Distinct association patterns of chemokine profile and cardiometabolic status in children and adolescents with type 1 diabetes and obesity.

Objective: We compared peripheral blood (PBL) chemokine ligand/receptor profiles in children and adolescents with type 1 diabetes mellitus (T1D) or obesity (OB) (both involving inflammation and vascular complications) to identify their associations with cardiometabolic risk factors. Materials and methods: PBL samples from children and adolescents (12-18 years) included: healthy controls (n=29), patients with T1D (n=31) and OB subjects (n=34). Frequency of mononuclear cell populations and chemokine receptor expression (CCR2, CCR4, CXCR3, CXCR4) were determined by flow cytometry. Chemokine levels of CCL2, CCL5, CXCL10 and CXCL11 were measured by bead-based assay and CXCL12 by ELISA. Data were correlated with cardiovascular, metabolic and inflammatory parameters. Results: The proportion of CD14+ monocytes was higher in T1D, whereas the proportion of CD19+ B lymphocytes was higher and CD3+ T lymphocytes was lower in OB. The level of CCL2 was higher in T1D (241.0 (IQR 189.6-295.3) pg/mL in T1D vs 191.5 (IQR 158.0-254.7) pg/mL in control, p=0.033), CXCL11 was lower in OB (6.6 (IQR 4.9-7.7) pg/mL in OB vs 8.2 (IQR 6.9-11.3) pg/mL in control, p=0.018) and CXCL12 was lower in both diseases (2.0 (IQR 1.8-2.5) ng/mL in T1D, 2.1 (IQR 1.9-2.4) ng/mL in OB vs 2.4 (IQR 2.2-2.5) ng/mL in control, p=0.016). Numerous significant associations were found for chemokine ligand/receptor profiles and clinical data. Among these, we are suggesting the most important indicators of cardiometabolic risk in T1D: positive associations of CCR2+ monocytes with blood pressure and CCL12 levels with urine albumin-to-creatinine ratio (ACR), inverse association of CXCR3+ B lymphocytes with AST but positive with triglycerides; and OB: positive associations of CXCL12 levels with triglycerides and AST/ALT, inverse association of CCR4+ and CXCR3+ monocytes with ACR. Both diseases share positive associations for CCR4+ T lymphocytes and blood pressure, inverse associations of CXCR4+ subsets with ACR and CXCR3+ T lymphocytes with lipid profile. Conclusion: Significantly changed chemokine ligand/receptor profiles were found in both T1D and OB even at a young age. Although different associations with cardiometabolic risk factors indicate disease-specific changes, overlapping pattern was found for the associations between CCR4+ T lymphocytes and vascular inflammation, CXCR4+ subsets and albuminuria as well as CXCR3+ T lymphocytes and dyslipidemia. Thus, chemokine axes might present potential therapeutic targets for disease-related morbidity.

Risk of Fat Mass- and Obesity-Associated Gene-Dependent Obesogenic Programming by Formula Feeding Compared to Breastfeeding.

It is the purpose of this review to compare differences in postnatal epigenetic programming at the level of DNA and RNA methylation and later obesity risk between infants receiving artificial formula feeding (FF) in contrast to natural breastfeeding (BF). FF bears the risk of aberrant epigenetic programming at the level of DNA methylation and enhances the expression of the RNA demethylase fat mass- and obesity-associated gene (FTO), pointing to further deviations in the RNA methylome. Based on a literature search through Web of Science, Google Scholar, and PubMed databases concerning the dietary and epigenetic factors influencing FTO gene and FTO protein expression and FTO activity, FTO's impact on postnatal adipogenic programming was investigated. Accumulated translational evidence underscores that total protein intake as well as tryptophan, kynurenine, branched-chain amino acids, milk exosomal miRNAs, NADP, and NADPH are crucial regulators modifying FTO gene expression and FTO activity. Increased FTO-mTORC1-S6K1 signaling may epigenetically suppress the WNT/ß-catenin pathway, enhancing adipocyte precursor cell proliferation and adipogenesis. Formula-induced FTO-dependent alterations of the N6-methyladenosine (m6A) RNA methylome may represent novel unfavorable molecular events in the postnatal development of adipogenesis and obesity, necessitating further investigations. BF provides physiological epigenetic DNA and RNA regulation, a compelling reason to rely on BF.

