Exposure to 4,4'-DDE in visceral adipose tissue and weight loss in adolescents from the Teen-LABS cohort.

OBJECTIVE: Dichlorodiphenyldichloroethylene (DDE), an obesogen accumulating in adipose tissue, is released into circulation with weight loss, although its impact is underexplored among adolescents. We tested the association using an integrative translational approach of epidemiological analysis among adolescents with obesity and in vitro measures exploring the impact of DDE on adipogenesis via preadipocytes. METHODS: We included 63 participants from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort. We assessed 4,4'-DDE in visceral adipose tissue at surgery and BMI and waist circumference at surgery and 0.5, 1, 3, and 5 years after. We conducted longitudinal analysis to estimate the interaction on weight loss between DDE and time since surgery. In vitro analysis quantified adipogenic differentiation in commercial human preadipocytes exposed to 4,4'-DDE via fluorescent staining and imaging. RESULTS: A dose-response relationship was observed, with the low-exposure group having a greater reduction in BMI during the first year compared to higher-exposure groups and showing smaller regains compared to higher-exposure groups after the first year. In vitro analysis of preadipocytes treated with 4,4'-DDE during adipogenic differentiation for 12 days showed a concentration-dependent increase in lipid accumulation. CONCLUSIONS: DDE could contribute to weight trajectory among adolescents undergoing bariatric surgery, potentially mediated via promoted adipogenesis in preadipocytes.

Integrative metabolomics highlights gut microbiota metabolites as novel NAFLD-related candidate biomarkers in children.

Altered gut microbiota and metabolites are important for non-alcoholic fatty liver disease (NAFLD) in children. We aimed to comprehensively examine the effects of gut metabolites on NAFLD progression. We performed integrative metabolomics (untargeted discovery and targeted validation) analysis of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and obesity in children. Fecal samples were collected from 75 subjects in the discovery cohort (25 NAFL, 25 NASH, and 25 obese control children) and 145 subjects in an independent validation cohort (53 NAFL, 39 NASH, and 53 obese control children). Among 2,491 metabolites, untargeted metabolomics revealed a complete NAFLD metabolic map containing 318 increased and 123 decreased metabolites. Then, machine learning selected 65 important metabolites that can distinguish the severity of the NAFLD. Furthermore, precision-targeted metabolomics selected 5 novel gut metabolites from 20 typical metabolites. The functionality of candidate metabolites was validated in hepatocyte cell lines. In the end, this study annotated two novel elevated pathogenic metabolites (dodecanoic acid and creatinine) and a relationship between depleted protective gut microbiota (Butyricicoccus and Alistipes), increased inflammation (IL-1ß), lipid metabolism (TG), and liver function (ALT and AST). This study demonstrates the role of novel gut metabolites (dodecanoic acid and creatinine), as the fatty acid metabolism regulator contributing to NAFLD development through its influence on inflammation and liver function. IMPORTANCE: Altered gut microbiota and metabolites are a major cause of non-alcoholic fatty liver disease (NAFLD) in children. This study demonstrated a complete gut metabolic map of children with NAFLD, containing 318 increased and 123 decreased metabolites by untargeted metabolomic. Multiple validation approaches (machine learning and targeted metabolomic) selected five novel gut metabolites for targeted metabolomics, which can distinguish NAFLD status and severity. The gut microbiota (Butyricicoccus and Alistipes) and metabolites (creatinine and dodecanoic acid) were novel biomarkers associated with impaired liver function and inflammation and validated by experiments of hepatocyte cell lines. The data provide a better understanding of the importance of gut microbiota and metabolite alterations in NAFLD, which implies that the altered gut microbiota and metabolites may represent a potential target to prevent NAFLD development.

Altered extracellular matrix dynamics is associated with insulin resistance in adolescent children with obesity.

