategy for overweight or obese children and adolescents. RegistrationPROSPERO registry number: CRD42022329226

BackgroundAlthough poor sleep health is associated with weight gain and obesity in the non-pregnant population, research on the impact of sleep health on weight change among pregnant people using a multidimensional sleep-health framework is needed. This study examined associations among mid-pregnancy sleep health indicators, multidimensional sleep health, and gestational weight gain (GWG). MethodsWe conducted a secondary data analysis of the Nulliparous Pregnancy Outcome Study: Monitoring Mothers-to-be Sleep Duration and Continuity Study (n=745). Indicators of individual sleep domains (i.e., regularity, nap duration, timing, efficiency, and duration) were assessed via actigraphy between 16 and 21 weeks of gestation. We defined "healthy" sleep in each domain based on empirical thresholds. Multidimensional sleep health was based on sleep profiles derived from latent class analysis. Total GWG, the difference between self-reported pre-pregnancy weight and the last measured weight before delivery, was converted to z-scores using gestational age- and BMI-specific charts. GWG was defined as low (<-1 SD), moderate (-1 or +1 SD), and high (>+1 SD). ResultsNearly 50% of the participants had a healthy sleep profile (i.e., healthy sleep in most domains), whereas others had a sleep profile defined as having varying degrees of poor health in each domain. While indicators of individual sleep domains were not associated with GWG, multidimensional sleep health was related to low and high GWG. Participants with a sleep profile characterized as having low efficiency, late timing, and long sleep duration (vs. healthy sleep profile) had a higher risk (RR 1.7; 95% CI 1.0, 3.1) of low GWG a lower risk of high GWG (RR 0.5 95% CI 0.2, 1.1) (vs. moderate GWG). ConclusionsMultidimensional sleep health was more strongly associated with GWG than individual sleep domains. Future research should determine whether sleep health is a valuable intervention target for optimizing GWG. SynopsisO_ST_ABSStudy questionC_ST_ABS- What is the association between mid-pregnancy multidimensional sleep health and gestational weight gain? Whats already known?- Sleep is associated with weight and weight gain outside of pregnancy What does this study add?- We identified patterns of sleep behaviors associated with an increased risk of low gestational weight gain

Objective: To investigate the effects of breaking up prolonged sedentary behavior (SB) on daily movement behavior and energy balance in adults with overweight/obesity. Methods: Thirty 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. Results: Only 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<0.012), 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. Conclusions: Spreading 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.

AimsTo characterize trends in the initiation of newer anti-obesity medications (AOMs) and determine factors associated with their use among obese/overweight populations. Materials and methodsThis retrospective study utilized electronic health record data from OneFlorida+ (2015-2024). Adults eligible for AOMs were included, defined as having a BMI [&ge;]30 kg/m{superscript 2} or a BMI of 27-29.9 kg/m{superscript 2} with at least one obesity-related comorbidity. The primary outcome was the initiation of newer AOMs, specifically glucagon-like peptide-1 receptor agonists (GLP-1 RAs) including liraglutide, semaglutide, and tirzepatide. Trends across years were examined, and a multivariable logistic regression identified sociodemographic, clinical, and healthcare utilization factors associated with AOM initiation. ResultsOf 319,949 adults, 1.8% initiated newer AOMs. Semaglutide accounted for 77.9% of initiations, tirzepatide 19.7%, and liraglutide 17.8%. Initiation trends showed liraglutide uptake peaked at 5% in 2018 but declined afterward, while semaglutide and tirzepatide uptake increased exponentially since 2022. Odds of initiation were lower for Black (aOR (95% CI): 0.87 [0.80- 0.94]) and Hispanic (0.84 [0.78-0.91]) groups vs. Whites, and for Medicaid (0.69 [0.63-0.76]) and uninsured (0.81 [0.74-0.87]) patients vs. privately insured. Higher odds were associated with being female, middle-aged, having more outpatient visits, and visiting endocrinologists. ConclusionsThe initiation of newer AOMs among overweight and obese populations remains low, but uptake has increased exponentially since 2022. Our findings reveal significant disparities in obesity care, highlighting the importance of addressing inequities in AOM access to improve obesity 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

