Notoriously, pediatric obesity represents an alarming phenomenon in industrialized countries from both a health and a socio-economic point of view. In addition, according to the World Health Organization, rate of children with obesity (OB) is expected to double by 2035 [1]. Noteworthy, this condition is closely associated with several comorbidities or preclinical signs of organ damage, such as prediabetes, hypertension, dyslipidemia, and fatty liver disease (FLD) [2]. This scenario is supposed to track into adulthood and produce serious long-term consequences on cardiometabolic health. Indeed, the early presence of obesity-related comorbidities may contribute to accelerate the risk of cardiovascular morbidity in adulthood [2].

The presence of cardiometabolic comorbidities has been largely studied in the pediatric population [3], but little is known about the influence of sex on this association. This aspect should not be overlooked in children, since it has been widely demonstrated that men are more frequently exposed to early morbidity and mortality for cardiovascular disease than females [4]. Given the well-documented protective role of oestrogens, this advantage is attenuated after menopause [5]. In addition, diseases associated to high cardiometabolic risk, such as type 2 diabetes [6] and FLD are more prevalent in males [7]. On the contrary, a higher risk of chronic kidney disease has been reported in females [8].

Given the high burden of cardiovascular risk in pediatric OB [9], it may be interesting to analyze in-depth whether and which kind of cardiovascular risk factors or preclinical signs of target organ damage are associated to a non-modifiable risk factor such as sex.

Based on these premises, we hypothesized that sex-related differences in cardiovascular risk might be present in adolescents with excess weight. Therefore, the aim of this study was to compare the traditional cardiovascular risk factors and preclinical signs of cardiac, vascular and renal impairment between adolescent boys and girls with overweight (OW) or OB.

This is a multicenter cross-sectional study that included 1562 youths with OW or OB. Participants were consecutively admitted to nine Italian endocrinology centers of the Pediatric Obesity Study Group within the Italian Society for Pediatric Endocrinology and Diabetology between 2016 and 2020 [10]. This study was conducted according to the principles expressed in the Declaration of Helsinki and approved by the Research Ethical Committee of University of Campania “Luigi Vanvitelli” (protocol code 834/2016). An informed consent was obtained from the parents of all participants before any procedure.

Exclusion criteria were: age 10 years (n = 561), genetic obesity or endocrine disorders, chronic use of medications, glucose levels in the diabetic range (n = 13). Finally, the records of 988 adolescents (510 boys and 478 girls), mean age 12.9 $\pm$ 1.8 years, were examined.

Two separate samples of 142 young people with OW or OB (67 boys and 75 girls) with echocardiographic evaluation performed in the Pozzuoli Hospital (Naples) [11], and 107 youths (59 boys and 48 girls) with carotid ultrasound performed in the Cardarelli Hospital of Naples [12] between 2003 and 2013, were included in the study.

The present study highlighted several sex-related differences in cardiovascular risk factors in adolescents with OW or OB, demonstrating that boys presented a higher degree of visceral adiposity, FLD, cardiac and vascular abnormalities compared to girls, while girls showed a higher risk of mild reduced glomerular function.

These findings are consistent with the sex-related cardiovascular risk described in non-elderly adults. Indeed, it is well established that males are considered at higher risk of cardiovascular morbidity and mortality than females, although this difference varies over time and geographically [26]. Due to the multifactorial nature of cardiometabolic risk, sex-related differences can be explained not only by the protective role of estrogens, but also by the complex interplay of several conditions, such as those correlated to lifestyle behaviours (e.g., smoking, alcohol consumption), or traditional cardiometabolic risk factors (such as visceral adiposity, dyslipidemia, and hypertension) which are more prevalent in non-elderly and non-diabetic males than females [26].

More complex and conflicting data are available on the role of sex as non modifiable risk factor for cardiovascular mortality among adults with OW or OB. For instance, the hazard ratio of cardiovascular death was higher in men with obesity (BMI $\ge$ 30 40 Kg/m${}^2$) [1.55 (1.22–1.96)] than in females [1.09 (0.85–1.40)] as demonstrated by Khan et al. [27] by analyzing several longitudinal studies in the United States (Cardiovascular Disease Lifetime Risk Pooling Project). Another study demonstrated that men showed a higher mortality for cardiovascular disease as compared to women independently of the severity of OB on the basis of 11 prospective cohorts from four European countries [28]. On the contrary, Mongraw-Chaffin et al. [29] reported that higher BMI had the same deleterious effect on risk of incident cardiac heart disease in women and men.

