The mechanisms linking obesity, inflammation, and their complications remain only partially understood. Over the last decade, evidence has consolidated the concept that obesity represents a state of chronic, low-grade inflammation that mediates the connection between excess adiposity, insulin resistance, endothelial dysfunction, and the development of Metabolic Syndrome (MetS) [1][2]. MetS is characterized by the coexistence of several metabolic risk factors including visceral obesity, dyslipidemia, hyperglycemia and elevated blood pressure that, together, increase the likelihood of developing cardiovascular disease, type 2 diabetes, reproductive disorders, and certain types of cancer [3][4]. The inflammatory response initiated in white adipose tissue contributes to systemic low-grade inflammation, where adipocytes and infiltrated immune cells release adipokines and cytokines—such as adiponectin, resistin, leptin, and C-Reactive Protein (CRP)—that regulate inflammatory signaling and perpetuate a chronic cycle leading to insulin resistance, and atherosclerosis [3][4]. MetS is therefore recognized as a chronic inflammatory condition characterized by elevated CRP, Interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) [5]-[7]. Nonetheless, inflammation and metabolic markers are not always concordant: some obese individuals exhibit normal cytokine profiles, whereas some lean subjects with hypertension or type 2 diabetes show increased inflammatory mediators [5][7]. This variability suggests that endothelial dysfunction may occur early in the MetS pathophysiological continuum, preceding overt clinical manifestations.

Recent evidence supports endothelial activation as one of the earliest detectable events in metabolic dysregulation. The upregulation of adhesion molecules—such as E-selectin, Vascular Cell Adhesion Molecule-1 (VCAM-1), and Intercellular Adhesion Molecule-1 (ICAM-1)—facilitates leukocyte attachment and transmigration across the vascular wall, promoting a pro-inflammatory and pro-atherogenic environment [5][6][8]. Elevated plasma concentration of their soluble forms (sE-selectin, sVCAM-1, sICAM-1) serves as an early indicator of endothelial perturbation, and correlates with the severity of MetS and cardiovascular risk [5][7][9]. Adipokines further modulate endothelial inflammation: adiponectin exerts protective and anti-inflammatory effects, whereas leptin and resistin promote adhesion-molecule expression, endothelial dysfunction, and oxidative stress [2][4][9]. This complex interaction between adipokines and adhesion molecules underlies the systemic inflammatory milieu characteristic of MetS. However, most available studies have been conducted in adults with advanced metabolic alterations. Little is known about the early inflammatory and endothelial changes occurring in young, apparently healthy individuals, despite their increasing exposure to risk factors such as sedentary lifestyle and high-calorie diets [9][10]. The evaluation of endothelial adhesion molecules and adipokines could, therefore, help identify early biomarkers of metabolic imbalance in this population. This study aimed to evaluate the serum values of endothelial adhesion molecules (sVCAM-1, sICAM-1, sE-selectin) and adipokines (adiponectin, resistin, leptin) in young adults with and without diagnostic criteria for MetS, to identify potential early endothelial biomarkers of metabolic syndrome in an apparently healthy young population [8]-[11].

Metabolic Syndrome (MetS) represents the convergence of multiple metabolic abnormalities that substantially increase the risk of Type 2 Diabetes (T2D), and cardiovascular disorders [1][3][7][8][12]. Over the last decade, most studies have either described the prevalence of MetS in different populations or examined molecular alterations associated with its clinical expression [8][12][13]. However, the majority have focused on middle-aged or older adults in whom metabolic disturbances are already established, whereas research into early endothelial and inflammatory changes in young, apparently healthy individuals remains limited.

Early identification of biological alterations preceding overt MetS is crucial for prevention. Our group previously reported a 14.4% prevalence of MetS in asymptomatic young Mexican adults, underscoring the relevance of studying this population [13]. The present work expands these findings by demonstrating that endothelial adhesion molecules—particularly sICAM-1 and E-selectin—are already elevated at early stages of metabolic imbalance, supporting their utility as candidate biomarkers of early endothelial activation.