Background and aimsThe relationships between obesity-related traits and the brains white matter characteristics and the context of sex- and age-related differences, remain unclear. This study aims to elucidate these body-brain connections using a large-scale dataset. MethodsWe analyzed data from 40,040 participants from the UK Biobank (52.2% female; ages 44-83 years) using multiple linear regression to evaluate associations between obesity-related traits (obesity, body anthropometrics) and white matter diffusion tensor imaging (DTI) metrics (fractional anisotropy, axial diffusivity, radial diffusivity, mean diffusivity). We also examined interactions with age and sex. ResultsOur analyses revealed significant associations between obesity-related traits and DTI metrics with partial correlation coefficient |r| effect sizes ranging from 0.02 to 0.20 for most regions of interest with largest effects in brainstem tracts. We observed more widespread sex-by-obesity-related than age-by-obesity-related interaction effects on DTI metrics. ConclusionsOur results link obesity-related traits and white matter phenotypes, suggesting that shared body fat-related pathways linking physical and brain health that may vary based on sex and age. Understanding these relationships could enhance the development and evaluation of targeted, individualized, treatment strategies for conditions that co-occur with obesity, although further longitudinal studies are needed to map the dynamics of these associations.

Osteoporosis, amenorrhea, and low energy with or without disordered eating (the female athlete triad) are frequent clinical outcomes associated with female athletes in constant low energy availability (LEA). The rigorous training demands of the Army and the strict weight limits suggest that female service members may be susceptible to states of LEA, where energy expenditure exceeds dietary energy intake. To understand the prevalence of the female athlete triad among female service members and how restrictive weight requirements influence these symptoms, we compared survey responses measuring symptoms of the female athlete triad between female active-duty service members and female veterans. The results indicated that female veterans had significantly higher female athlete triad and disordered eating scores. Therefore, female veterans are more likely to demonstrate female athlete triad symptoms than active-duty service members. Specifically, female veterans are more likely to demonstrate symptoms of low energy with or without disordered eating. Female veterans unique stressors of no longer being in the military (reintegration into society and losing support system within the military) could be why they are more likely to present with female athlete triad symptoms than active-duty female service members.

Background & AimsWeight loss is associated with an improvement of insulin sensitivity. Both, a negative energy balance and changes of body composition are integrative components of weight loss interventions. However, the individual impact of these two components on insulin sensitivity and energy metabolism is unclear. MethodsWe performed a randomized controlled trial including 80 overweight or obese post-menopausal women. Participants randomly assigned to the intervention group underwent an 800 kcal/d liquid diet for 2 months followed by four weeks in which the formula diet was substituted by a calorie reduced healthy diet to facilitate further weight loss. This weight loss phase was followed by a 4-week weight maintenance phase, where weight stability was achieved by individualized daily caloric intake without negative energy balance. Volunteers of the control group were instructed to keep their weight stable during the entire period of 4 months. Metabolic phenotyping was performed in both groups at baseline (M0), after weight loss (M3) and after the maintenance period (M4). Additional phenotyping was performed during follow-up at 12 (M12) and 24 months (M24). Primary outcomes were changes of lean body mass (LBM) and changes of insulin sensitivity (ISIClamp) between baseline and M3 and M4. Estimates of energy metabolism were secondary endpoints. ResultsNo significant changes of body weight or LBM were found in the control group between any time points. A significant reduction of body weight, fat mass (FM) and LBM was found in the intervention group between M0 and M3, while no further change was seen between M3 and M4. Only subjects of the intervention group were characterized by an improvement of the second primary outcome ISIClamp at M3, which was preserved until M4. Notably, a lower resting energy expenditure per LBM (REELBM) at M3 as well as the individual difference of REELBM between M3 and M4 significantly predicted a stronger regain of fat mass during follow-up. ConclusionsIn summary, our data demonstrate that modulation of LBM and insulin sensitivity during weight loss is predominantly driven by changes in body weight and body composition, rather than an individual effect of negative energy balance. However, the variance in energy expenditure during negative and steady energy balance indicates a thrifty phenotype, which is highly susceptible to future regain of fat mass.