Maternal Serum Metabolomics in Mid-Pregnancy Identifies Lipid Pathways as a Key Link to Offspring Obesity in Early Childhood.

Maternal metabolism during pregnancy shapes offspring health via in utero programming. In the Healthy Start study, we identified five subgroups of pregnant women based on conventional metabolic biomarkers: Reference (n = 360); High HDL-C (n = 289); Dyslipidemic-High TG (n = 149); Dyslipidemic-High FFA (n = 180); Insulin Resistant (IR)-Hyperglycemic (n = 87). These subgroups not only captured metabolic heterogeneity among pregnant participants but were also associated with offspring obesity in early childhood, even among women without obesity or diabetes. Here, we utilize metabolomics data to enrich characterization of the metabolic subgroups and identify key compounds driving between-group differences. We analyzed fasting blood samples from 1065 pregnant women at 18 gestational weeks using untargeted metabolomics. We used weighted gene correlation network analysis (WGCNA) to derive a global network based on the Reference subgroup and characterized distinct metabolite modules representative of the different metabolomic profiles. We used the mummichog algorithm for pathway enrichment and identified key compounds that differed across the subgroups. Eight metabolite modules representing pathways such as the carnitine-acylcarnitine translocase system, fatty acid biosynthesis and activation, and glycerophospholipid metabolism were identified. A module that included 189 compounds related to DHA peroxidation, oxidative stress, and sex hormone biosynthesis was elevated in the Insulin Resistant-Hyperglycemic vs. the Reference subgroup. This module was positively correlated with total cholesterol (R:0.10; p-value < 0.0001) and free fatty acids (R:0.07; p-value < 0.05). Oxidative stress and inflammatory pathways may underlie insulin resistance during pregnancy, even below clinical diabetes thresholds. These findings highlight potential therapeutic targets and strategies for pregnancy risk stratification and reveal mechanisms underlying the developmental origins of metabolic disease risk.

Exploring the Link between Oxidative Stress, Selenium Levels, and Obesity in Youth.

Obesity is a worldwide increasing concern. Although in adults this is easily estimated with the body mass index, in children, who are constantly growing and whose bodies are changing, the reference points to assess weight status are age and gender, and need corroboration with complementary data, making their quantification highly difficult. The present review explores the interaction spectrum of oxidative stress, selenium status, and obesity in children and adolescents. Any factor related to oxidative stress that triggers obesity and, conversely, obesity that induces oxidative stress are part of a vicious circle, a complex chain of mechanisms that derive from each other and reinforce each other with serious health consequences. Selenium and its compounds exhibit key antioxidant activity and also have a significant role in the nutritional evaluation of obese children. The balance of selenium intake, retention, and metabolism emerges as a vital aspect of health, reflecting the complex interactions between diet, oxidative stress, and obesity. Understanding whether selenium status is a contributor to or a consequence of obesity could inform nutritional interventions and public health strategies aimed at preventing and managing obesity from an early age.

Molecular insights into Sertoli cell function: how do metabolic disorders in childhood and adolescence affect spermatogonial fate?

Male infertility is a major public health concern globally with unknown etiology in approximately half of cases. The decline in total sperm count over the past four decades and the parallel increase in childhood obesity may suggest an association between these two conditions. Here, we review the molecular mechanisms through which obesity during childhood and adolescence may impair future testicular function. Several mechanisms occurring in obesity can interfere with the delicate metabolic processes taking place at the testicular level during childhood and adolescence, providing the molecular substrate to hypothesize a causal relationship between childhood obesity and the risk of low sperm counts in adulthood.

Amelioration of Insulin Resistance by Whey Protein in a High-Fat Diet-Induced Pediatric Obesity Male Mouse Model.