Endothelial dysfunction is widely recognized as an initiating and central event in the pathophysiology of MetS and its cardiovascular complications. It is characterized by reduced Nitric Oxide (NO) bioavailability, an imbalance between vasodilatory and vasoconstrictive factors, and heightened vascular inflammation and oxidative stress [10][11]. Emerging evidence suggests that endothelial dysfunction is not only a consequence of metabolic alterations but also a precipitating factor, linking insulin resistance and vascular injury through shared inflammatory and oxidative pathways [11][14]. Mechanistically, mitochondrial oxidative stress, activation of pro-inflammatory signaling cascades (e.g., NF-κB, MAPK), and impaired calcium-dependent endothelial responses contribute to the upregulation of adhesion molecules (E-selectin, ICAM-1, VCAM-1), promoting leukocyte adhesion and transmigration and amplifying vascular inflammation [5][6].

Contemporary reviews highlight that these adhesion molecules function as early biomarkers of endothelial stress, with chronic oxidative and mitochondrial dysfunction driving their elevation before overt structural vascular damage occurs [15]. Ray et al. (2023) also reported that impaired flow-mediated dilation, accompanied by increased adhesion molecules, constitutes an early indicator of endothelial activation in cardiometabolic diseases [14]. Clinical studies further reinforce this concept: metabolically healthy individuals with obesity exhibit higher concentrations of sICAM-1 and sE-selectin than metabolically healthy, non-obese controls [16], and in T2D these markers correlate with poor glycemic control and endothelial dysfunction [17][18]. In young adults, elevated adhesion molecules have been linked to early microvascular injury, even prior to clinical manifestations [18][19]. Additionally, novel biomarkers such as endocan have been proposed as complementary indicators of endothelial activation; Vatansever et al. (2025) demonstrated correlations between serum endocan, sICAM-1, and MetS components [11]. Altogether, these findings support the hypothesis that elevated circulating adhesion molecules reflect early endothelial involvement in metabolic dysregulation. Our results, showing higher sICAM-1 and E-selectin in participants with 1 - 2 alterations and in those with MetS, are consistent with this pattern.

Sex-specific biology strongly influences the development and presentation of metabolic dysregulation, including endothelial dysfunction, inflammatory responses, and adipokine signaling. In our cohort, men showed more pronounced increases in sICAM-1, E-selectin, and leptin, whereas changes were less consistent in women. These observations align with evidence that sex hormones, sex-chromosome-linked gene expression, and body-fat distribution modulate vascular responses to metabolic stress [1]-[3][20][21]. Estrogen enhances endothelial nitric oxide synthase activity, reduces oxidative stress, suppresses NF-κB activation, and downregulates adhesion molecule expression, conferring vascular protection in premenopausal women [4][19]. Conversely, androgens may exacerbate vascular inflammation and accelerate endothelial dysfunction in men [13][20][21]. Beyond hormonal influences, sex-specific immune and vascular responses are shaped by intrinsic genetic and cellular mechanisms, as reported by McClements et al. (2025) and Robert (2023) [20][21]. Santos-Marcos et al. (2023) further described how sex hormones modulate endothelial interactions under diet-induced dysbiosis, producing sex-dependent vascular inflammation and altered endothelial permeability [22]. Collectively, these data suggest that sex modulates both the timing and magnitude of endothelial and inflammatory alterations in MetS. Our findings of higher adhesion molecules in men support this evidence and underscore the importance of sex-specific biomarker interpretation.

Adipose tissue functions not only as an energy reservoir but also as a dynamic endocrine organ governing systemic metabolism, inflammation, and vascular homeostasis. The balance between pro- and anti-inflammatory adipokines determines the transition from healthy adipose expansion to metabolic dysfunction [1][3][4]. In our study, leptin was significantly elevated in men with MetS, while adiponectin showed a decreasing trend and resistin remained unchanged. This pattern reflects an early shift toward a pro-inflammatory adipokine phenotype, consistent with reports demonstrating that leptin promotes oxidative stress, endothelial activation, and vascular remodeling [23]-[26]. Reduced adiponectin impairs NO bioavailability, enhances inflammatory signaling, and has been associated with endothelial dysfunction and increased cardiometabolic risk [27][28]. Resistin, derived from macrophages and pre-adipocytes, also contributes to vascular inflammation and stiffness [29]; the absence of differences in resistin in our cohort may indicate a very early stage before macrophage infiltration intensifies. Reviews emphasize that evaluating adipokine patterns, rather than individual molecules, provides a more accurate representation of early metabolic risk [30]. Our findings support this multidimensional model, suggesting that adipokine imbalance contributes to endothelial activation early in the course of metabolic deterioration.