Glucagon-like peptide-1 receptor (Glp1r) agonists have transformed obesity treatment, but weight loss responses to these drugs vary widely. Elucidating behavioral and metabolic phenotypes throughout Glp1r agonist treatment could identify mechanisms underlying this response spectrum. We characterized food intake, meal patterns, energy expenditure (EE), and substrate oxidation during chronic semaglutide treatment and post-treatment recovery in obese male mice at room temperature (RT) and thermoneutral temperature (TN). Semaglutide-induced weight loss and post-treatment weight regain were similar at RT and TN. Weight loss was divided into three stages at both temperatures: 1) rapid initial weight loss, 2) slower gradual weight loss, and 3) weight maintenance. Initial weight loss was marked by reduced food intake, smaller and less frequent meals, and increased lipid oxidation. Food intake gradually returned to pre-treatment levels through increased meal frequency, while meal size remained suppressed. Lipid oxidation gradually decreased while carbohydrate oxidation increased. Weight-adjusted EE and locomotor activity increased throughout semaglutide treatment. Mice rapidly regained weight after treatment cessation, and this was associated with increased food intake, meal size and frequency, carbohydrate oxidation, EE, and activity. These findings reveal that semaglutide-induced weight loss and regain after treatment cessation involve dynamic, stage-specific changes in feeding behavior, EE, and substrate oxidation. ARTICLE HIGHLIGHTSO_LIAlthough many studies demonstrate acute behavioral and metabolic effects of glucagon- like peptide-1 receptor (Glp1r) agonists, few have assessed chronic effects of these drugs on these phenotypes. C_LIO_LIWe wanted to assess changes to various behavioral and metabolic phenotypes throughout a chronic treatment regimen with semaglutide and post-treatment. C_LIO_LIWeight loss in response to chronic semaglutide treatment can be divided into distinct phases, and each phase is characterized by different effects on food intake, meal patterns, energy expenditure, and substrate oxidation. C_LIO_LIOur findings suggest that differences in behavioral changes and/or metabolic adaptations may underlie the degree of weight loss responsiveness to Glp1r agonists. C_LI

BackgroundChildhood obesity and precocious puberty (PP) are escalating public health concerns with a significant comorbidity. Emerging evidence implicates gut microbiota dysbiosis in both conditions, yet microbial associations with their co-occurrence remain unexplored. MethodsA total of 68 girls (18 normal, 25 PP-only, 18 obesity-only, and 7 obesity-PP comorbidity) were enrolled. 16S rRNA sequencing was applied to determine gut microbiota of girls. Microbial diversity, composition, and differential abundant taxa were analyzed. ResultsWhile overall microbial diversity and community structure were similar across groups, obesity-only subjects exhibited significantly increased microbial richness (Chao1 index, P<0.01 vs. all groups), characterized by a higher Firmicutes/Bacteroidota ratio (P<0.001 vs. normal/PP), increased Proteobacteria (P<0.001 vs. normal), and enrichment of genera including Blautia, Faecalibacterium, Roseburia, Anaerostipes, Haemophilus, and Lachnospiraceae_NK4A136_group (P<0.05 vs. other groups). PP-only subjects showed reduced Verrucomicrobiota (P<0.001 vs. normal/obesity) and elevated Escherichia_Shigella (P<0.05 vs. normal). Most strikingly, the obesity-PP comorbid group exhibited a unique gut microbiota profile characterized by a dramatic depletion of Firmicutes compared to the obesity-only group (P<0.001) and a remarkable nearly 100-fold increase in Verrucomicrobiota abundance (P<0.001 vs. other groups), suggesting a distinct microbial ecotype potentially contributing to the pathophysiology of this comorbidity. ConclusionThis study delineated unique gut microbiota alterations associated with isolated obesity, isolated PP, and their comorbidity in girls. The distinct dysbiotic pattern in comorbid obesity-PP suggested complex microbiota-host interactions, providing a new microbiological perspective for understanding the mechanism of comorbidity between obesity and precocious puberty.

