International Journal of Obesity

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

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

BackgroundObesity arises from a complex interplay of genetic and environmental factors, with alterations of transcriptional networks that integrate metabolic, immune, and regulatory pathways. Conventional measures such as body mass index (BMI) quantify body size but fail to capture the molecular heterogeneity underlying divergent metabolic outcomes. We therefore sought to construct a gene expression-based transcriptomic representation of obesity, using BMI as a practical training anchor, and to use this framework to delineate transcriptional programs associated with metabolically healthy and pathogenic obesity, with subsequent projection to mouse transcriptomic data for cross-species validation. MethodsTranscriptome data of human visceral adipose tissue (N= 1,298) were used to derive the transcriptomic BMI model, and genes contributing to the model were functionally annotated by gene set enrichment analysis. The human-trained model was subsequently applied to mouse selection lines (N = 18) with divergent obesity phenotypes. In the human cohort, post hoc stratification into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) groups was performed using a downstream classification framework incorporating observed BMI together with predicted BMI, to assess whether model-derived predicted BMI reflected obesity-related pathophysiologic status. ResultsModel-selected genes were involved in coordinated regulation of lipid metabolism, immune activation, and growth signaling, extending to mitochondrial and translational pathways. Cross-species analyses uncovered conserved metabolic polarization: DU6 mice exhibited lipid-anabolic and inflammatory remodeling, whereas DU6P mice displayed oxidative, mitochondrial, and GH-axis-enriched transcriptional states. In human cohorts, MHO individuals showed upregulation of mitochondrial energetics and protein synthesis, while MUO individuals were characterized by increased autophagy, lipid catabolism, and stress-adaptive signaling on the transcriptional level. Together, these findings define a conserved molecular continuum linking oxidative efficiency to metabolic health and inflammation to metabolic vulnerability. ConclusionsThis integrative transcriptomic framework bridges human and mouse adipose biology to uncover conserved mechanisms underlying obesity phenotypes. By contrasting mitochondrial and translational programs with inflammatory and catabolic pathways, it provides mechanistic insight into metabolic resilience and a foundation for precision approaches to obesity management.

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

Objective Fatty Acid esters of Hydroxy-Fatty Acids (FAHFAs) are anti-diabetic and anti-inflammatory lipokines produced mainly by adipose tissue (AT). As exercise training enhances FAHFA levels, we investigated the impact of acute exercise (AE) and exercise-mimicking conditions on circulating and adipocyte FAHFA levels. Methods Clinical trial (NCT05572905) in 60 women, grouped by BMI (lean vs. obese) and age (young vs. older), was combined with in vitro experiments on human adipocytes. Following baseline characterization (body composition, VO2max, insulin sensitivity, AT/plasma FAHFAs), women underwent a cross-over AE and control interventions with repeated blood sampling for FAHFA analysis. Results In AT, lean and older women exhibited higher FAHFA levels than obese and young women, respectively; older women also showed a shift toward higher levels of 13/12-carbon-branched FAHFAs. Circulating FAHFA levels were similar across all groups and were not positively associated with insulin sensitivity, VO2max or FAHFA levels in AT. Although AE increased circulating free fatty acids (FFA), plasma FAHFAs dropped in response to both AE and control interventions. In adipocytes, FAHFAs were unaffected by glucocorticoids but increased in response to lipolysis together with gene expression related to FFA oxidation (FAO). Nevertheless, blocking mitochondrial FAO partially mimicked the lipolytic effect, while peroxisomal inhibition synergistically boosted FAHFA lipolysis-driven production despite having no effect alone. Conclusions While adiposity and aging modulate FAHFA levels in AT, circulating levels remain stable and unaffected by AE, challenging subcutaneous AT as their primary systemic source. In vitro, FAHFA synthesis is driven by high FFA availability but limited by competing peroxisomal FAO.