This study examined whey protein's impact on insulin resistance in a high-fat diet-induced pediatric obesity mouse model. Pregnant mice were fed high-fat diets, and male pups continued this diet until 8 weeks old, then were split into high-fat, whey, and casein diet groups. At 12 weeks old, their body weight, fasting blood glucose (FBG), blood insulin level (IRI), homeostatic model assessment for insulin resistance (HOMA-IR), liver lipid metabolism gene expression, and liver metabolites were compared. The whey group showed significantly lower body weight than the casein group at 12 weeks old (p = 0.034). FBG was lower in the whey group compared to the high-fat diet group (p < 0.01) and casein group (p = 0.058); IRI and HOMA-IR were reduced in the whey group compared to the casein group (p = 0.02, p < 0.01, p < 0.01, respectively). The levels of peroxisome proliferator-activated receptor α and hormone-sensitive lipase were upregulated in the whey group compared to the casein group (p < 0.01, p = 0.03). Metabolomic analysis revealed that the levels of taurine and glycine, both known for their anti-inflammatory and antioxidant properties, were upregulated in the whey group in the liver tissue (p < 0.01, p < 0.01). The intake of whey protein was found to improve insulin resistance in a high-fat diet-induced pediatric obesity mouse model.

Metabolomic distance between normal and obese children.

This paper presents the metabolomic distance between normal and obese children. Our PCA results quantitatively explain why girls are more prone to obesity than boys.

Pro- and anti-inflammatory cytokines are the game-changers in childhood obesity-associated metabolic disorders (diabetes and non-alcoholic fatty liver diseases).

Childhood obesity is a chronic inflammatory epidemic that affects children worldwide. Obesity affects approximately 1 in 5 children worldwide. Obesity in children can worsen weight gain and raise the risk of obesity-related comorbidities like diabetes and non-alcoholic fatty liver disease (NAFLD). It can also negatively impact the quality of life for these children. Obesity disrupts immune system function, influencing cytokine (interleukins) balance and expression levels, adipokines, and innate and adaptive immune cells. The altered expression of immune system mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-17 (IL-17), interleukin-18 (IL-18), transforming growth factor (TGF), tumor necrosis factor (TNF), and others, caused inflammation, progression, and the development of pediatric obesity and linked illnesses such as diabetes and NAFLD. Furthermore, anti-inflammatory cytokines, including interleukin-2 (IL-2), have been shown to have anti-diabetes and IL-1 receptor antagonist (IL-1Ra) anti-diabetic and pro-NAFLFD properties, and interleukin-10 (IL-10) has been shown to have a dual role in managing diabetes and anti-NAFLD. In light of the substantial increase in childhood obesity-associated disorders such as diabetes and NAFLD and the absence of an effective pharmaceutical intervention to inhibit immune modulation factors, it is critical to consider the alteration of immune system components as a preventive and therapeutic approach. Thus, the current review focuses on the most recent information regarding the influence of pro- and anti-inflammatory cytokines (interleukins) and their molecular mechanisms on pediatric obesity-associated disorders (diabetes and NAFLD). Furthermore, we discussed the current therapeutic clinical trials in childhood obesity-associated diseases, diabetes, and NAFLD.

Modelling and assessment of glucose-lactate kinetics in youth with overweight, obesity and metabolic dysfunction-associated steatotic liver disease: A pilot study.

AIM: In this study, we investigated glucose and lactate kinetics during a 75 g oral glucose tolerance test (OGTT) in 23 overweight and obese adolescents and assessed putative differences among participants with and without metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: We enrolled 23 young people (six girls) with obesity [body mass index 33 (29-37)]. Glucose-lactate kinetics parameters (disposal glucose insulin sensitivity, SID; fraction of glucose converted into lactate, fr; fractional lactate clearance rate, kL) and lactate production rate (LPR) were estimated using the oral glucose-lactate minimal model. MASLD presence was assessed using the proton density fat fraction. We analysed glucose, lactate and LPR time to peak, peak values and area under the curve and evaluated differences using the Wilcoxon test. MASLD and no-MASLD participants were compared using the Mann-Whitney test. Correlations between parameters were assessed using the Spearman correlation coefficient (ρ). We also tested the performance of two (4 or 3 h OGTT) protocols in estimating oral glucose-lactate minimal model and LPR parameters. RESULTS: Glucose peaks 30 min earlier than lactate (p = .0019). This pattern was present in the no-MASLD group (p < .001). LPR peaks 30 min later in the MASLD group (p = .02). LPR and kL were higher in MASLD, suggesting higher glycolysis and lactate utilization. SID and fr correlate significantly (ρ = -0.55, p = .008). SID and fr were also correlated with the body mass index, (ρ = -0.45, p = .04; and ρ = 0.45; p = .03). The protocol duration did not influence the estimates of the parameters. DISCUSSION: Youth with MASLD showed a delayed glucose metabolism, possibly because of greater utilization of the underlying substrates. A 3-h OGTT may be used to assess lactate metabolism effectively.

