Could AGE/RAGE-Related Oxidative Homeostasis Dysregulation Enhance Susceptibility to Pathogenesis of Cardio-Metabolic Complications in Childhood Obesity?

Abstract

Background: Advanced glycation end-products (AGEs) and their cell receptor (RAGE) are involved in the pathophysiology of cardio-metabolic diseases. Interaction of AGEs with RAGE results in increased generation of oxygen radicals and pro-inflammatory cytokines. Circulating soluble RAGE (sRAGE) interacts with AGEs in order to counterbalance the negative effects of AGEs-RAGE interaction. Objectives: To define factors influencing AGEs, sRAGE, AGEs/sRAGE-ratio, and advanced oxidation-protein products (AOPPs) levels and to investigate changes in oxidative balance among overweight/obese children. Materials and methods: Cross-sectional, one Center, case-control study included 41 overweight and obese children aged between 5 and 16 years and 36 lean matched controls. Inclusion criteria were: BMI ≥ 1 SD; term birth; no genetic or endocrine causes of obesity; no associated chronic diseases neither chronic therapies. All patients underwent clinical and biochemical investigations (lipid and glucose profiles, liver, renal and thyroid function tests, uric acid, C-reactive protein (CRP), AGEs, sRAGE, and AOPPs serum concentrations). Significance was established at 0.050. Results: AOPPs, AGEs/sRAGE-ratio, HOMA-IR, triglycerides, triglycerides/HDL-ratio, total cholesterol (TC)/HDL-ratio, atherogenic-index of plasma (AIP), uric acid, CRP were significantly higher, whereas sRAGE and HDL were significantly lower in overweight/obese children than controls. sRAGE was significantly negatively correlated with BMI SD, TC/HDL-ratio, CRP, AOPPs, and positively with HDL. AGE/sRAGE-ratio and AOPPs were significantly positively correlated with BMI SD, TC/HDL-ratio, AIP, CRP, and negatively with HDL. BMI SD was independently associated with AGEs/sRAGE-ratio ( B = 0.06; p = 0.008), AOPPs ( B = 0.13; p = 0.02), and sRAGE ( B = −73.18; p = 0.000). Conclusions: We demonstrated, for the first time in a pediatric cohort, a significant higher value of AGEs/sRAGE-ratio among overweight/obese children, expression of a relative shift to oxidant from anti-oxidant factors, suggesting an AGE/RAGE-related oxidative homeostasis dysregulation that could enhance susceptibility to oxidative/inflammatory tissues damage. Severity of overweight, influencing the increase of oxidative stress in human organism and even in children, may contribute to the pathogenesis of long-term cardiovascular and metabolic alterations.

Precocious Preclinical Cardiovascular Sonographic Markers in Metabolically Healthy and Unhealthy Childhood Obesity

“…Obesity in childhood is related to a wide spectrum of cardiovascular and metabolic comorbidities. Obese children and adolescents are more likely to become obese adults, with an increased risk of premature morbidity and mortality due to cardiovascular diseases (CVD) (1)(2)(3)(4)(5). The presence of early signs of cardiovascular (CV) dysfunction have already been demonstrated in obese children and adolescents, even in absence of other obese-related comorbidities, as insulin resistance, dyslipidemia, and arterial hypertension (6).…”

Sex Hormone-Binding Globulin Is Associated with Obesity and Dyslipidemia in Prepubertal Children

“…Third, we could not include influencing factors such as lifestyle habits, diet differences, family history data of cardiovascular risk, and metabolic alteration. Further, we could not consider important markers in the pathogenesis of cardio-metabolic complications such as insulin levels, pro-inflammatory markers, hepatic lipid content, and oxidative stress [18,[33][34][35]. Obesity increases oxidative stress, and it contributes to the pathogenesis of cardiovascular and metabolic complications [35].…”

“…Further, we could not consider important markers in the pathogenesis of cardio-metabolic complications such as insulin levels, pro-inflammatory markers, hepatic lipid content, and oxidative stress [18,[33][34][35]. Obesity increases oxidative stress, and it contributes to the pathogenesis of cardiovascular and metabolic complications [35]. In addition, SHBG level is negatively associated with hepatic lipid content and insulin resistance as well as pro-inflammatory markers [2,3].…”

Advanced Glycation End Products (AGEs): Biochemistry, Signaling, Analytical Methods, and Epigenetic Effects

“…Numerous studies showed that the AGEs and the advanced lipoxidation end products (ALEs) are involved in the development and progression of chronic degenerative diseases, including diabetes [28][29][30], cardiovascular diseases [29,31,32], neurological disorder [33,34], some types of cancer [35,36], and all those pathologies in which the mechanisms of oxidative stress are involved, as well as the senescence processes [33].…”