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

Background Cardiometabolic-based chronic disease (CMBCD) at an individual level results from complex interactions among a multi-tiered network of sociodemographic, behavioral, and metabolic factors. Though a consensus set of risk factors drives CMBCD, population context influences risk factor effects and interactions. To better understand this phenomenon, we investigated the multi-tiered networking of cardiometabolic variables across diverse populations using a comparative modelling approach. Methods and Findings Utilizing nationally representative cross-sectional data from 48 countries participating in the World Health Organization "STEPwise approach to noncommunicable disease risk factor surveillance" survey, we learned country-specific Bayesian networks including sociodemographic, behavioral, and cardiometabolic variables (adiposity, diabetes, hypertension, hyperlipidemia, and cardiovascular disease). By computing the structural Hamming distance between pairs of networks, we compared differences in network structures across regions and country income levels. We then used the learned networks to assess individual risk factor influences and interactions on cardiometabolic outcomes. Country-specific Bayesian networks varied in terms of the risk factors directly and indirectly associated with the cardiometabolic outcomes. Network structures differed significantly across regions (p = 0.023) but not across income levels (p = 0.91). These results were robust to an alternative learning algorithm, network comparison metric, and data imputation approach. Older age (60+ vs. 30-44 years old) was associated with a greater increase in probability of obesity in Europe and Central Asia (+80%) compared to other regions. Higher education was associated with increased probability of obesity (+53%), diabetes (+18%), and hypertension (+2%) in South Asia but decreased probability of obesity (-10%), diabetes (-32%), hypertension (-16%), and hyperlipidemia (-25%) in Middle East and North Africa. The interaction between age and sex in predicting obesity was significant in the highest proportion of countries in Europe and Central Asia compared to other regions. While this dataset provided standardized data across multiple countries to define cardiometabolic risk factors and drivers, there was limited data on certain health outcomes and uneven availability of data across regions. Conclusions These results revealed specific regional patterns of multi-tiered cardiometabolic risk structures, emphasizing the need for regionally tailored public health strategies rather than applying generalized consensus evidence-based models. Future research should explore the structural drivers of regional differences in inter-relationships of cardiometabolic risk factors, drivers, and disease.

BackgroundPredictors of arterial health impairment from childhood to adolescence remain largely unknown. We investigated associations of childhood cardiometabolic risk factors with several measures of arterial health in adolescence. MethodsAltogether, 222 children were examined at age 7-9 years and eight years later at age 15-17 years. Body fat percentage (BF%), glucose, insulin, lipids, blood pressure (BP), and inflammation biomarkers were measured and homeostatic model assessment for insulin resistance (HOMA-IR), a metabolic syndrome score (MetSscore), and an inflammation score were calculated at baseline. Pulse wave velocity (PWV) and cardio-ankle vascular index (CAVI) were assessed using impedance cardiography and carotid intima-media thickness (cIMT), carotid distensibility (cDIST), Youngs elastic modulus (YEM), and stiffness index (SI) using ultrasonography. Associations of childhood cardiometabolic risk factors with measures of arterial health were analyzed using linear regression models adjusted for childhood age and sex. ResultsBF% was positively associated with PWV (standardized regression coefficient {beta}=0.207, p=0.008), CAVI ({beta}=0.171, p=0.031), cIMT ({beta}=0.146, p=0.034), and YEM ({beta}=0.164, p=0.016). HOMA-IR was positively associated with PWV ({beta}=0.242, p=0.001) and CAVI ({beta}=0.216, p=0.004) and inversely with cDIST ({beta}=-0.162, p=0.015). MetSscore was positively associated with PWV ({beta}=0.266, p<0.001), CAVI ({beta}=0.219, p=0.004), and YEM ({beta}=0.141, p=0.032) and inversely with cDIST ({beta}=-0.140, p=0.035). SBP was positively associated with PWV ({beta}=0.257, p<0.001) and YEM ({beta}=0.156, p=0.018) and inversely with cDIST ({beta}=0.169, p=0.012). ConclusionIncreased adiposity, insulin resistance, elevated SBP, and cardiometabolic risk factor clustering in childhood association of arterial stiffness and reduced arterial distensibility in adolescence, emphasizing prevention of cardiovascular diseases since childhood.