OBJECTIVE: The objective of this study was to examine the hypothesis that abdominal and gluteal adipocyte turnover, lipid dynamics, and fibrogenesis are dysregulated among insulin-resistant (IR) compared with insulin-sensitive (IS) adolescents with obesity. METHODS: Seven IS and seven IR adolescents with obesity participated in a 3-h oral glucose tolerance test and a multi-section magnetic resonance imaging scan of the abdominal region to examine body fat distribution patterns and liver fat content. An 8-week 70% deuterated water (2 H2 O) labeling protocol examined adipocyte turnover, lipid dynamics, and fibrogenesis in vivo from biopsied abdominal and gluteal fat. RESULTS: Abdominal and gluteal subcutaneous adipose tissue (SAT) turnover rates of lipid components were similar among IS and IR adolescents with obesity. However, the insoluble collagen (type I, subunit α2) isoform measured from abdominal, but not gluteal, SAT was elevated in IR compared with IS individuals. In addition, abdominal insoluble collagen Iα2 was associated with ratios of visceral-to-total (visceral adipose tissue + SAT) abdominal fat and whole-body and adipose tissue insulin signaling, and it trended toward a positive association with liver fat content. CONCLUSIONS: Altered extracellular matrix dynamics, but not expandability, potentially decreases abdominal SAT lipid storage capacity, contributing to the pathophysiological pathways linking adipose tissue and whole-body IR with altered ectopic storage of lipids within the liver among IR adolescents with obesity.

Toxicity of Polystyrene Nanoplastics in the Liver and Intestine of Normal and High-Fat-Diet Juvenile Zebrafish.

Nanoplastics (NPs) are widely found and threaten environmental and biological safety, because they do not degrade completely. We aimed to preliminarily explore the toxicity of NPs in obese children, because childhood obesity is a growing global health concern. We used zebrafish as a vertebrate toxicological model to examine the hepatic lipid metabolism and gut microbiota in juvenile zebrafish exposed to 1000 µg/L polystyrene NPs and a high-fat diet (HFD) using Raman spectroscopy, pathological examination, transcriptome analysis, and 16S sequencing techniques. Our study showed that polystyrene NPs perturb the lipid metabolism and gut microbiota stability in zebrafish. Furthermore, the combined effects of polystyrene NPs and HFD resulted in gastrointestinal injury. Our study is one of the first to investigate the toxicity of polystyrene NPs to normal-diet and HFD juvenile zebrafish using confocal Raman spectroscopy. Our results show the importance of a healthy diet and a reduction in the use of plasticware. Environ Toxicol Chem 2024;43:147-158. © 2023 SETAC.

Circulating extracellular vesicles are associated with pathophysiological condition including metabolic syndrome-related dysmetabolism in children and adolescents with obesity.

Obesity of children and adolescents (OCA) is often accompanied by metabolic syndrome (MetS), which often leads to adult obesity and subsequent complications, yet the entire pathophysiological response is not fully understood. The number and composition of circulating extracellular vesicles (EV) reflect overall patient condition; therefore, we investigated the pathophysiological condition of OCA, including MetS-associated dysmetabolism, using circulating EVs. In total, 107 children and adolescents with or without obesity (boys, n = 69; girls, n = 38; median age, 10 years) were enrolled. Circulating EV number and EV protein composition were assessed via flow cytometry and liquid chromatography tandem-mass spectrometry, respectively. In a multivariate analysis, relative body weight (standardized partial regression coefficient (SPRC) 0.469, P = 0.012) and serum triglyceride level (SPRC 0.548, P < 0.001) were detected as independent parameters correlating with circulating EV number. Proteomic analysis identified 31 upregulated and 45 downregulated EV proteins in OCA. Gene ontology analysis revealed upregulated proteins to be involved in various biological processes, including intracellular protein transport, protein folding, stress response, leukocyte activation, innate immune response, and platelet degranulation, which can modulate lipid and glucose metabolism, skeletal and cardiac muscle development, inflammation, immune response, carcinogenesis, and cancer progression. Notably, several identified EV proteins are involved in neuro-development, neurotransmitter release, and neuro-protective agents in OCA. Circulating EVs were derived from adipocytes, hepatocytes, B cell lymphocytes, and neurons. Circulating EV number is significantly associated with MetS-related dysmetabolism and the EV protein cargo carries a special "signature" that reflects the alteration of various biological processes under the pathophysiological condition of OCA. KEY MESSAGES: Circulating EV number correlates with physical and laboratory parameters for obesity in children and adolescents. Relative body weight and triglyceride are independent factors for increased circulating EVs. EV composition is significantly changed in obesity of children and adolescents. Identified EV composition changes associated with obesity and involves in metabolism, immune response, and cancer progression. Circulating EVs are partially derived from adipocyte, hepatocytes, B cells, and neurons.