Cultivated Enterococcus faecium B6 from children with obesity promotes nonalcoholic fatty liver disease by the bioactive metabolite tyramine.

Gut microbiota plays an essential role in nonalcoholic fatty liver disease (NAFLD). However, the contribution of individual bacterial strains and their metabolites to childhood NAFLD pathogenesis remains poorly understood. Herein, the critical bacteria in children with obesity accompanied by NAFLD were identified by microbiome analysis. Bacteria abundant in the NAFLD group were systematically assessed for their lipogenic effects. The underlying mechanisms and microbial-derived metabolites in NAFLD pathogenesis were investigated using multi-omics and LC-MS/MS analysis. The roles of the crucial metabolite in NAFLD were validated in vitro and in vivo as well as in an additional cohort. The results showed that Enterococcus spp. was enriched in children with obesity and NAFLD. The patient-derived Enterococcus faecium B6 (E. faecium B6) significantly contributed to NAFLD symptoms in mice. E. faecium B6 produced a crucial bioactive metabolite, tyramine, which probably activated PPAR-γ, leading to lipid accumulation, inflammation, and fibrosis in the liver. Moreover, these findings were successfully validated in an additional cohort. This pioneering study elucidated the important functions of cultivated E. faecium B6 and its bioactive metabolite (tyramine) in exacerbating NAFLD. These findings advance the comprehensive understanding of NAFLD pathogenesis and provide new insights for the development of microbe/metabolite-based therapeutic strategies.

Plasma fatty acid esters of hydroxy fatty acids and surrogate fatty acid esters of hydroxy fatty acids hydrolysis activity in children with or without obesity and in adults with or without coronary artery disease.

AIM: Fatty acid esters of hydroxy fatty acids (FAHFA) are a class of bioactive lipids with anti-inflammatory, antidiabetic and cardioprotective properties. FAHFA hydrolysis into its fatty acid (FA) and hydroxy fatty acid (HFA) constituents can affect the bioavailability of FAHFA and its subsequent biological effects. We aimed to investigate FAHFA levels and FAHFA hydrolysis activity in children with or without obesity, and in adults with or without coronary artery disease (CAD). MATERIALS AND METHODS: Our study cohort included 20 children without obesity, 40 children with obesity, 10 adults without CAD and 28 adults with CAD. We quantitated plasma levels of four families of FAHFA [palmitic acid hydroxy stearic acid (PAHSA), palmitoleic acid hydroxy stearic acid (POHSA), oleic acid hydroxy stearic acid (OAHSA), stearic acid hydroxy stearic acid] and their corresponding FA and HFA constituents using liquid chromatography-tandem mass spectrometry analysis. Surrogate FAHFA hydrolysis activity was estimated as the FA/FAHFA or HFA/FAHFA ratio. RESULTS: Children with obesity had lower plasma PAHSA (p = .001), OAHSA (p = .006) and total FAHFA (p = .011) levels, and higher surrogate FAHFA hydrolysis activity represented by PA/PAHSA (p = .040) and HSA/OAHSA (p = .025) compared with children without obesity. Adults with CAD and a history of myocardial infarction (MI) had lower POHSA levels (p = .026) and higher PA/PAHSA (p = .041), POA/POHSA (p = .003) and HSA/POHSA (p = .038) compared with those without MI. CONCLUSION: Altered FAHFA metabolism is associated with obesity and MI, and inhibition of FAHFA hydrolysis should be studied further as a possible therapeutic strategy in obesity and MI.