Background Early onset obesity in children, almost always accompanied by significant health complications, may be driven by rare genetic variants that influence appetite, metabolism, and nutrient absorption. Traditional treatment approaches are usually insufficient for those with monogenic obesity of this type. Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, and related drugs such as melanocortin 4 receptor agonists, have emerged as promising first-line treatments for severe obesity. There is no established protocol or pathway in England for identifying children with monogenic obesity who could benefit from these and similar treatments Methods We undertook early economic modelling to examine the cost-effectiveness, from a health service perspective, of implementing a new pharmacotherapeutic care pathway for the identification and treatment of monogenic obesity in children. We modelled a hypothetical population of children with hyperphagia and body mass index (BMI) three standard deviations above mean values for age and sex. We evaluated the clinical decision to initiate the pathway using a decision tree model with patient quality-adjusted life years (QALYs) and NHS healthcare costs 12 months from an initial clinic visit as outcomes, and calculated incremental cost effectiveness ratios and a cost-effectiveness acceptability curve. Results Both costs and QALYs were higher under further investigation (GBP3,247 and 0.47 QALYs) compared to no further investigation (GBP1,589 and 0.24 QALYs). The incremental cost-effectiveness ratio in the base case was GBP7,133 per QALY. Further examination of these children was therefore likely to be cost effective in this model. Conclusion A decision-tree model suggested that further investigation of severely obese children potentially eligible for treatment with semaglutide is likely to be cost-effective for the NHS. However, this result is associated with uncertainty arising from a lack of evidence for many key model parameters.

Weight cycling (WC), defined as weight gain, loss, and regain, is common in obesity, but its metabolic consequences remain unclear. We tested whether WC-aggravated glucose intolerance in obesity is age-dependent and linked to circadian disruption. Young (7w) and mid-aged (12m) mice underwent a 15-week dietary intervention: Lean and Obese mice fed normal chow (NC) and high-fat diet (HFD) throughout, respectively. WC mice undergone HFD-induced weight gain, NC-induced weight loss, and a second HFD-induced weight regain. Late-onset obese (LO) mice ate HFD only paralleling weight regain of WC. In young, but not mid-aged mice, prior obesity accelerated weight regain upon HFD re-exposure, and aggravated glucose intolerance beyond that observed in Obese mice. This occurred without a worse adipose inflammatory profile. Rather, WC young mice exhibited blunting of light/dark-phase oscillation of feeding and energy metabolism, adipose and hepatic core clock gene oscillation, and increased hepatic expression of clock and gluconeogenic genes during the inactive phase. Restricting food availability to the active phase did not alter final weight regain, but improved glucose tolerance selectively in WC mice, normalized hepatic gluconeogenic and clock-genes expression in both liver and adipose tissue. These findings identify circadian disruption as a modifiable mediator of the adverse metabolic impact of WC in young-adulthood obesity. HighlightsO_LIWeight cycling is common in obesity, but whether it worsens metabolic dysfunction beyond persistent obesity remains unclear. C_LIO_LIWe asked whether weight cycling aggravates glucose intolerance in an age-dependent manner and whether circadian disruption contributes to this effect. C_LIO_LIIn young, but not mid-aged mice, weight cycling accelerated weight regain and worsened glucose intolerance, accompanied by blunted diurnal oscillation of behavioral parameters and core clock gene expression, without exaggerated adipose inflammation. C_LIO_LIActive-phase time-restricted feeding improved WC-induced aggravated glucose tolerance and circadian oscillation, identifying circadian disruption as a modifiable mechanism linking weight cycling adverse metabolic outcomes in young-adulthood obesity. C_LI

