Bariatric surgery can contribute to weight loss and the improvement of obesity-related diseases. Laparoscopic sleeve gastrectomy (LSG) is among the most frequently performed procedures worldwide, including in Japan. Skeletal muscle plays an essential role in energy metabolism and whole-body glucose homeostasis, and diabetes decreases insulin-induced glucose uptake in skeletal muscle. The present study investigated postoperative outcomes and factors related to type 2 diabetes (T2D) remission rates in LSG cases, including skeletal muscles. This retrospective study analyzed perioperative outcomes and factors associated with T2D remission after LSG, with a particular focus on skeletal muscle mass assessed by bioelectrical impedance analysis. LSG was performed on 90 patients between October 2016 and February 2024. First, the perioperative outcomes and weight loss effects in these 90 patients were examined. Muscle or skeletal mass perioperative factors were compared between patients with and without T2D remission. At 6 months after surgery, the median total weight loss was 21%, and the median excess weight loss was 52%. The rate of remission and improvement of T2D was 75%. The group that showed T2D remission generally had a significantly higher skeletal muscle mass or percentage throughout the preoperative and postoperative period (P<0.05). The remission rate of T2D after LSG was favorable, and a relationship was observed between T2D remission after LSG, and skeletal muscle mass before and after surgery.

The anti-obesity potential of Cassiae Semen: A review based on ethnopharmacology and modern pharmacology.

Obesity is associated with metabolic disorders due to unhealthy white adipose tissue (WAT) failing to sustain energy homeostasis, highlighting the importance of adipose development. The lactation period is critical for epididymal WAT (eWAT) development and metabolic programming. However, the role of lactoferrin (LF) in the early development of adipose remains unclear. Using a mouse model of lactational LF deficiency and single-nucleus RNA sequencing, we assessed the long-term impact of LF deficiency on eWAT plasticity and metabolic homeostasis at weaning, adulthood, and under a high-fat diet (HFD). LF deficiency persistently impaired eWAT development, causing restricted adipocyte hyperplasia, exacerbated hypertrophy, diminished lipid uptake, and sustained adiponectin decline with resistin elevation. These defects led to long-term metabolic disorders, worsening HFD-induced eWAT remodeling, glucose intolerance, dyslipidemia, and chronic inflammation. Mechanistically, LF could bind CSK and PRMT5. LF promoted CSK degradation, activating SRC to drive preadipocyte proliferation. Additionally, LF stabilized PRMT5 to enhance PPARg-mediated differentiation and lipid uptake. Rescue experiments confirmed that CSK overexpression reversed LF-induced proliferation, while PRMT5 knockdown blocked LF-enhanced differentiation. This study reveals lactational LF as a key nutritional signal that programs adipose development and long-term metabolic health via CSK-SRC and PRMT5-PPARg pathways,offering an early-life intervention strategy against obesity-related metabolic diseases.

The Lancet Diabetes & Endocrinology Commission undertook the complex task of addressing limitations in existing definitions and classification of obesity. Its consensus framework moves beyond body mass index (BMI) toward direct or surrogate measures of excess adiposity and distinguishes "clinical obesity" (excess adiposity plus objective organ/system dysfunction or functional limitation attributable to adiposity) from "preclinical obesity" (excess adiposity without such evidence). The Endocrine Society (ES) recognizes the substantial effort and expertise underlying this work and its intent to improve diagnostic precision and therefore provides an independent appraisal of the framework's conceptual coherence, empirical support, operational feasibility, and implications for coverage, equity, and clinical implementation. The shift away from BMI-only screening is supported by evidence that central adiposity and fat distribution better predict cardiometabolic risk than BMI alone. Validation studies (All of Us; UK Biobank) demonstrate elevated risk among individuals classified with "preclinical" obesity and even higher risk among those with "clinical" obesity, underscoring the importance of safeguards against undertreatment in the preclinical state. At the same time, lack of standardized anthropometric measurement protocols, increased resource utilization, limited distinction between subcutaneous and visceral fat depots, and insufficient data regarding the long-term implications of obesity-related disease absence prompted the ES to pause before fully endorsing the Commission's consensus. Accordingly, we outline an evaluation framework addressing available evidence, feasibility, coverage and equity considerations, and clinical impact. We advocate harmonization with established staging systems (EOSS, EASO), explicit measurement protocols, age-, sex-, and ancestry-specific thresholds, integration of mental health and patient-reported outcomes, and policies that prevent unintended care restrictions. The Commission's reframing represents a meaningful conceptual advance; broader adoption will require practical and equitable implementation.

