13Endocrine and Metabolic Consequences of Childhood Obesity part III Editorial

Elpis Vlachopapadopoulou ^1* Artur Mazur ² Aneta Monika Gawlik-Starzyk ³ Grzegorz Telega ⁴ Malgorzata Wojcik ⁵ Dénes Molnár ⁶

• ¹ Panagiotis & Aglaia Kyriakou Children's Hospital, Athens, Greece
• ² University of Rzeszow, Rzeszów, Podkarpackie Voivodeship, Poland
• ³ Faculty of Medical Sciences, Medical University of Silesia, Katowice, Poland
• ⁴ Medical College of Wisconsin, Milwaukee, WI, United States, Milwaukee, United States
• ⁵ Department of Pediatric and Adolescent Endocrinology,Pediatric Institute, Jagellonian University Medical College, Krakow, Poland
• ⁶ RRF-2.3.1-21-2022-00012, National Laboratory for Human Reproduction, Szentágothai Research Centre, University of Pécs, Pecs, Hungary

recognition of contributing factors and children at higher risk for overweight or obesity and call for early action (2). Furthermore, it is very important, from a scientific point of view, to investigate new molecules, new pathways associated with obesity as well as mechanisms contributing to the obesity phenotype and its co-morbidities as well as to investigate novel ways to address them. Thus, this is the third special issue on Endocrine and Metabolic Comorbidities of childhood obesity In this special issue researchers have investigated associations of recently described proteins such as irisin, zonulin (5), asprosin (6) and angiopoietin-like protein 8 (ANGPTL8) (7) with anthropometric and metabolic parameters, while others have reported on the importance of gut microbiota, and inflammatory Th17 cells in regard to sleep apnea and insulin resistance.Association of increased ANGPTL8 and increased body weight as well as the impact of maternal nutrition during pregnancy on the development of offspring's obesity were reported.The effect of novel treatment options such as exenatide on secretory patterns of endogenous hormones, was also highlighted. The importance of recognizing the presence of sarcopenia was documented. The association of the two novel composite inflammatory markers: The Systemic Immune-Inflammatory Index (SII) and Systemic Inflammatory Response Index (SIRI) with body mass index (BMI) in children was first reported based on epidemiological data.In more detail the papers address physiology issues, inflammation, epigenetics and therapeutic intervention. Important findings reported in the papers published in this issue are the following: ANGPTL8 levels were found elevated in adolescents with overweight and obesity, in the Arab population from Kuwait, with a strong positive correlation with hsCRP, leptin, and chemerin. This study is of importance since ANGPTL8 has diverse biological effects depending on its location and is involved in various pathological processes-such as inflammation, tumor progression, ventricular remodeling, and ectopic fat deposition-elevated levels during early adolescence could serve as an early marker for metabolic and cardiovascular complications and a potential target for novel pharmacological interventions.Zonulin is a protein secreted mainly by the liver and the enterocytes and it represents the only measurable blood protein known to regulate the permeability of intestinal tight junctions. Furthermore, it may play a role in the pathogenesis of obesity and related metabolic disturbances. The first-time documentation of the meal-related secretion pattern of serum zonulin in a pediatric cohort suggests that hyperglycemia during an OGTT or post-meal in reallife conditions may lead to prolonged upregulation of zonulin, potentially impacting intestinal function. This finding is significant, as it highlights the connection between intestinal permeability, inflammation, and obesity, reinforcing the rationale for developing novel therapeutic strategies targeting microbiome modifications.There is clinical significance in the pathogenesis of fatty liver of the association demonstrated between plasma asprosin levels (a fasting-induced protein hormone that modulates hepatic glucose release, and obesity and insulin resistance) and HOMA-IR, in Korean children and adolescents, in a clinical setting.Irisin, a recently identified adipomyokine, exhibits a range of effects, including influences on metabolism, energy balance, insulin resistance, and the browning of white adipose tissue. In a study published in this issue, irisin levels were found to correlate positively with fasting glucose, insulin, HOMA-IR, and osteocalcin, while showing a negative correlation with HDL.Additionally, the research demonstrated a positive association between irisin levels and the total body-less head (TBLH) BMD