Cardiovascular risk biomarkers and metabolically unhealthy status in prepubertal children: Comparison of definitions.

BACKGROUND AND AIMS: The early onset of cardio-metabolic abnormalities, known as metabolically unhealthy (MU) status, is highly associated with obesity and cardiovascular disease (CVD), as well as with increased morbidity and mortality later in life. Given the lack of a consensus MU classification for prepubertal children, we aimed to compare available MU definitions in terms of their association with CVD risk biomarkers. METHODS AND RESULTS: A total of 930 prepubertal children (622 with overweight/obesity, 462 males) aged 5-10.9 years were recruited, anthropometric measures were taken and biomarkers were analyzed. Children were classified using eight MU definitions based on different cut-offs for blood pressure, triacylglycerides, high-density lipoprotein cholesterol, glucose and homeostasis model assessment for insulin resistance (HOMA-IR). MU prevalence in children with overweight/obesity ranged between 30% and 60% across definitions. Plasma concentrations of resistin, leptin, myeloperoxidase (MPO) and total plasminogen activator inhibitor 1 (tPAI-1) were higher, and those of adiponectin were lower, in MU compared to MH children with overweight/obesity. Linear regression analyses confirmed the contribution of MPO and tPAI-1 concentrations to MU status, with most significant results derived from definitions that use age and sex-specific criteria and that account for HOMA-IR. CONCLUSION: Plasma concentrations of MPO and tPAI-1 are increased in prepubertal MU children irrespective of having normal-weight or overweight/obesity. Inclusion of age and sex-specific cut-offs for cardio-metabolic components as well as insulin resistance criteria increases the quality of MU definitions as seen by their stronger association with CVD biomarkers concentrations.

Inflammation in metabolically healthy and metabolically abnormal adolescents: The HELENA study.

BACKGROUND AND AIMS: Inflammation may influence the cardio-metabolic profile which relates with the risk of chronic diseases. This study aimed to assess the inflammatory status by metabolic health (MH)/body mass index (BMI) category and to assess how inflammatory markers can predict the cardio-metabolic profile in European adolescents, considering BMI. METHODS AND RESULTS: A total of 659 adolescents (295 boys) from a cross-sectional European study were included. Adolescents were classified by metabolic health based on age- and sex-specific cut-off points for glucose, blood pressure, triglycerides, high density cholesterol and BMI. C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin (IL-6), complement factors (C3, C4) and cell adhesion molecules were assessed. RESULTS: Metabolically abnormal (MA) adolescents had higher values of C3 (p < 0.001) and C4 (p = 0.032) compared to those metabolically healthy (MHy). C3 concentrations significantly increased with the deterioration of the metabolic health and BMI (p < 0.001). Adolescents with higher values of CRP had higher probability of being in the overweight/obese-MH group than those allocated in other categories. Finally, high C3 and C4 concentrations increased the probability of having an unfavorable metabolic/BMI status. CONCLUSIONS: Metabolic/BMI status and inflammatory biomarkers are associated, being the CRP, C3 and C4 the most related inflammatory markers with this condition. C3 and C4 were associated with the cardio-metabolic health consistently.

Paraoxonase 1 activities and genetic variation in childhood obesity.

Changes in paraoxonase 1 (PON1) activities have been observed in a variety of diseases involving oxidative stress, such as CVD. However, its role in obesity has not been fully established. In the present study, we aimed (1) to genotype sixteen PON1 SNP, (2) to measure serum PON1 activities and (3) to correlate these findings with the incidence of childhood obesity and related traits. We conducted a case-control study of 189 normal-weight and 179 obese prepubertal children, and we measured four different PON1 activities: lactonase; paraoxonase; arylesterase; diazoxonase. Although none of these activities was significantly different between the obese and normal-weight children, lactonase activity was found to be positively correlated with HDL-cholesterol and ApoA1 levels and negatively correlated with myeloperoxidase and fatty acid-binding protein 4 levels. Among the sixteen genotyped PON1 SNP, only the intronic SNP rs854566 exhibited a significant association with obesity (OR 0·61, 95 % CI 0·41, 0·91; P= 0·016). This genetic variant was also associated with increased diazoxonase, lactonase and arylesterase activities and decreased paraoxonase activity. Other genetic variants exhibited different association patterns with serum activities based on their location within the PON1 gene, and SNP that were located within the promoter were strongly associated with lactonase, arylesterase and diazoxonase activities. The functional variant Q192R exhibited the greatest effect on paraoxonase activity (P= 5·88 × 10(-42)). In conclusion, SNP rs854566 was negatively associated with childhood obesity and with increased serum PON1 activities in prepubertal children. We determined that lactonase is a reliable indicator of PON1 activities and should be included in future studies of PON1 function.

A gene variant of 11ß-hydroxysteroid dehydrogenase type 1 is associated with obesity in children.

BACKGROUND: The 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme catalyses the regeneration of active cortisol from inert cortisone and plays a critical role in tissue-specific corticosteroid reactions; therefore, 11ß-HSD1 is a key molecule associated with the development of obesity. Despite evidence for its role in obesity, no genetic polymorphisms have been significantly associated with the disease per se. OBJECTIVE: The aim of this study was to evaluate whether HSD11B1 gene variants, which have never been studied before, are associated with obesity and its related traits, as well as its relation to biomarkers of inflammation, liver damage and cardiovascular disease in a cohort of Spanish children. DESIGN: We performed a prospective case-control study. SUBJECTS: A total of 534 children were examined and classified as being obese (n=292) or normal weight (n=242). Anthropometric and biochemical measurements related to obesity, including inflammation, liver damage and cardiovascular disease, were determined. Genomic DNA was extracted and 10 HSD11B1 gene single-nucleotide polymorphisms (SNPs) were genotyped. RESULTS: A novel SNP, rs3753519, was strongly associated with obesity and this SNP was the only statistically significant HSD11B1 gene SNP remaining after a Bonferroni correction (odds ratio=1.97 for allelic effect, 95% confidence interval 1.23-3.16; P=0.004 and Bonferroni corrected P=0.046). In addition, this SNP was significantly and positively associated with increased body mass index (BMI), BMI z-score, weight, waist circumference, plasma γ-glutamyl transpeptidase and plasma active plasminogen activator inhibitor 1. The SNP was negatively associated with plasma adiponectin and cortisol after adjusting for sex and age. None of the inflammation biomarkers tested were associated with the risk allele. CONCLUSION: These data, which link an HSD11B1 genotype with both disease prevalence and its related phenotypes, strongly support a role for the rs3753519 polymorphism in the pathogenesis of pediatric-onset obesity.