ImportanceWeight recurrence occurs in nearly 20% of patients following metabolic and bariatric surgery (MBS) and can diminish long-term metabolic benefits. While glucagon-like peptide-1 receptor agonists and gastric inhibitory polypeptide receptor agonists (GLP-1 RA) have emerged as potential adjuvant therapies, evidence supporting their use is limited primarily to liraglutide with minimal real-world data on newer agents or population-level effectiveness. ObjectiveTo evaluate the effectiveness and safety of GLP-1 RA therapy compared to non-use among patients experiencing weight recurrence following MBS. Design, Setting, and ParticipantsThis retrospective new-user cohort study utilized from the OneFlorida+ Data Trust (2015-2024) to identify adults who underwent MBS and subsequently experienced [&ge;]10% weight recurrence from nadir weight. Propensity score matching based on BMI and clinical encounter timing, combined with inverse probability of treatment weighting, was used to minimize confounding. Of 1,098 patients who underwent MBS and experienced weight recurrence, the final weighted analytic cohort included 68 GLP-1 RA users and 131 non-users at 6 months, and 72 users and 139 non-users at 12 months. ExposureInitiation of any GLP-1 RA (dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, or tirzepatide) after MBS among patients with weight recurrence. Main Outcomes and MeasuresThe primary effectiveness outcome was percentage of recurrent weight lost at 6 and 12 months. Safety outcomes included composite gastrointestinal and surgical adverse events. ResultsGLP-1 RA use was associated with significantly greater mean weight recurrence loss compared to non-use at 6 months (9.6% vs 4.3%, p = 0.005) and 12 months (14.8% vs 8.1%, p = 0.017). Among individual agents, tirzepatide was associated with the largest reductions at both 6 and 12 months (25.1% vs 5.4% and 34.4% vs 8.8%, respectively; both p < 0.001). Liraglutide demonstrated a statistically significant difference at 12 months (18.3% vs 8.4%, p = 0.004), while semaglutide and dulaglutide were not associated with statistically significant differences at either time point. No significant differences in adverse event rates were observed between groups, with composite safety outcomes occurring in 47.1% of users versus 56.5% of non-users at 6 months (HR = 1.24, 95% CI: 0.92-1.68, p > 0.05). Conclusions and RelevanceUse of GLP-1 RA for the treatment of weight recurrence following MBS represents an effective option with sustained benefits through 12 months without increased risk of adverse events. These real-world findings support adjuvant GLP-1 RA use for managing weight recurrence following MBS across diverse patient populations. Key PointsO_ST_ABSQuestionC_ST_ABSDoes the use of glucagon-like peptide-1 and gastric inhibitory polypeptide receptor agonists (GLP-1 RA) for the treatment of weight recurrence after bariatric surgery lead to significant weight loss in real-world populations? FindingsIn this cohort study of 1,098 individuals who underwent bariatric surgery and experienced weight recurrence, use of GLP-1 RA was associated with significant loss of regained weight. MeaningUse of GLP-1 RA for weight recurrence after bariatric surgery represents a viable treatment option.

BackgroundObesity is a multifactorial metabolic disorder driven by genetic predisposition and gut microbiome composition, influencing key metabolic pathways through the gut-brain axis, gut-liver interactions, immune modulation, and insulin resistance. This study integrates gut microbiome and genetic data to uncover microbial and genetic signatures linked to obesity across these metabolic dimensions. MethodsWe analyzed gut microbiome composition and polygenic risk scores (PGS) for BMI in a cohort of 3,319 individuals, with genetic data available for 2,883 participants. Regression analyses were performed to identify bacterial taxa and microbial metabolic pathways associated with baseline BMI. Interaction analyses assessed how genetic predisposition modifies microbiome associations with BMI. A subset of individuals (n = 180) with longitudinal microbiome data was analyzed to examine microbial changes associated with BMI reduction. ResultsSeveral bacterial taxa, including Oscillospiraceae, Faecalibacterium, and Christensenellaceae, were inversely associated with BMI, while Lachnoclostridium and Dorea exhibited positive associations. Microbial pathways related to neurotransmitter metabolism, amino acid degradation, and short-chain fatty acid synthesis were significantly associated with BMI, highlighting their potential role in obesity. Interaction analyses revealed that BMI-PGS attenuated the association of butyrate synthesis and tryptophan degradation with BMI, while Faecalibacterium exhibited a stronger association in individuals with high genetic risk. Longitudinal analysis showed that shifts in microbial composition accompanied BMI reduction, particularly increases in Christensenellaceae and reductions in Dorea. ConclusionThe gut microbiome is intricately linked to obesity through its modulation of metabolic pathways across the gut-brain axis, gut-liver axis, inflammation, and insulin resistance. Genetic predisposition further modifies these relationships, emphasizing the need for personalized approaches in microbiome-based obesity interventions.