Exercised breastmilk: a kick-start to prevent childhood obesity?

Exercise has systemic health benefits through effects on multiple tissues, with intertissue communication. Recent studies indicate that exercise may improve breastmilk composition and thereby reduce the intergenerational transmission of obesity. Even if breastmilk is considered optimal infant nutrition, there is evidence for variations in its composition between mothers who are normal weight, those with obesity, and those who are physically active. Nutrition early in life is important for later-life susceptibility to obesity and other metabolic diseases, and maternal exercise may provide protection against the development of metabolic disease. Here we summarize recent research on the influence of maternal obesity on breastmilk composition and discuss the potential role of exercise-induced adaptations to breastmilk as a kick-start to prevent childhood obesity.

Proinflammatory pattern in the lower airways of non-asthmatic obese adolescents.

BACKGROUND: Obesity is known to be a pro-inflammatory condition affecting multiple organs. Obesity as a systemic pro-inflammatory state, might be associated with bronchial inflammation in non-smoking adolescents with a BMI ≥ 30 kg/m2 without evidence of concomitant chronic diseases. MATERIALS AND METHODS: We studied non-asthmatic obese patients (n = 20; median age 15.8 years; BMI 35.0 kg/m2) compared to age matched healthy control subjects (n = 20; median age 17.5 years; BMI 21.5 kg/m2). Induced sputum differential cell counts and sputum mRNA levels were assessed for all study subjects. Serum levels of CRP, IL-6, and IL-8 were measured. Further, IL-5, IL-6, IL-8, IL-13, IL-17, TNF-α, IFN-γ, and IP-10 protein levels were analyzed in induced sputum was. RESULTS: Serum CRP levels, sputum inflammatory cell load and sputum eosinophils differed significantly between obese and non-obese subjects, for sputum neutrophils, a correlation was shown with BMI ≥ 30 kg/m2. Differences were also observed for sputum mRNA expression of IL6, IL8, IL13, IL17, IL23, and IFN-γ, as well as the transcription factors T-bet, GATA3, and FoxP3. CONCLUSIONS: Increased bronchial inflammation, triggered by systemic or local inflammatory effects of obesity itself, may account for the higher rates of airway disease in obese adolescents.

Loss of Uncoupling Protein 1 Expression in the Subcutaneous Adipose Tissue Predicts Childhood Obesity.

Stimulation of thermogenesis by inducing uncoupling protein 1 (UCP1) expression in adipocytes is thought to promote weight loss by increasing energy expenditure, and it is postulated that the human newborn has thermogenic subcutaneous fat depots. However, it remains unclear whether a relevant number of UCP1-expressing (UCP1+) adipocytes exist in the early postnatal life. Here we studied the distribution of UCP1 and the expression of thermogenic genes in the subcutaneous adipose tissues of the human fetus, infant and child. We show that the deep layer of human fetal and neonatal subcutaneous fat, particularly the abdominal wall, is rich in UCP1+ adipocytes. These adipocytes develop in the late third trimester and persist throughout childhood, expressing a panel of genes linked to mitochondrial biogenesis and thermogenesis. During the early childhood adiposity rebound-a critical phase that determines obesity risk later in life-the absence of adipose tissue UCP1 expression in children with normal body mass index (BMI) correlates with an obesity-associated gene expression signature. Finally, UCP1 expression is negatively correlated with BMI z-score and adipocyte size in infants and children. Overall, our results show that the absence of UCP1 expression in adipose tissue is an early indicator of adipose tissue expansion in children.