Obesity and its related metabolic diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD), represent a major global health challenge. Mitochondrial dysfunction is a key driver in their pathogenesis. This review explores the emerging role of mitochondrial transfer, a novel mode of cellular communication that can occur via tunneling nanotubes, extracellular vesicles, or as free mitochondria, in these conditions. Increasing evidence suggests that mitochondrial transfer may contribute to tissue homeostasis and metabolic adaptation, and that disruption of this process may participate in the pathogenesis of obesity and MASLD. In parallel, therapeutic strategies aimed at restoring mitochondrial function by enhancing endogenous mitochondrial transfer or through mitochondrial transplantation are beginning to emerge. This review summarizes current knowledge of the mechanisms underlying mitochondrial transfer, discusses roles in obesity and MASLD, and evaluates the therapeutic potential and translational challenges of targeting mitochondrial transfer in obesity and obesity-related metabolic disease.

Abdominal fat distribution, particularly visceral fat, is commonly assessed as a marker of obesity-related and metabolic diseases in people. While this relationship may exist, few studies consider the factors related to the relative distribution of visceral and subcutaneous abdominal fat in dogs. This cross-sectional study evaluated associations between measures of abdominal adiposity, visceral and subcutaneous fat distribution (V/SQ), body condition score (BCS), age, sex, neuter status, and breed conformation in 205 dogs presenting to a tertiary veterinary hospital between March 2006 and March 2020. The influence of several disease states on abdominal adiposity and fat distribution was also evaluated. Additionally, the study aimed to assess the criterion validity of average computed tomography (CT) Hounsfield units, and linear and cross-sectional area measures of abdominal adiposity and fat distribution relative to CT-derived volumetric analysis and for intra-observer reliability. Greater total abdominal adiposity was seen in older dogs, with values highest around 10 years of age and lower after 10 years of age, and was lower in terrier breeds and dogs with neoplasia. Greater V/SQ was observed in older dogs, hounds, and terriers, but decreased with increasing BCS, total abdominal adiposity, and thoracic height-width ratio. Additionally, V/SQ was higher in dogs with hyperadrenocorticism. Body condition score was moderately correlated with total abdominal, visceral, and subcutaneous adiposity. Abdominal fat areas measured at L3 overestimated total abdominal and visceral fat percentages but underestimated subcutaneous fat percentages, with increasing bias at higher fat percentages. Linear fat measurements were moderately correlated with total abdominal adiposity, but only weakly correlated with abdominal fat distribution. This study supports the association between abdominal adiposity, age, breed category, and potentially certain diseases like neoplasia. Moreover, it highlights the correlation between V/SQ, age, and total adiposity, while emphasising the preferential distribution of fat to the visceral compartment in dogs with hyperadrenocorticism. The study also identified a novel association between V/SQ, specific breed categories, and body conformation (i.e., thoracic height-width ratio). Importantly, CT volumetric measures are more reliable in determining abdominal fat distribution than area and linear measures, supporting the use of CT volumetric measures in the study's methodology and its implications for future research and clinical practice.