Inulin supplementation exhibits increased muscle mass via gut-muscle axis in children with obesity: double evidence from clinical and in vitro studies.

Gut microbiota manipulation may reverse metabolic abnormalities in obesity. Our previous studies demonstrated that inulin supplementation significantly promoted Bifidobacterium and fat-free mass in obese children. We aimed to study gut-muscle axis from inulin supplementation in these children. In clinical phase, the plasma samples from 46 participants aged 7-15 years, were analyzed for muscle biomarkers before and after 6-month inulin supplementation. In parallel, the plausible mechanism of muscle production via gut-muscle axis was examined using macrophage cell line. Bifidobacterium was cultured in semi-refined medium with inulin used in the clinical phase. Cell-free supernatant was collected and used in lipopolysaccharide (LPS)-induced macrophage cell line to determine inflammatory and anti-inflammatory gene expression. In clinical phase, IL-15 and creatinine/cystatin C ratio significantly increased from baseline to the 6th month. In vitro study showed that metabolites derived from Bifidobacterium capable of utilizing inulin contained the abundance of SCFAs. In the presence of LPS, treatment from Bifidobacterium + inulin downregulated TNF-α, IL-6, IL-1ß, and iNOS, but upregulated FIZZ-1 and TGF-ß expression. Inulin supplementation promoted the muscle biomarkers in agreement with fat-free mass gain, elucidating by Bifidobacterium metabolites derived from inulin digestion showed in vitro anti-inflammatory activity and decreased systemic pro-inflammation, thus promoting muscle production via gut-muscle axis response.Clinical Trial Registry number: NCT03968003.

Prediction of resting energy expenditure for adolescents with severe obesity: A multi-centre analysis.

BACKGROUND AND OBJECTIVES: Resting energy expenditure (REE) assessments can help inform clinical treatment decisions in adolescents with elevated body mass index (BMI), but current equations are suboptimal for severe obesity. We developed a predictive REE equation for youth with severe obesity and obesity-related comorbidities and compared results to previously published predictive equations. METHODS: Data from indirect calorimetry, clinical measures, and body composition per Dual x-ray absorptiometry (DXA) were collected from five sites. Data were randomly divided into development (N = 438) and validation (N = 118) cohorts. A predictive equation was developed using Elastic Net regression, using sex, race, ethnicity, weight, height, BMI percent of the 95th%ile (BMIp95), waist circumference, hip circumference, waist/hip ratio, age, Tanner stage, fat and fat-free mass. This equation was verified in the validation cohort and compared with 11 prior equations. RESULTS: Data from the total cohort (n = 556, age 15 ± 1.7 years, 77% female, BMIp95 3.3 ± 0.94) were utilized. The best fit equation was REE = -2048 + 18.17 × (Height in cm) - 2.57 × (Weight in kg) + 7.88 × (BMIp95) + 189 × (1 = male, 0 = female), R2 = 0.466, and mean bias of 23 kcal/day. CONCLUSION: This new equation provides an updated REE prediction that accounts for severe obesity and metabolic complications frequently observed in contemporary youth.

Obesity and dyslipidemia in early life: Impact on cardiometabolic risk.

Childhood obesity with its growing prevalence worldwide presents one of the most important health challenges nowadays. Multiple mechanisms are involved in the development of this condition, as well as in its associations with various cardiometabolic complications, such as insulin resistance, diabetes, metabolic dysfunction-associated steatotic liver disease and cardiovascular diseases. Recent findings suggest that childhood obesity and associated dyslipidemia at least partly originate from epigenetic modifications that take place in the earliest periods of life, namely prenatal and perinatal periods. Hence, alterations of maternal metabolism could be fundamentally responsible for fetal and neonatal metabolic programming and consequently, for metabolic health of offspring in later life. In this paper, we will review recent findings on the associations among intrauterine and early postnatal exposure to undesirable modulators of metabolism, development of childhood obesity and later cardiometabolic complications. Special attention will be given to maternal dyslipidemia as a driven force for undesirable epigenetic modulations in offspring. In addition, newly proposed lipid biomarkers of increased cardiometabolic risk in obese children and adolescents will be analyzed, with respect to their predictive potential and clinical applicability.