The Protective Effects of Cinnamyl Alcohol Against Hepatic Steatosis, Oxidative and Inflammatory Stress in Nonalcoholic Fatty Liver Disease Induced by Childhood Obesity.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive intracellular lipid accumulation, oxidative stress, and inflammation. Cinnamyl alcohol (CA), one of the cinnamon extracts, has been shown to exhibit anti-oxidative and anti-inflammatory activities. We proposed that CA was beneficial to NAFLD. METHODS: Serum cytokines and components of the lipid metabolism were determined in children with NAFLD against age-matched comparisons. A NAFLD mouse model was established by high fat and high carbohydrate (HFHC) diet in male C57BL/6 mouse pups, followed by administration of CA. The effects of CA on lipid metabolism, oxidative stress, and inflammation in hepatic tissues were assessed. RESULTS: Abnormal lipid metabolism and inflammatory responses were observed in the children with NAFLD as compared with the controls. CA reduced the weight of obese mice without affecting food intake as well as alleviating liver injury caused by HFHC feeding. CA was found to mitigate dyslipidemia and reduce hepatic steatosis in HFHC-fed mice by down-regulating genes related to lipogenesis, including peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding transcription factor-1c (SREBP-1c), and acetyl-CoA carboxylase 1 (ACC1). Additionally, CA treatment reversed HFHC-induced oxidative stress and inflammation, evidenced by the decreased liver reactive oxygen species (ROS), hepatic inflammatory cytokine levels, and F4/80-positive macrophage infiltration in HFHC diet mice. CA reduced the protein levels of pyrin domain-containing protein 3 (NLRP3), adapter protein apoptosis-associated speck-like protein (ASC), and caspase-1 in the liver tissues significantly. CONCLUSION: CA alleviates HFHC-induced NAFLD in mice, which is associated with the amelioration in lipid metabolism, oxidative stress, and inflammation.

CD8 cytotoxic T-cell infiltrates and cellular damage in the hypothalamus in human obesity.

Rare cases of paraneoplastic obesity in children suggest sporadic obesity might also arise from an adaptive immune cell-mediated mechanism. Since the hypothalamus is a central regulator of feeding behavior and energy expenditure, we quantified lymphocytic inflammation in this region in a cohort of obese and non-obese human post-mortem brains. We report that CD8-positive cytotoxic T-cells are increased in hypothalamic median eminence/arcuate nucleus (ME/Arc) and bed nucleus of the stria terminalis in 40% of obese compared to non-obese patients, but not in other hypothalamic nuclei or brain regions. CD8 T-cells were most abundant in individuals with concurrent obesity and diabetes. Markers of cytotoxic T-cell induced damage, activated caspase 3 and poly-ADP ribose, were also elevated in the ME/Arc of obese patients. To provoke CD8 cytotoxic T-cell infiltrates in ventromedial region of hypothalamus in mice we performed stereotactic injections of an adeno-associated virus expressing immunogenic green fluorescent protein or saline. AAV but not saline injections triggered hypothalamic CD8 T-cell infiltrates associated with a rapid weight gain in mice recapitulating the findings in human obesity. This is the first description of the neuropathology of human obesity and when combined with its reconstitution in a mouse model suggests adaptive immunity may drive as much as 40% of the human condition.

Metformin restores prohormone processing enzymes and normalizes aberrations in secretion of proinsulin and insulin in palmitate-exposed human islets.

AIM: To elucidate how proinsulin synthesis and insulin was affected by metformin under conditions of nutrient overstimulation. MATERIALS AND METHODS: Isolated human pancreatic islets from seven donors were cultured at 5.5 mmol/L glucose and 0.5 mmol/L palmitate for 12, 24 or 72 h. Metformin (25 µmol/L) was introduced after initial 12 h with palmitate. Proinsulin and insulin were measured. Expression of prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE), was determined by western blot. Adolescents with obesity, treated with metformin and with normal glucose tolerance (n = 5), prediabetes (n = 14), or type 2 diabetes (T2DM; n = 7) were included. Fasting proinsulin, insulin, glucose, 2-h glucose and glycated haemoglobin were measured. Proinsulin/insulin ratio (PI/I) was calculated. RESULTS: In human islets, palmitate treatment for 12 and 24 h increased proinsulin and insulin proportionally. After 72 h, proinsulin but not insulin continued to increase which was coupled with reduced expression of PC1/3 and CPE. Metformin normalized expression of PC1/3 and CPE, and proinsulin and insulin secretion. In adolescents with obesity, before treatment, fasting proinsulin and insulin concentrations were higher in subjects with T2DM than with normal glucose tolerance. PI/I was reduced after metformin treatment in subjects with T2DM as well as in subjects with prediabetes, coupled with reduced 2-h glucose and glycated haemoglobin. CONCLUSIONS: Metformin normalized proinsulin and insulin secretion after prolonged nutrient-overstimulation, coupled with normalization of the converting enzymes, in isolated islets. In adolescents with obesity, metformin treatment was associated with improved PI/I, which was coupled with improved glycaemic control.