Visceral adipose tissue (VAT) plays a crucial role in obesity-related metabolic diseases, making its reduction an important target for obesity treatment. Although exercise has been shown to significantly reduce visceral fat, the specific mechanisms underlying the effects of different exercise modalities and exercise doses on VAT reduction remain unclear, particularly regarding the dose-response relationship, which has not been systematically explored. This study aims to systematically compare the effects of different exercise modalities on visceral adipose tissue (VAT) reduction and to explore in depth the dose-response relationship between exercise dose and VAT decrease, thereby providing scientific evidence for optimizing individualized exercise prescriptions in obesity treatment. A systematic search of randomized controlled trials (RCTs) up to November 2024 was conducted (search updated in September 2025). Network meta-analysis (NMA) was employed to compare the effects of different exercise interventions on VAT, while Bayesian network meta-analysis (MBNMA) was used for dose-response analysis to evaluate the impact of exercise intensity, frequency, and duration on VAT reduction. This study included 61 RCTs involving 4,136 participants. The NMA results indicated that all exercise interventions significantly reduced VAT compared to the control group. Among them, HIIT was the most effective in reducing VAT (SMD = -0.84, 95% CI [-1.08, -0.61], p < 0.0001, GRADE: Moderate; SUCRA = 99.3%, GRADE: High), followed by AE + RT (SMD = -0.54, 95% CI [-0.75, -0.32], p < 0.0001, GRADE: Moderate; SUCRA = 59.1%, GRADE: High), AE (SMD = -0.53, 95% CI [-0.68, -0.38], p < 0.001, GRADE: Low; SUCRA = 58.9%, GRADE: High), and RT (SMD = -0.41, 95% CI [-0.63, -0.20], p < 0.001, GRADE: Moderate; SUCRA = 32.7%, GRADE: High). The dose-response analysis showed a significant nonlinear dose-response relationship between total exercise volume and VAT, with the minimum effective dose being 730 METs min/week. Furthermore, the minimum effective doses for different exercise types varied. Specifically, HIIT significantly reduced VAT at a lower dose (400 METs min/week), while AE and AE + RT required a higher dose (1100 METs min/week) for significant reduction. This study reveals a nonlinear dose-response relationship between exercise dose and VAT reduction, demonstrating that HIIT is the most effective exercise modality for reducing VAT, with significant effects at low doses. AE and AE + RT are also effective but require higher doses (1100 METs min/week) to achieve significant VAT reduction. These findings provide specific dosage recommendations for exercise prescriptions for individuals with obesity, helping to optimize treatment plans and improve obesity management outcomes.

Obesity and its metabolic complications remain major global health challenges. Beyond excess caloric intake, emerging evidence implicates diet-induced gut microbiota dysfunction as a modulator of metabolic homeostasis. This review examines recent advances in understanding how functional alterations of the gut microbiota contribute to obesity pathogenesis. Current data indicate that obesity is characterized less by specific microbial taxa and more by disruption of key microbial functions. Diet-induced dysbiosis alters short-chain fatty acid production, bile acid metabolism, tryptophan-derived signaling, and intestinal barrier integrity. These changes promote metabolic endotoxemia, impair enteroendocrine hormone secretion, and disrupt gut-brain and gut-liver communication, contributing to adipose tissue inflammation, hepatic steatosis, and insulin resistance. Experimental and clinical studies further suggest that microbiota-targeted interventions, including dietary fiber enrichment, prebiotics, synbiotics, and fecal microbiota transplantation, can partially restore microbial metabolic function and improve selected metabolic outcomes. Obesity is increasingly conceptualized as a state of diet-driven functional gut microbiota disruption. Targeting microbial metabolic pathways rather than individual taxa may offer a promising adjunctive strategy to complement established therapies for obesity-related metabolic disease.

A thioacrylamide-based compound directly counteracts hepatic fibrosis with profound anti-obesity action.

This systematic review and meta-analysis evaluated the effects of probiotic and synbiotic supplementation on metabolic and hepatic outcomes in children and adolescents with obesity, including those with obesity-related metabolic dysfunction-associated steatotic liver disease (MASLD). A comprehensive literature search of PubMed, Scopus and Web of Science was conducted up to September 2025. Randomised controlled trials (RCTs) investigating probiotic or synbiotic supplementation in paediatric populations with obesity or MASLD were included. Data were pooled using a random-effects model, and the Cochrane Risk of Bias tool and GRADE framework were used for quality assessment. Thirteen RCTs (n = 848) were included. Pooled analyses demonstrated significant reductions in total cholesterol (WMD: -6.40 mg/dL, 95% CI: -8.78, -4.01), LDL-C (WMD: -2.68 mg/dL, 95% CI: -4.85, -0.50) and alanine aminotransferase (ALT) (WMD: -6.15 U/L, 95% CI: -10.14, -2.16). No significant improvements were observed in BMI z-score, waist circumference, triglycerides, HDL-C or fasting blood sugar. A significant increase in HOMA-IR was found (WMD: 0.68, 95% CI: 0.53, 0.83). Evidence certainty was high for lipid outcomes but low or very low for most other measures. Despite these mixed results, substantial heterogeneity and limited evidence quality underscore the need for well-designed, strain-specific trials. Probiotic and synbiotic supplementation show promise for specific metabolic outcomes in paediatric populations, though caution is warranted regarding glucose homeostasis, and personalised approaches should be considered in clinical practice.

Dietary phospholipids alleviate high fat diet-induced intestinal lipid deposition through ATF4-PPARα-MTTP/SAR1B pathway in yellow catfish.