Baseline higher hair cortisol moderated some effects in a healthy lifestyle intervention.

Children and families from socioeconomically marginalized background experience high levels of stress, especially persistent chronic stress, due to unstable housing, employment, and food insecurity. Although consistent evidence supports a stress-obesity connection, little research has examined the potential moderation role of stress in childhood obesity interventions. Therefore, this study aimed to explore how chronic stress (hair cortisol) moderated the effects of a healthy lifestyle intervention on improving behavioral and anthropometric outcomes among 95 socioeconomically marginalized parent-child dyads. Data were collected in a cluster randomized controlled trial with 10 Head Start childcare centers being randomized into intervention and control. The child sample (3-5 years old) included 57.9 % female, 12.6 % Hispanic, and 40.0 % Black. For the parents, 91.6 % were female, 8.4 % were Hispanic, 36.8 % were Black, and 56.8 % were single. Parent baseline hair cortisol significantly moderated the intervention effects on child fruit intake (B = -1.56, p = .030) and parent nutrition self-efficacy (B = 1.49, p = .027). Specifically, higher parent hair cortisol lowered the increases in child fruit intake but improved the increases in parent nutrition self-efficacy in the intervention group compared to control group. Child higher baseline hair cortisol was significantly associated with the decreases in child fruit intake (B = -0.60, p = .025). Child baseline hair cortisol significantly moderated the intervention effects on parent physical activity (PA) self-efficacy (B = -1.04, p = .033) and PA parental support (B = -0.50, p = .016), with higher child hair cortisol decreasing the improvement on these two outcomes in the intervention group compared to control group. Results from this study shed lights on the moderation role of chronic stress on impacting healthy lifestyle intervention effects. Although needing further investigation, the adverse effects of chronic stress on intervention outcomes should be considered when developing healthy lifestyle interventions for preschoolers and their families.

Decreased vitamin D bio-availability with altered DNA methylation of its metabolism genes in association with the metabolic disorders among the school-aged children with degree I, II, and III obesity.

Obesity is strongly associated with disturbances of vitamin D (VD) metabolites in the animal models. However, the related epidemiological evidence is still controversial, especially the different degrees of obesity children. Hence, in this present representative case-control study, 106 obesity school-age children aged 7-12 years were included and divided into different subgroups as degree I (the age- and sex-specific BMI≥95th percentile, n=45), II (BMI ≥120% percentile, n=34) and III (BMI ≥140% percentile, n=27) obesity groups across the ranges of body mass index (BMI). While the age- and sex-matched subjects without obesity were as the control group. Notably, it was significantly different of body composition, anthropological and clinical characteristics among the above four subgroups with the dose-response relationships (P<.05). Moreover, comparing with the control group, the serum VD concentrations were higher, VD metabolites like 25(OH)D, 25(OH)D3 and 1,25(OH)2D, and related hydroxylases as CYP27A1, CYP2R1 and CYP27B1 were lower in the degree I, II, and III obesity subgroups (P<.05), which were more disorder with the anthropological and clinical characteristics as the obesity was worsen in a BMI-independent manner (P<.05). However, there was a significant increase of CYP27B1 in the degree III obesity group than those in the degree I and II obesity subgroups. Furthermore, the methylation patterns on the genome-wide (Methylation/Hydroxymethylation) and VD metabolism genes (CYP27A1, CYP2R1 and CYP27B1) were negatively correlated with the worse obesity and their related expressions (P<.05). In summary, these results indicated that obesity could affect the homeostasis of VD metabolism related genes such as CYP27A1, CYP2R1, CYP27B1 and etc through abnormal DNA methylation, resulting in the disorders of VD related metabolites to decrease VD bio-availability with the BMI-independent manner. In turn, the lower levels of VD metabolites would affect the liver function to exacerbate the progression of obesity, as the Degree II and III obesity subgroups.

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.

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.

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.