Macrophage-associated markers of metaflammation are linked to metabolic dysfunction in pediatric obesity.

BACKGPOUND: Metabolically driven chronic low-grade adipose tissue inflammation, so-called metaflammation, is a central feature in obesity. This inflammatory tone is largely driven by adipose tissue macrophages (ATM), which express pro- and anti-inflammatory markers and cytokines such as, e.g., IL-1 receptor antagonist (IL-1RA), CD163 and osteopontin (OPN). Metaflammation ultimately leads to the development of cardiometabolic diseases. This study aimed to evaluate the association between selected adipose tissue macrophage-associated markers and metabolic comorbidities in pediatric obesity. METHODS: From a pediatric cohort with obesity (n = 108), clinically thoroughly characterized including diverse routine blood parameters, oral glucose tolerance test and liver MRI, plasma IL-1RA, soluble (s)CD163 and OPN were measured by ELISA. RESULTS: We observed significantly higher IL-1RA, sCD163, and OPN levels in the plasma of children with metabolic-dysfunction associated fatty liver disease (MAFLD) and metabolic syndrome. Moreover, IL-1RA and sCD163 correlated with hepatic disease and apoptosis markers alanine aminotransferase and CK-18. IL-1RA concentrations additionally correlated with insulin resistance, while children with disturbed glucose metabolism had significantly higher levels of sCD163. CONCLUSION: MAFLD and other metabolic disorders in pediatric patients with obesity are associated with an elevation of adipose tissue macrophage-related inflammation markers.

Childhood obesity: Implications on adipose tissue dynamics and metabolic health.

Obesity is the leading risk factor for the development of type 2 diabetes and cardiovascular diseases. Childhood obesity represents an alarming health challenge because children with obesity are prone to remain with obesity throughout their life and have an increased morbidity and mortality risk. The ability of adipose tissue to store lipids and expand in size during excessive calorie intake is its most remarkable characteristic. Cellular and lipid turnovers determine adipose tissue size and are closely related with metabolic status. The mechanisms through which adipose tissue expands and how this affects systemic metabolic homeostasis are still poorly characterized. Furthermore, the mechanism through which increased adiposity extends from childhood to adulthood and its implications in metabolic health are in most part, still unknown. More studies on adipose tissue development in healthy and children with obesity are urgently needed. In the present review, we summarize the dynamics of white adipose tissue, from developmental origins to the mechanisms that allows it to grow and expand throughout lifetime and during obesity in children and in different mouse models used to address this largely unknown field. Specially, highlighting the role that excessive adiposity during the early life has on future's adipose tissue dynamics and individual's health.

Perinatal metabolic inflammation in the hypothalamus impairs the development of homeostatic feeding circuitry.

Over the past few decades, there has been a global increase in childhood obesity. This rise in childhood obesity contributes to the susceptibility of impaired metabolism during both childhood and adulthood. The hypothalamus, specifically the arcuate nucleus (ARC), houses crucial neurons involved in regulating homeostatic feeding. These neurons include proopiomelanocortin (POMC) and agouti-related peptide (AGRP) secreting neurons. They play a vital role in sensing nutrients and metabolic hormones like insulin, leptin, and ghrelin. The neurogenesis of AGRP and POMC neurons completes at birth; however, axon development and synapse formation occur during the postnatal stages in rodents. Insulin, leptin, and ghrelin are the essential regulators of POMC and AGRP neurons. Maternal obesity and postnatal overfeeding or a high-fat diet (HFD) feeding cause metabolic inflammation, disrupted signaling of metabolic hormones, netrin-1, and neurogenic factors, neonatal obesity, and defective neuronal development in animal models; however, the mechanism is unclear. Within the hypothalamus and other brain areas, there exists a wide range of interconnected neuronal populations that regulate various aspects of feeding. However, this review aims to discuss how perinatal metabolic inflammation influences the development of POMC and AGRP neurons within the hypothalamus.