Metabolic inflammation, triggered by obesity is a core pathological link in complications such as type 2 diabetes, cardiovascular diseases, and non-alcoholic fatty liver disease. This review explains the central hub role of microRNAs in obesity-related chronic low-grade inflammation, achieved through their precise regulation of macrophage polarisation, inflammatory signalling pathways, and adipokine secretion. Importantly, this relationship is bidirectional-while miRNAs regulate inflammatory cascades, the inflammatory environment itself can alter miRNA expression, forming complex feedback loops. Circulating miRNAs, due to their stability (conferred by encapsulation in exosomes or binding to proteins), tissue specificity, and strong correlation with pathological processes, show great potential as promising non-invasive biomarkers for metabolic inflammation, useful for assessing its activity and complication risk. Furthermore, miRNA-based intervention strategies have demonstrated significant metabolic improvements in animal models. However, their clinical translation still faces challenges such as insufficient delivery targeting, off-target effects, and pharmacokinetic defects. This article aims to summarise the regulatory network of miRNAs in metabolic inflammation and discuss in depth their potential and the bottlenecks to be solved for moving from basic research to clinical application, providing new theoretical basis and strategic directions for the diagnosis and targeted therapy of obesity-related metabolic diseases.

This Perspective argues for a reconceptualization of clinical obesity in Asian populations, moving beyond BMI-centric definitions towards an adiposity-based and function-based framework. Asian populations exhibit a distinctive obesity phenotype, characterized by excess visceral and ectopic adipose tissue accumulation, reduced β-cell reserve, sarcopenic obesity and heightened cardiometabolic risk at lower BMI thresholds than forwhite European and North American populations, leading to systematic under-recognition of obesity-related disease when conventional criteria are applied. Building on the Lancet Commission's framework for defining and diagnosing clinical obesity, we propose an integrated approach that combines anthropometric measures, body composition assessment, metabolic and organ-specific markers and emerging biomarkers to distinguish preclinical obesity from clinical obesity on the basis of organ dysfunction and functional impairment. This approach improves risk stratification, supports earlier and more precise diagnosis and informs stage-specific management, including lifestyle intervention, pharmacotherapy and metabolic surgery, particularly in Asian populations. We discuss implications for clinical practice, prevention strategies and public health policy, emphasizing the need to align clinical guidelines, reimbursement systems and education with a function-based definition of obesity. Finally, we highlight key research priorities, including validation of biomarker-driven classifications, assessment of long-term clinical and economic outcomes and development of scalable diagnostic tools, to advance precision care and metabolic health equity across diverse Asian populations.

Studies on Alarin, a newly identified orexigenic adipokine, have mainly focused on adults, while research investigating Alarin levels and its association with obesity in children remains limited. The aim of this study was to measure Alarin levels in children and adolescents with obesity and investigate their relationship with various metabolic parameters, as well as explore how these associations may differ by age group and gender. This prospective case-control study included 30 children with obesity (body mass index [BMI] standard deviation score [SDS] > +2) and 49 age- and gender-matched controls (BMI SDS between -1.9 and +1.9). Participants were recruited at the pediatric endocrinology outpatient clinic between April 2022 and April 2023. Clinical data, including chronological age, physical examination findings, and laboratory test results (alanine transaminase [ALT], aspartate transaminase [AST], total cholesterol, triglycerides, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], fasting blood glucose, and insulin levels), were collected from the hospital's information management system. The presence and severity of hepatosteatosis were assessed by abdominal ultrasound. Insulin resistance (IR) was determined using the HOMA-IR index, with a cutoff value of 2.5 for prepubertal patients and 3.16 for pubertal patients. The mean age of the participants was 11.6 ± 3.5 years (range: 4.5-17.7 years), with 58.2% (n = 46) being female. Serum Alarin, LDL-C, γ-glutamyl transferase (GGT), insulin, and HOMA-IR levels were significantly higher in the obesity group (P < .05). In the obese group, Alarin levels showed positive correlations with age, BMI SDS, fasting glucose, and presence of hepatic steatosis (P < .05). No significant correlations were found in the control group. The study found elevated Alarin levels in children and adolescents with obesity, similar to previous findings in adults. This suggests that Alarin may play a role in energy homeostasis and insulin resistance in childhood obesity. The results contribute to a deeper understanding of obesity's molecular mechanisms of obesity and may help to identify new therapeutic targets for preventing obesity-related complications and metabolic diseases.

