Oxidative Homeostasis Dysregulation May Promote Pathogenesis of Cardio-Metabolic Complications in Childhood Obesity

Introduction: Advanced glycation end-products (AGEs) are heterogeneous groups of irreversible adducts resulting from nonenzymatic glycation and glyoxidation of proteins, lipids, and nucleic acid. AGEs and its cell receptor RAGE have been involved in the pathophysiology of cardiovascular and metabolic diseases. Interaction of AGEs with RAGE results in an increased generation of oxygen radicals and increased expressions of pro-inflammatory cytokines. Circulating soluble AGE receptor (sRAGE) competes with RAGE for AGEs, to counterbalance the negative effects of their interaction. AGE/sRAGE-ratio have been suggested to be expression of the oxidative state, as well as advanced oxidation protein products (AOPPs). Objective: To investigate the changes in oxidative balance and to define factors influencing AGEs, sRAGE, AGEs/sRAGE-ratio and AOPPs levels in a cohort of obese children compared to controls. Material and methods: Forty-one overweight and obese children and adolescents (range 5–16 years) and thirty-six healthy, lean, age and sex-matched controls were recruited. Inclusion criteria: BMI SD>1 corrected for age and sex, born as healthy fullterm infant. Exclusion criteria were: genetic and endocrinological causes of obesity, arterial hypertension, chronic diseases and therapies, smoking. Lipid and glucose profiles, liver, renal and thyroid functionality, uric acid, C-reactive protein (CRP), AGEs, sRAGE and AOPPs serum concentrations, were evaluated in both groups. Results: HOMA, triglycerides, cholesterol/HDL-ratio, atherogenic- index of plasma (AIP), CRP, AOPPs, AGEs/sRAGE-ratio were significantly higher whereas HDL and sRAGE were significantly lower in overweight/obese patients compared to controls. AGE/sRAGE-ratio and AOPPs positively correlate with BMI SD (p<0.005), cholesterol/HDL-ratio(p=0.000), AIP (p=0.02 and p=0.000,respectively), CRP (p=0.000), and negatively correlate with HDL(p=0.004 and p=0.000,respectively). AOPPs positively correlate with HOMA (p=0.002) and AGEs (p=0.003), and negatively with sRAGE (p=0.003). BMI SD was a significant predictor of AGEs/sRAGE-ratio (B=0.06; p=0.000),AOPPs (B=0.202; p=0.000) and sRAGE (B=- 67.1;p=0.000). CRP was significant predictor of AGEs/sRAGE-ratio (B=0.21; p=0.000),AOPPs (B=0.55; p=0.01) and AGEs (B=34.1; p=0.04). Cholesterol/HDL-ratio was a significant predictor of AGEs/sRAGE-ratio (B=0.06; p=0.008), AOPPs (B=0.23; p=0.000), AGEs (B=14.1; p=0.02), and sRAGE (B=-56.3; p=0.01). HOMA was a significant predictor of AOPPs (B=0.12; p=0.03). Conclusions: Our findings demonstrate a relative shift in stressors from anti-stressors in overweight/obese children, suggesting the presence of oxidative homeostasis dysregulation and an enhanced susceptibility to oxidative/inflammatory tissues damage, that may contribute to the pathogenesis of long-term cardiovascular and metabolic complications. Moreover, we confirmed the role of AGEs/sRAGE-ratio as biomarkers for oxidative state.