Shared gene expression signatures between visceral adipose and skeletal muscle tissues are associated with cardiometabolic traits in children with obesity.

Obesity in children is related to the development of cardiometabolic complications later in life, where molecular changes of visceral adipose tissue (VAT) and skeletal muscle tissue (SMT) have been proven to be fundamental. The aim of this study is to unveil the gene expression architecture of both tissues in a cohort of Spanish boys with obesity, using a clustering method known as weighted gene co-expression network analysis. For this purpose, we have followed a multi-objective analytic pipeline consisting of three main approaches; identification of gene co-expression clusters associated with childhood obesity, individually in VAT and SMT (intra-tissue, approach I); identification of gene co-expression clusters associated with obesity-metabolic alterations, individually in VAT and SMT (intra-tissue, approach II); and identification of gene co-expression clusters associated with obesity-metabolic alterations simultaneously in VAT and SMT (inter-tissue, approach III). In both tissues, we identified independent and inter-tissue gene co-expression signatures associated with obesity and cardiovascular risk, some of which exceeded multiple-test correction filters. In these signatures, we could identify some central hub genes (e.g., NDUFB8, GUCY1B1, KCNMA1, NPR2, PPP3CC) participating in relevant metabolic pathways exceeding multiple-testing correction filters. We identified the central hub genes PIK3R2, PPP3C and PTPN5 associated with MAPK signaling and insulin resistance terms. This is the first time that these genes have been associated with childhood obesity in both tissues. Therefore, they could be potential novel molecular targets for drugs and health interventions, opening new lines of research on the personalized care in this pathology. This work generates interesting hypotheses about the transcriptomics alterations underlying metabolic health alterations in obesity in the pediatric population.

Visceral fat and cardiometabolic future in children and adolescents: a critical update.

Cardiovascular disease (CVD) is a process whose pathogenetic mechanisms start very early in life. Recently, the importance of visceral adipose tissue (VAT) has been highlighted in the development of CVD. VAT does not always depend on body mass index (BMI) and has been implicated in unfavorable metabolic activity and cardiovascular adverse events. Abnormally high deposition of VAT is associated with metabolic syndrome, obesity-associated phenotype, and cardiometabolic risk factors. Although the importance of visceral fat has not been studied broadly or extensively in long-term studies in children and adolescents, it appears that it does not have the same behavior as in adults, it is related to the appearance of cardiac risk factors. In adolescents, it plays a role in the pathogenesis of CVD that occur later in adulthood. Excess body weight and adiposity may lead to the development of early myocardial and pathological coronary changes in childhood. The purpose of this review is to summarize the risk factors, the clinical significance, and the prognostic role of visceral obesity in children and adolescents. In addition, extensive reference is made to the most commonly used techniques for the evaluation of VAT in clinical settings. IMPACT: Visceral obesity, plays an important role in cardiovascular health from very early in an individual's life. Visceral adipose tissue (VAT) distribution is not entirely related to body mass index (BMI) and provides additional prognostic information. There is a need to pay more attention to the assessment of VAT in young people, to develop methods that would go beyond the measurement of only BMI in clinical practice and to identify individuals with excess visceral adiposity and perhaps to monitor its changes.

Nutritional Approaches in Children with Overweight or Obesity and Hepatic Steatosis.

Childhood obesity is a global public health problem. Worldwide, 41 million children under 5 years and 340 million children and adolescents between 5 and 19 years are overweight. In addition, the recent COVID-19 epidemic has further amplified this social phenomenon. Obesity is a condition associated with various comorbidities, such as nonalcoholic fatty liver disease (NAFLD). The pathophysiology of NAFLD in obesity is intricate and involves the interaction and dysregulation of several mechanisms, such as insulin resistance, cytokine signaling, and alteration of the gut microbiota. NAFLD is defined as the presence of hepatic steatosis in more than 5% of hepatocytes, evaluated by histological analysis. It can evolve from hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma, and end-stage liver failure. Body weight reduction through lifestyle modification remains the first-line intervention for the management of pediatric NAFLD. Indeed, studies suggest that diets low in fat and sugar and conversely rich in dietary fibers promote the improvement of metabolic parameters. This review aims to evaluate the existing relationship between obesity and NAFLD in the pediatric population and to assess the dietary patterns and nutritional supplementations that can be recommended to prevent and manage obesity and its comorbidities.