Background: Obesity is globally recognized as a complex, multifactorial chronic disease, with biological, psychological, environmental and behavioural factors involved in both disease pathogenesis and maintenance. Although previous group-based studies demonstrated involvement of each of these factors, there is large inter-individual variability in the factors contributing to disease development as well as intervention outcomes, causing limited translatability to the individual level. This heterogeneity in treatment effectiveness might be due to differential causal and maintenance factors of obesity. To enable the transition from a one-size-fits-all approach to a more personalized approach for individuals with overweight or obesity, this study aims to investigate if and how the degree of weight loss and changes in daily life behaviour after a combined lifestyle intervention depend on individual baseline profiles comprising of person characteristics, biological, psychological, environmental and behavioural factors. Methods: This study will include 600 individuals varying in BMI, 200 participants with a healthy BMI (18.5-24.9kg/m2), 200 with overweight (BMI 25.0-29.9kg/m2), and 200 with obesity (BMI [&ge;]30.0kg/m2). For all participants, a comprehensive individual baseline profile is created, including person characteristics, biological, psychological, environmental and behavioural factors. A clustering method is applied to identify clusters of participants with similar characteristics. Next, we examine if and how these clusters are linked to bodyweight indicators measured at baseline, and how they relate to daily lifestyle behaviour, as measured by ecological momentary assessment (EMA) using a smartphone app and sensor technology (3-week measurements). Individuals with overweight or obesity will be randomized to the intensive lifestyle intervention or a lifestyle information condition, to determine if treatment response can be predicted based on cluster characteristics, how daily lifestyle behaviour changes after an intervention, and how changes in daily lifestyle behaviour relate to treatment response. Discussion: The End of Average study aims to characterize a large set of individuals varying in body weight to predict intervention effectiveness measured as changes in body weight indicators and in daily lifestyle behaviours. If reliable predictors of treatment success can be identified, these can be applied in personalized lifestyle interventions to improve lifestyle behaviour, body weight management and overall health.

BackgroundSeveral lipid ratios have been linked to obstructive sleep apnea (OSA) risk in NHANES, yet two questions central to clinical translation remain unanswered: how much of the association is carried by central adiposity, and whether the dose-response curve contains an actionable threshold. We addressed both for the remnant cholesterol-to-HDL-C ratio (RC/HDL-C). MethodsWe analysed 3,635 adults aged [&ge;]20 years from NHANES 2015-2018. OSA risk was ascertained from the Sleep Disorders Questionnaire. Multivariable logistic regression estimated odds ratios across three nested models. Restricted cubic splines and segmented regression characterised the dose-response and located the inflection point. Mediation by body roundness index (BRI) was quantified by nonparametric percentile bootstrap (1,000 resamples). Discrimination was compared by ROC analysis, with stratified and trimmed-sample sensitivity analyses. ResultsOSA risk was identified in 1,361 participants (37.4%). Each one-unit rise in RC/HDL-C carried 23% higher adjusted odds of OSA (OR 1.23, 95% CI 1.03-1.47); the highest quartile carried 49% higher odds than the lowest (P-trend < 0.001). The dose-response was nonlinear, with an inflection at RC/HDL-C = 0.232: below this point each 0.1-unit increase raised odds by 54% (OR 1.54, 95% CI 1.16-2.05); above it the curve plateaued. BRI mediated 82.7% of the total effect (ACME 0.039, P < 0.001), with the indirect pathway 2.8 times stronger in women. AUCs were 0.599 (BRI) and 0.564 (RC/HDL-C). ConclusionsRC/HDL-C showed a modest, threshold-shaped association with OSA risk in U.S. adults, with central adiposity (BRI) as the predominant mediating factor. These exploratory findings, based on questionnaire-defined OSA, warrant prospective validation in cohorts with polysomnography.