Robust evidence has linked traditional pediatric cardiometabolic risk factors, such as increased adiposity, hypertension, hyperlipidemia, and risk factor clustering with subclinical cardiovascular disease [30]. The adverse cardiometabolic risk profile related to OB starting in early adolescence and even in early childhood has been also associated with fatal and not fatal cardiovascular events as early as 40 years of age [31].

The association between OB and cardiometabolic risk factors may begin at different stages of youth, depending on the degree of OB, cardiometabolic risk factors, and sex [32]. The emergence of sex-related differences in the trajectories of atherogenic lipids (apolipoprotein B containing very low-density lipoprotein and low density lipoprotein traits) and predictive biomarkers (glucose and HDL-C) for cardiometabolic diseases has been demonstrated in a prospective birth cohort study from childhood (age 7 years) to early adulthood (25 years) in United Kingdom [33]. Most changes of causal and predictive cardiometabolic traits were detrimental for males, and emerged only in late childhood and adolescence. It may be possible that multiple mediators such as adiposity, puberty timing, and other health behaviours might have played a role, but this aspect was not assessed in that study.

Of note, we did not find any sex-related difference in the traditional cardiometabolic risk factors, either when they were considered as continuous or categorical variables, in our sample of adolescents with OW or OB, except for higher values of fasting plasma glucose in boys and a slightly higher frequence of impaired glucose tolerance in girls. Moreover, a significally higher WHtR values and frequence of individuals with WHtR $\ge$0.60 were found in boys. It is well known the important role played by visceral fat on cardiovascular risk. In particular, the WHtR is a sex- and age-independent proxy for visceral adiposity and it is strongly associated with higher cardiometabolic risk in children with OW or OB. Fundamentally, our data are in partial agreement with another cross-sectional study of treatment-seeking Norwegean adolescents with severe obesity, in whom no sex-related differences were found in diastolic BP, total cholesterol, HOMA-IR, and HbA1c levels [34]. Instead, several discordances were noted likely due to the different genetic, environmental or socio-economic background. Firstly, we did not confirm the higher systolic BP values and the lower HDL-Cholesterol values reported in boys in the Norwegean study. Secondly, we found that girls and not boys were exposed to higher levels of triglycerides and had a higher TG/HDL-C ratio, whereas boys had higher levels of fasting glucose that were non reported in the Norwegean study.

Similarly to visceral adiposity, we found a higher frequence of FLD in boys than girls. The close relationship of FLD with cardiometabolic risk in children with OB has been largely demonstrated [34, 35, 36]. As observed in adults [37, 38, 39], accumulating pediatric evidence described non-alcoholic FLD as a condition with sexual dimorphism, with a higher prevalence in boys than in girls [40, 41, 42]. This might be attributable to the predominant visceral distribution of adipose tissue in males that is associated with insulin resistance and free fatty acids flux, leading to FLD development [39]. On the other hand, females have a prevalent subcutaneous fat distribution and leptin production that prevents from visceral fatty tissue accumulation in cooperation with estrogens, which may play a protective role against liver fat accumulation. However, the role of sex steroids on metabolic impairments is still complex and needs to be further elucidated [41, 42, 43].

In the wide perspective of cardiometabolic burden of pediatric obesity, the obesity-related glomerulopathy has recently gained remarkable attention [44, 45]. Similarly to adults [46], emerging data demonstrated that children with OB are at higher risk of kidney damage (expressed as renal function decline with or without hypertension and/or proteinuria) [47, 48, 49, 50]. Of note, cardiometabolic parameters have been closely associated to kidney injury, suggesting an intimate link between renal function and OB, but also with the obesity-related dysmetabolic state [45, 51, 52].