From a clinical standpoint, early biomarkers should be evaluated not only through statistical differences but also through diagnostic performance. In our cohort, sICAM-1 and E-selectin showed high specificity and favorable PPV despite modest sensitivity, reflecting strong rule-in value for early metabolic alterations. The combined use of both biomarkers improved diagnostic accuracy, consistent with growing evidence that multi-marker strategies enhance early detection of cardiometabolic risk [24][31]-[33]. These findings support the robustness of using adhesion molecules as early endothelial indicators, particularly in populations where metabolic disease is still subclinical.

This study has some limitations that should be considered when interpreting the findings. Its cross-sectional design does not allow the establishment of temporal or causal relationships; however, it provides a valuable snapshot of early endothelial and metabolic changes in a large cohort of young adults. The sample was drawn from a single university population, which may limit broad generalization, yet it offers a well-defined and homogeneous group ideal for detecting early alterations. Biomarkers were measured at a single time point, but this approach ensured standardized conditions for all participants. Additionally, inflammatory cytokines such as CRP, IL-6, and TNF-α were not assessed; incorporating these markers in future research may help refine mechanistic interpretations. Despite these considerations, the study provides novel and relevant evidence of early endothelial activation associated with metabolic risk in young individuals.

In light of these limitations, our findings nevertheless identify sICAM-1 and E-selectin as practical candidates for early endothelial risk assessment in young adults. Future prospective studies should test sex-specific cut-offs, evaluate multi-biomarker panels, and define their integration into clinical and public-health screening programs.

From a practical standpoint, the assessment of sICAM-1 and E-selectin could complement existing metabolic screening strategies for young adults. These biomarkers can be measured with widely available ELISA-based methods, require only a single blood sample, and could be incorporated alongside routine assessments such as fasting glucose, lipid profiles, and waist circumference in university health services or primary-care settings. Their high specificity suggests that they may be particularly valuable for identifying individuals who warrant closer metabolic follow-up, despite having only mild or subclinical alterations. Integrating these markers into early screening initiatives could facilitate timely lifestyle interventions, and targeted prevention strategies before the onset of overt MetS.

This study shows that endothelial adhesion molecules sICAM-1 and E-selectin, are early, non-invasive biomarkers of endothelial dysfunction in young adults with initial metabolic alterations. Even in the absence of clinically defined MetS, elevated concentrations indicate early vascular activation, supporting the notion that endothelial stress precedes overt metabolic disease.

The high specificity and Positive Predictive Values (PPV) observed for both markers, and the incremental diagnostic performance when they are evaluated together, support their combined use within a multi-biomarker approach for early cardiometabolic screening, potentially strengthening preventive strategies by enabling earlier identification of at-risk individuals.

A sex-specific pattern emerged, with men showing earlier and more pronounced alterations in endothelial markers and adipokines. These differences highlight the need for sex-aware thresholds and tailored preventive strategies in future clinical applications.

In summary, the simultaneous assessment of sICAM-1 and E-selectin offers a promising and cost-effective tool, for the early detection of endothelial dysfunction and metabolic risk in apparently healthy young adults. Longitudinal studies are warranted to confirm predictive value, refine cut-offs (by sex), and define integration into clinical and public health screening programs.

Supported in part by grants PICDS08-69 from Instituto de Ciencia y Tecnología del Distrito Federal to RVM; PAPIIT-DGAPA, UNAM (IN221123, IN228826 to IAGO and IN228825 to RVM). To M. Murguía for technical assistance.