ObjectiveTo examine associations of BMI-related polygenic scores (PGSs) with BMI-for-age z-score (BMIz), height-for-age z-score (HAZ), and weight; assess sex-specific effects; and test PGS-by-diet interactions in youth experiencing the double burden of malnutrition. MethodsIn this cross-sectional study of Filipino youth aged 6-19 years, we analyzed genome-wide genotype, anthropometric, and dietary data from two 24-hour recalls. Four ancestry-standardized BMI PGSs were evaluated using linear regression adjusted for age, sex, and ancestry principal components, with platform-specific estimates combined by fixed-effects meta-analysis. ResultsAll four PGSs were positively associated with BMIz ({beta} range: 0.119 - 0.320). The strongest association was observed for the multi-ancestry score PGS005202 ({beta} = 0.320; P = 2.39 x 10-9; {Delta}R2 = 4.98%). No PGS was associated with HAZ. PGS005202 and PGS005279 were associated with higher weight independent of HAZ. A significant PGS000716-by-sex interaction was observed for BMIz (q = 0.034), with an association in boys ({beta} = 0.253; P = 0.002) but not in girls ({beta} = -0.007; P = 0.93). No PGS-by-diet interaction remained significant after multiple-testing correction. ConclusionsBMI-related PGSs were associated with adiposity-related traits, but not linear growth, in Filipino youth. Findings support sex-stratified analyses and further evaluation of ancestry-inclusive PGSs in similar pediatric settings.

Background: Black adults bear a disproportionate burden of cardiometabolic dysfunction, yet most dietary trial evidence comes from predominantly White cohorts. Objective: To evaluate whether a personalized whole-food dietary intervention improves cardiometabolic outcomes more in Black than White young adults with overweight or obesity. Methods: In this 8-week randomized, controlled trial (ClinicalTrials.gov: NCT04635917), 112 Black and White adults (18-35 years; BMI 25-45 kg/m2) were block-randomized by race to a personalized dietary intervention providing whole foods (PD, n=57) or conventional dietary counseling at baseline (BL) using MyPlate guidelines (CD, n=55). Primary outcomes were Matsuda Index and fasting and OGTT-derived glucose, insulin, and non-esterified fatty acids. Other glucoregulatory, cardiovascular, anthropometric, appetite, and cognitive outcomes were also assessed. Outcomes were analyzed using baseline-adjusted linear models with sensitivity analyses adjusting for baseline BMI and food security score. Results: Compliance with study food consumption was 85-91%. Diet quality was higher in PD than CD (P < 0.05), with larger gains in vegetable-related outcomes among Black participants (group x race, P < 0.05). HOMA-{beta} was lower in PD than CD overall (P < 0.05). In sensitivity analyses, Black PD participants had greater fasting insulin reductions than White, especially in the latter half of intervention (week x group x race, P < 0.05), with a similar tendency for HOMA-IR. Glucose AUC 0-30 min was higher in White than Black PD participants (group x race, P < 0.05). Concentration performance was higher in PD than CD overall (P < 0.05), with larger gains in processing speed and accuracy among Black than White participants (group x race, P < 0.05). No effects were observed for cardiovascular or appetite outcomes. Conclusions: The personalized whole-food intervention produced differential effects in fasting insulin and early-phase glucose handling, and greater benefits in attention, in Black compared with White young adults with overweight or obesity during weight maintenance.

BackgroundVertical sleeve gastrectomy (VSG) improves glycaemic control in type 2 diabetes (T2D) through mechanisms that extend beyond weight loss. The interaction between glucocorticoid metabolism and inflammation in this context remains unclear. MethodsWe investigated the role of 11{beta}-hydroxysteroid dehydrogenase type 1 (11{beta}HSD1) in mediating the metabolic effects of VSG in humans and mice. Subcutaneous adipose tissue biopsies were collected before and 6 months after VSG. Parallel studies were conducted in lean and high-fat diet-fed mice undergoing VSG or sham surgery, alongside 11{beta}HSD1 knockout models. Glucose tolerance and expression of 11{beta}HSD1 and interleukin-6 (IL6) were assessed. Mechanistic interactions were examined in IL6-treated human hepatocytes. ResultsVSG reduced 11{beta}HSD1 and IL6 expression in human adipose tissue and improved insulin resistance. In lean mice, VSG improved glucose tolerance and downregulated both markers independently of weight loss. 11{beta}HSD1 knockout mice exhibited improved glucose tolerance despite increased adiposity, partially recapitulating the VSG phenotype. Both interventions reduced circulating and tissue IL6 levels. IL6 stimulation increased HSD11B1 expression in hepatocytes. Conclusions11{beta}HSD1 links glucocorticoid metabolism, inflammation, and glucose homeostasis following VSG. Targeting this pathway may offer a strategy to replicate key metabolic benefits of metabolic bariatric surgery.