The Relationship Between Vitamin-D Deficiency and Protein Oxidation Among Obese Children.

Aim: The aim of the study is to examine the relationship between obesity, Vitamin-D deficiency, and protein oxidation. Methods: Thiol-disulfide homeostasis, Vitamin-D, ischemia modified albumin, insulin, and lipid levels were compared among obese, pre-obese and normal-weight healthy children. Results: A total of 136 children (69 boys and 67 girls) were included in the study. The vitamin-D levels of obese children were lower than those of pre-obese and normal weight (p < 0.05). In the normal weight group, total thiol and native thiol were lower in the pubertal period than in adolescence; were higher in those with sufficient Vitamin-D level than those with insufficient and deficient Vitamin-D (p < 0.05). Vitamin-D level was lower in pre-obese girls than boys (p < 0.05). Those with high triglycerides had high disulfide/total thiol, disulfide, and disulfide/native thiol and low native thiol/total thiol (p < 0.05). Conclusion: Thiol-disulfide homeostasis is negatively affected by low vitamin D levels, pubertal period and high triglyceride levels.

Sexually dimorphic metal alterations in childhood obesity are modulated by a complex interplay between inflammation, insulin, and sex hormones.

Although growing evidence points to a pivotal role of perturbed metal homeostasis in childhood obesity, sexual dimorphisms in this association have rarely been investigated. In this study, we applied multi-elemental analysis to plasma and erythrocyte samples from an observational cohort comprising children with obesity, with and without insulin resistance, and healthy control children. Furthermore, a wide number of variables related to carbohydrate and lipid metabolism, inflammation, and sex hormones were also determined. Children with obesity, regardless of sex and insulin resistance status, showed increased plasma copper-to-zinc ratios. More interestingly, obesity-related erythroid alterations were found to be sex-dependent, with increased contents of iron, zinc, and copper being exclusively detected among female subjects. Our findings suggest that a sexually dimorphic hormonal dysregulation in response to a pathological cascade involving inflammatory processes and hyperinsulinemia could be the main trigger of this female-specific intracellular sequestration of trace elements. Therefore, the present study highlights the relevance of genotypic sex as a susceptibility factor influencing the pathogenic events behind childhood obesity, thereby opening the door to develop sex-personalized approaches in the context of precision medicine.

Chronic Exposure to High Fat Diet Affects the Synaptic Transmission That Regulates the Dopamine Release in the Nucleus Accumbens of Adolescent Male Rats.

Obesity is a pandemic caused by many factors, including a chronic excess in hypercaloric and high-palatable food intake. In addition, the global prevalence of obesity has increased in all age categories, such as children, adolescents, and adults. However, at the neurobiological level, how neural circuits regulate the hedonic consumption of food intake and how the reward circuit is modified under hypercaloric diet consumption are still being unraveled. We aimed to determine the molecular and functional changes of dopaminergic and glutamatergic modulation of nucleus accumbens (NAcc) in male rats exposed to chronic consumption of a high-fat diet (HFD). Male Sprague-Dawley rats were fed a chow diet or HFD from postnatal day (PND) 21 to 62, increasing obesity markers. In addition, in HFD rats, the frequency but not amplitude of the spontaneous excitatory postsynaptic current is increased in NAcc medium spiny neurons (MSNs). Moreover, only MSNs expressing dopamine (DA) receptor type 2 (D2) increase the amplitude and glutamate release in response to amphetamine, downregulating the indirect pathway. Furthermore, NAcc gene expression of inflammasome components is increased by chronic exposure to HFD. At the neurochemical level, DOPAC content and tonic dopamine (DA) release are reduced in NAcc, while phasic DA release is increased in HFD-fed rats. In conclusion, our model of childhood and adolescent obesity functionally affects the NAcc, a brain nucleus involved in the hedonic control of feeding, which might trigger addictive-like behaviors for obesogenic foods and, through positive feedback, maintain the obese phenotype.