In line with adult evidence reporting that females are more susceptible to chronic kidney disease development than males [53, 54], we demonstrated for the first time sex-related differences for mild renal injury in adolescents with OB.

It is well established that LVH or abnormal LV geometry act as risk factors for cardiovascular morbidity and mortality in adult populations [55, 56]. The assessment of LVH depends on the cut-off used to calculate LV mass or on the presence of hypertension, which is the principal determinant of LVH [13]. In any case, using the method proposed by Chinali et al. [16], that indexes the LVM for height${}^{2.16}$ with a single cut-point for both sex, we observed higher LVMi, and higher prevalence of LVH and even of concentric LVH in boys than in girls, as demonstrated in adults. Of note, we observed lower levels of RWT${}_{\text{a}}$ in girls vs boys, likely due to several factors such as body weight or fat mass. This finding may be expression of reduced adaptation of LVM to increased body weight or to the postload in girls vs boys. This kind of cardiac geometry may predispose later in life to higher risk of eccentric LVH notoriously associated with cardiac failure that is prevalent in females than males with OB [57].

With regard to cIMT as a marker of preclinical atherosclerosis in adolescents, studies regarding the impact of sex are limited and not conclusive. In addition, the lack of robust normative tables makes difficoult the interpretation of cIMT [56]. We observed a higher prevalence of high cIMT in boys than girls, but the finding that approximately 76% of youths with OW/OB had cIMT levels above 90th percentile [25] highlights the difficulty of interpreting cIMT in adolescents with OW or OB from a clinical point of view.

This study has some limitations that should be acknowledged. Firstly, the cross sectional design does not allow to understand whether the sex-related differences in the traditional cardiometabolic risk factors might increase in the following years. Secondly, information about pubertal stage, family history or lifestyle behaviours were not available to assess their possible influence on the sex prevalence of visceral adiposity, hypertension, fatty liver disease, and preclinical signs of target organ damage. On the other hand, study strengths include the multicenter study design and the large and well-phenotyped sample allowing to show significant sex-differences in the cardiovascularrisk profile of children with obesity.

In conclusion, this cross-sectional study conducted in adolescents with OW/OB confirmed our hypothesis that sex-related differences in cardiovascular risk might be present in adolescents with OW/OB. Boys exhibited a higher degree of visceral adiposity, hypertension, FLD, LVH, and cIMT than girls. Conversely, a higher prevalence of MReGFR was detectable in girls. These findings mirror the cardiovascular risk profile observed in non-elederly and non-diabetic adults. Considering that cardiovascular risk might occur early in life, the role of a non modifiable factor such as sex should be considered for early cardiovascular risk stratification.

Worthy of note, relevant clinical and prognostic implications could be also drawn. Indeed, a better understanding of sex-differences related to cardiometabolic health of children with OW/OB might enhance the effectiveness of obesity prevention interventions by significantly improving the challenging management of these at-risk patients in clinical practice.

Therefore, more research efforts are needed to expand knowledge about sex-differences in the context of pediatric OB. As a matter of fact, this could pave the way for an insightful approach of personalized medicine through targeted strategies for children with OB.

BP, blood pressure; BMI, body mass index; cIMT, carotid intima media thickness; eGFRFAS${}_{\text{height}}$, Full Age Spectrum for height equation; FLD, fatty liver disease; GFR, glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; HbA1c, glycosylated hemoglobin A1c; HOMA-IR, Homeostasis model assessment of insulin-resistance; IVST, interventricular septum thickness; LVH, left ventricular hypertrophy; LVM, left ventricular mass; MReGFR, mild reduced eGFR; OB, obesity; OW, overweight; RWT, relative wall thickness; TG/HDL-C ratio, triglycerides to high-density lipoprotein-cholesterol ratio; WHtR, waist to height ratio.

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

PDB and GV designed the research study. ADS, MRL, DC, MW, EMdG, AM, CM, MFF, EM, VC, FF, GM, NM, AI performed the research. PDB analyzed the data. PDB, ADS, and GV wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The research was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Research Ethical Committee of University of Campania “Luigi Vanvitelli” (protocol code 834/2016) and an informed parental consent was obtained before any procedure.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.