White adipose tissue (WAT) is a remarkably plastic organ integrating metabolic, endocrine and immune functions. In humans, perturbations in adipocyte turnover, size regulation and cellular heterogeneity underpin the transition from metabolic health to obesity-related disease. This review, based on the 2025 Camillo Golgi Prize Lecture, highlights selected mechanistic and translational insights, primarily from our work and that of close collaborators, that have contributed to reshaping our understanding of human adipose biology. 14C-dating and clinical studies demonstrate that adipocytes are continuously renewed, and that impaired lipid turnover predisposes to weight gain, insulin resistance and type 2 diabetes. Obesity induces persistent transcriptional and structural alterations, an 'adipose memory', that provides a biological basis for understanding the difficulty of maintaining weight loss. Spatial transcriptomics has revealed at least three major adipocyte states in human WAT that differ in insulin responsiveness and lipid-handling capacity, suggesting that adipocyte composition influences depot function and responsiveness to interventions such as weight loss or pharmacological therapies. In addition, depot-specific enrichment of immunomodulatory adipocytes, particularly in epiploic WAT, highlights local adipocyte-immune crosstalk as a contributor to systemic inflammation. Collectively, these advances redefine human WAT as an active driver of cardiometabolic disease and highlight therapeutic strategies targeting adipocyte plasticity and immune-metabolic interactions.

Obesity-related metabolic disease is linked to impaired adipose tissue function, but the underlying molecular programs are difficult to assign to specific adipose-resident cell types, to mechanistically connect to inflammation, and to distinguish from alterations that normalize with weight loss. We integrated here a layered design combining untargeted proteomics and lipidomics to define obesity-associated, cell-type-resolved molecular phenotypes across isolated adipocytes and adipose microvascular endothelial cells, explore whether an obesity-like inflammatory milieu reproduces adipose-resident cell dysfunction, and identify molecular features that show evidence of recovery after surgery-induced weight loss. As expected, adipocytes from people with obesity show suppression of mitochondrial energy metabolism together with impaired lipid plasticity, as reflected by triglyceride remodelling. By mimicking an obesity-like inflammatory milieu with macrophage-conditioned media, we reproduced most of these changes in adipocyte cultures. Endothelial cells exhibited yet another, opposite trajectory in obesity, with reduced cell-cycle signalling and increased mitochondrial activation, which were recapitulated in vitro when these cells were exposed, respectively, to the secretions of inflamed macrophages and adipocytes. Bulk adipose tissue proteomes and lipidomes showed evidence of metabolic improvement after weight loss, with broad restoration of mitochondrial and substrate-handling pathways and reciprocal triglyceride remodelling. Alongside the inflammation-responsive adipocyte mitochondrial and lipid-handling dysfunction, our cell-type-informed framework probes macrophage and adipocyte-to-endothelial activation in obesity and delineates cross-context cellular programs that recover with weight loss. Additionally, we identified the elements that exhibit the strongest association with dyslipidaemia, hypertriglyceridemia and hyperglycaemia in individuals with obesity, confirming molecular signatures relevant to metabolic obesity in two cross-sectional samples.

Kidney diseases represent a major global health burden and arise from complex interactions among multiple cellular and molecular processes. Ectopic lipid deposition (ELD), defined as the accumulation of excess lipids in non-adipose tissues when lipid supply exceeds adipose storage capacity, has emerged as a key contributor to the initiation and progression of renal injury. ELD occurs across multiple renal cell types, including proximal tubular epithelial cells, podocytes, mesangial cells, glomerular endothelial cells, as well as interstitial fibroblasts and macrophages. Owing to differences in metabolic profiles and lipid-handling capacity, these cells exhibit distinct susceptibilities and pathological responses to lipid accumulation. This review summarizes the major sources and underlying mechanisms of renal ELD, with particular emphasis on cell-specific injury pathways driven by different lipid subtypes. It further discusses how these divergent responses collectively contribute to renal dysfunction and structural damage. We also outline current approaches for the clinical assessment and diagnosis of renal ELD, and highlight the relevance of age stratification in improving diagnostic precision. Recent advances in therapeutic strategies targeting renal ELD are also reviewed, including evidence from diabetic kidney disease, obesity-related kidney disease, acute kidney injury, and Alport syndrome. Overall, this review provides a systematic overview of the molecular mechanisms and therapeutic implications of ELD in kidney diseases from a cell-specific perspective, and highlights its potential as a target for improved prevention and treatment strategies.