Background: The ECAIL trial, launched in 2017, targets hard-to-reach families and evaluates a multicomponent childhood obesity prevention intervention. At a maternity hospital in Lille, France, healthcare providers screened pregnant women experiencing social vulnerability, and dietitians delivered a home-based intervention until age 2. The COVID-19 pandemic led to a six-month suspension in 2020. This study compared eligibility and participation before the pandemic and after resumption, and examined how the pandemic and subsequent cost-of-living crisis shaped implementation and reach. Methods: We analyzed 5,744 eligibility questionnaires distributed at the maternity ward. Inclusion criteria included [&ge;]1 indicator of social vulnerability (e.g., socioeconomic disadvantage, precarious housing, or social isolation). To capture implementation experiences, a psychosocial researcher conducted a focus group with six dietitians delivering the intervention; it was recorded, transcribed, and analyzed thematically focusing on reach, acceptability, and adaptation. Results: Eligibility increased from 29.7% (n=955) prepandemic to 33.6% (n=849) after resumption, while the distribution of vulnerability criteriaremainedsimilar across periods:78.3% received social/medical benefits; employment was not the main source of household income for 58.7%; 24.4% experienced financial hardship; 14.7% reported social isolation; 6.0% lived in precarious housing; and 19.0% had three or more vulnerabilities. Participation among eligible women remained stable (24.6%; n=443). Qualitative findings indicated dietitians satisfaction and participants enthusiasm for the resumption of home visits, particularly in addressing social isolation. After resumption, the introduction of a pre-visit COVID-19 questionnaire reduced missed appointments. Converging qualitative and quantitative findings indicated sustained, and in some cases strengthened, provider engagement despite pandemic-related strain on hospital services. Conclusions: This study shows that a complex intervention can maintain reach and acceptability through adaptive implementation under major contextual disruptions.The rapid resumption of home-based services emerged as a robust strategy for engaging and retaining socially disadvantaged families, highlighting the importance of flexible, context-sensitive approaches during social and economic crises.

Circadian rhythms regulate diverse physiological processes, including metabolism, and their disruption has been implicated in metabolic disorders such as obesity. However, the tissue-specific effects of obesity on peripheral circadian clocks remain incompletely understood. Here, we investigated the impact of high-fat diet (HFD)-induced obesity on circadian gene expression in skeletal muscle, liver, and white adipose tissue (WAT). Mice were fed either a regular diet (RD) or HFD for 6 weeks, followed by tissue collection at 4-hour intervals over a 24-hour period. Under RD conditions, key circadian regulators and their downstream targets exhibited robust 24-hour oscillations across all tissues. In contrast, HFD feeding induced distinct, tissue-specific alterations. In the liver, Per2, Dbp, and Rev-erb showed phase-advanced expression patterns, whereas in WAT, rhythmic expression was markedly attenuated. Notably, skeletal muscle largely preserved circadian gene expression patterns, indicating relative resistance to HFD-induced circadian disruption. In addition, HFD feeding altered metabolic gene expression in adipose tissue, characterized by reduced Pgc1 expression and increased Leptin expression. Together, these findings demonstrate that HFD-induced obesity differentially disrupts peripheral circadian clocks in a tissue-specific manner and highlight skeletal muscle as a relatively resilient tissue. These results provide insight into how circadian dysregulation contributes to metabolic abnormalities in obesity.