z-score in Korean children and adolescents, highlighting that irisin is a significant mediator for metabolic actions.Currently, there is no consensus on diagnostic criteria for paediatric sarcopenic obesity. In this collection, a paper assessed obese children and adolescents for muscle mass, muscle strength and physical performance, reporting that sarcopenia detection varied with the criteria used.Further research using gold standard measures of body composition are required, specific to age and pubertal stages, with robust normative data.Age-and puberty-appropriate measures that identify insulin resistance may be useful in the assessment and treatment of paediatric and adolescent obesity, going beyond the flawed assessment simply using fasting insulin levels. In this collection, a surrogate insulin resistant estimate, SPLICE (Single Point Insulin Sensitivity Estimator), examined by pubertal stage. SPICE requires fasting measures of HDL-cholesterol and triglycerides and body mass index."SPISE values were significantly lower in patients with confirmed insulin resistance (total sum of insulin OGTT ≥ 535 μu/mL) in all pubertal groups. The authors conclude that SPICE strength lies in the use of widely accessible and affordable laboratory tests, making it well-suited for large-scale studies and ongoing monitoring across various populations.A narrative review explores literature of human studies on how maternal intake of macronutrients and vitamins affects DNA methylation patterns and their link to offspring phenotypes, including obesity and metabolic changes. The authors emphasize increasing evidence that maternal consumption of specific nutrients-such as fructose, fat, protein, vitamins, and methyl-group donors-during pregnancy can alter the offspring's DNA methylation patterns, potentially contributing to obesity and related metabolic disorders.Trying to elucidate the connection between increased adiposity and low grade inflammation in the body, the association between erythrocyte parameters, the proinflammatory Th17 lymphocytes, and IR markers was evaluated in children with excessive body weight. The study published in this issue, confirmed that erythrocyte parameters such as erythrocyte count and HGB concentrationare elevated in children with obesity and show a positive correlation with insulin resistance and proinflammatory Th17 lymphocytes. The clinical relevance of measuring these parameters lies in their role as indirect markers of low-grade systemic inflammation, which can be used to evaluate the impact of obesity in individuals and monitor their response to treatment, whether through diet and exercise or pharmacological intervention.The only paper addressing treatment effects is the collaborative study between Upsala Sweden and Saltzburg Austria groups evaluating in a randomized control manner, the effect of exenatide extended release treatment in adolescents with obesity. The authors have previously published the results in regard to BMI, cholesterol and glucose levels as well as safety and tolerability of the medication. Exenatide reduced BMI-SDS, weight, waist circumference, 2-hour-glucose during OGTT, total cholesterol, without significant change in liver fat content in comparison to placebo. Safety and tolerability profiles were comparable to placebo with the exception of mild adverse events being more frequent in exenatide-treated patients. (Weghuber ) In this sub-study they have evaluated prior and after treatment:GLP-1, glucose, insulin, glucagon and increased glicentin levels that were measured during OGTT and DPP-4 and proinsulin that were measured at fasting The authors conclude that treatment with weekly s.c. injections with 2 mg of exenatide extended release did not affect GLP-1 levels during OGTT. Treatment significantly lowered DPP-4, proinsulin and the proinsulin-to-insulin ratio at fasting, increased glicentin levels but did not affect insulin, C-peptide or glucagon levels during OGTT.By maintaining total GLP-1 levels and reducing DPP-4 (which degrades GLP-1), exenatide prolongs the hormone's effects, leading to improved glucose homeostasis, by enhancing glucose-dependent insulin secretion and decreasing hepatic glucose production.In conclusion, the papers featured in this special issue shed light on various pathways involved in the development of obesity and explored potential associations between different biomarkers, anthropometric measurements, and metabolic parameters, with a particular focus on insulin resistance. Additionally, they raise important scientific questions for future research on the etiology and metabolic complications of childhood obesity.