Obesity-related metabolic diseases are characterized by profound disturbances in glucose and lipid metabolism across multiple organs, yet the mediators that coordinate these tissue-specific alterations remain incompletely understood. Insulin-like growth factor-binding protein 2 (IGFBP2), a circulating and locally expressed regulatory protein, has emerged as a context-dependent modulator of metabolic homeostasis with potential relevance to obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD). In this review, we integrate evidence from in vitro studies, animal models, and human investigations to examine the tissue-specific roles of IGFBP2 in the liver, adipose tissue, pancreas, skeletal muscle, and cardiovascular system. We further discuss IGFBP2 within an autocrine, paracrine, and endocrine framework, with emphasis on its effects on glucose handling, lipid metabolism, insulin sensitivity, and metabolic adaptation in obesity-related disease states. In addition, we summarize current clinical evidence supporting circulating IGFBP2 as a candidate biomarker of metabolic dysfunction and discuss how nutritional factors and metabolic interventions may influence its expression and circulating levels. Collectively, available evidence suggests that IGFBP2 is a context-dependent regulator and potential translational indicator of metabolic dysregulation; however, important gaps remain regarding its tissue-specific sources and modes of action, receptor interactions, context-specific signaling mechanisms, and the strength of prospective human evidence.

Overall and abdominal obesity are associated with increased risks of various chronic diseases. A comprehensive understanding of nationwide trends and contributing factors is necessary to reduce obesity burdens. We conducted hierarchical age-period-cohort analyses using cross-classified random-effects models on measured body mass index (BMI) and waist circumference (WC) data from a nationally representative sample of 86 806 Korean adults aged 19-79 years in the Korea National Health and Nutrition Examination Survey 2007-2022. In 2007-2022, there were overall increasing trends in age-standardized mean BMI and WC and prevalence of overall and abdominal obesity. When stratified by sex, the age-standardized mean BMI and WC increased among men (BMI: from 24.1 to 25.2 kg/m2; WC: from 84.6 to 88.6 cm), whereas only small changes were observed among women (BMI: from 23.1 to 23.2 kg/m2; WC: from 78.8 to 77.9 cm). Mean BMI and WC increased with age through middle adulthood in men and late adulthood in women. After controlling for age and period effects, mean BMI and WC were lowest among the birth cohorts of the late 1950s and 1970s and increased in more recent birth cohorts. Among men, mean BMI and WC were higher in higher socioeconomic subgroups (higher income, higher education, urban areas), but, among women, mean BMI and WC were higher in lower socioeconomic subgroups. To reduce obesity-related disease burdens in Korea, tailored interventions are needed to target the most vulnerable populations, such as younger generations, men of higher socioeconomic subgroups, and women of lower socioeconomic subgroups.

Background:Metabolically healthy obesity (MHO) is unstable, with up to 80% of individuals progressing to metabolically abnormal obesity (MAO), yet mechanisms underlying this transition remain unclear. African Americans bear a disproportionate burden of obesity-related cardiovascular disease. Circulating extracellular vesicles (EVs) mediate inter-organ communication and may drive MAO-related vascular dysfunction.Methods:Adults of African ancestry were classified as metabolically healthy lean (MHL, n=14), MHO (n=9), or MAO (n=16). Plasma-derived EVs were characterized and their microRNA cargo profiled. Human coronary artery endothelial cells were treated with EVs from each group to assess nitric oxide signaling, oxidative stress, inflammatory activation, and mitochondrial dynamics.Results:MHO participants exhibited preserved insulin sensitivity and lower inflammation compared with MAO despite comparable adiposity. EVs from MHO carried a distinct microRNA signature enriched in miR-148a-5p, miR-181c-5p, and miR-1255a, linked to antioxidant and matrix regulatory pathways. MAO EVs were enriched in miR-3613-3p, miR6842-3p, and miR-326, targeting inflammation and insulin resistance pathways. Compared with both MHL and MHO EVs, MAO EVs suppressed endothelial nitric oxide synthase phosphorylation and reduced nitric oxide bioavailability, with increased reactive oxygen species and ICAM-1 expression. MHO EVs induced an intermediate phenotype with disrupted mitochondrial morphology, supporting a graded continuum of endothelial stress.Conclusions:MHO represents a biologically active intermediate state. Circulating EVs from MHO individuals convey molecular signals that impair endothelial and mitochondrial function, predisposing to vascular injury and progression toward MAO. EV-associated microRNAs are mechanistic mediators and candidate biomarkers of metabolic and vascular deterioration in obesity.