Administration of ciliary neurotrophic factor (CNTF) reduces food intake and body weight in both humans and experimental animals, where it also ameliorates hyperglycemia, hyperinsulinemia, and dyslipidemia. To exert its anti-obesogenic and anti-diabetogenic effects, CNTF targets brain feeding centers as well as multiple peripheral organs inducing the phosphorylation of the transcription factor signal transducer and activator of transcription 3 (p-STAT3). However, data showing which peripheral cytotypes are specifically targeted by exogenous CNTF in vivo in metabolically relevant organs are currently lacking. Here, we first evaluated the gene expression levels of the subunits of the tripartite CNTF receptor (Cntfr) complex, i.e., the Cntfr, the leukemia inhibitory factor receptor {beta} (Lifr{beta}) and the glycoprotein 130 (gp130), by quantitative real-time PCR in metabolically relevant organs of adult male mice: gastrointestinal (GI) tract, pancreas, liver, visceral and subcutaneous white (WAT) and interscapular brown adipose tissue (iBAT), skeletal muscle and the sciatic nerve. We then quantified p-STAT3 by Western blotting in these organs after intraperitoneal administration of CNTF (0.3 mg/kg) or saline. Finally, we mapped CNTF-responsive cells by immunohistochemistry, followed by morphometric quantification and confocal microscopy in both CNTF- and saline-treated mice. Lifr{beta} and gp130 were ubiquitously detected across all the investigated organs; the Cntfr showed the highest expression levels in the skeletal muscle, sciatic nerve, and iBAT, whereas it was found to be expressed to a lesser extent in the other sites. Administration of CNTF led to a significant increase of p-STAT3/STAT3 protein ratio in all organs examined, except the duodenum, and induced a distinctive pattern of cell nuclear p-STAT3 immunoreactivity. Notably, along the analyzed GI tract CNTF induced nuclear STAT3 phosphorylation in neurons of the submucosal and myenteric plexuses of the enteric nervous system and in contractile cells of the muscularis externa, where the response peaked in the mesenteric gut and colon. In the pancreas, CNTF triggered a higher activation within the endocrine component compared to the exocrine parenchyma. In the liver, CNTF induced STAT3 phosphorylation not only in parenchymal cells but also in sinusoids and resident macrophages. The cytokine activated p-STAT3 in subcutaneous and visceral white adipocytes, but also in brown adipocytes, with a prominent response observed in the beige subcutaneous adipocytes; adipose resident macrophages and endothelial cells of numerous blood vessels were also CNTF-responsive. Lastly, in skeletal muscle, a major site for glucose/lipid utilization, CNTF induced widespread nuclear p-STAT3 immunoreactivity in muscle fibers and in connective and Schwann cells of the peripheral nerves, including the sciatic nerve, supplying the gastrocnemius. In conclusion, our data indicate that CNTF acts across diverse cytotypes within metabolically relevant organs and tissues, likely fostering its peripheral metabolic effects through this cellular heterogeneity.

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

Objective: To verify the association between perceived social & emotional support and self-reported food insecurity in the United States Design: Cross-sectional secondary data analysis Setting: Behavioral Risk Factor Surveillance System (BRFSS) data from 2024, collected via a nationwide telephone survey. Food insecurity was defined as responding always, usually, or sometimes to "During the past 12 months how often did the food that you bought not last, and you didn't have money to buy more?" Social support was measured using a BRFSS item assessing the frequency with which respondents received the social and emotional support they needed. Adjusted logistic regression models were used to assess the relationship between these variables while controlling for a wide variety of demographic, socioeconomic, and health status factors. Participants: Adults (n = 190,577) aged 18-80 years old (72.3% non-Hispanic White) Results: Individuals who reported only "sometimes" receiving the social and emotional support they need were more likely to report food insecurity as compared to those who "always" receive such support (aOR = 1.75; 95% CI 1.56, 1.96). Conclusions: These findings indicate that decreased social support may put individuals at higher risk of food insecurity. Future work should seek to understand the mechanisms of this association to inform targeted policy and other interventional programs.