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The published article contained errors in the descriptive reporting of the number of per- and polyfluoroalkyl substances (PFAS) concentrations that were below the method limit of detection (LOD; 0.1 ng/mL) [...]

Objective: Fetal exposures may impact offspring epigenetic signatures and adiposity. The authors hypothesized that maternal metabolic traits associate with cord blood DNA methylation, which, in turn, associates with child adiposity. Methods: Fasting serum was obtained in 588 pregnant women (27–34 weeks' gestation), and insulin, glucose, high‐density lipoprotein cholesterol, triglycerides, and free fatty acids were measured. Cord blood DNA methylation and child adiposity were measured at birth, 4–6 months, and 4–6 years. The association of maternal metabolic traits with DNA methylation (429,246 CpGs) for differentially methylated probes (DMPs) and regions (DMRs) was tested. The association of the first principal component of each DMR with child adiposity was tested, and mediation analysis was performed. Results: Maternal triglycerides were associated with the most DMPs and DMRs of all traits tested (261 and 198, respectively, false discovery rate < 0.05). DMRs were near genes involved in immune function and lipid metabolism. Triglyceride‐associated CpGs were associated with child adiposity at 4–6 months (32 CpGs) and 4–6 years (2 CpGs). One, near CD226, was observed at both timepoints, mediating 10% and 22% of the relationship between maternal triglycerides and child adiposity at 4–6 months and 4–6 years, respectively. Conclusions: DNA methylation may play a role in the association of maternal triglycerides and child adiposity. [ABSTRACT FROM AUTHOR]

Background: Exposure to intrauterine obesity can disrupt clock gene rhythmicity in animal models. The aim of this pilot study was to determine if maternal obesity alters rhythmic expression of core clock in mesenchymal stem cells (MSCs) from umbilical cords of human infants born to mothers with obesity (Ob-MSC) vs. normal weight (NW-MSC). Methods: We compared in vitro rhythmic expression patterns of core clock (BMAL1, CLOCK, PER2) and clock-output (NR1D1), components in undifferentiated Ob-MSCs (n = 3) vs. NW-MSCs (n = 3). MSCs were harvested every 2 h, following a dexamethasone shock, for 30 h. Adipogenesis or myogenesis was induced in vitro and markers of adipogenesis and fat storage were assessed, respectively. Results: We detected significant rhythmicity in expression patterns of BMAL1, PER2, and NR1D1 at the group level in Ob- and NW-MSCs (p < 0.05). PER2 oscillatory amplitude was 3-fold higher in Ob-MSCs vs. NW-MSCs (p < 0.006). During adipogenesis, Ob-MSCs had higher PPARγ protein content (p = 0.04) vs. NW-MSC. During myogenesis, Ob-MSCs had higher saturated triacylglycerols (p = 0.04) vs. NW-MSC. Conclusion: Rhythmic expressions of BMAL1, PER2, and NR1D1 are detectable in undifferentiated MSCs. Higher PER2 oscillatory amplitude was paralleled by higher markers of fat storage during differentiation in Ob-MSCs vs. NW-MSCs, and supports that the core clock and cellular metabolism may be linked in infant MSCs. [ABSTRACT FROM AUTHOR]

Objective: In human studies, new model systems are needed for improved mechanistic investigation of developmental predisposition for metabolic disease but also to serve as benchmarks in early life prevention or intervention efforts. In this regard, human infant umbilical cord–derived mesenchymal stem cells (MSCs) are an emerging tool. However, long‐term clinical relevance to in vivo markers of metabolic disease is unknown. Methods: In a cohort of 124 mother/child dyads, this study tested the hypothesis that triglyceride content (TG) of infant MSCs undergoing adipogenesis in vitro (MSC‐TG) is associated with in vivo adiposity (percent fat mass) from birth to early childhood and with fasting glucose and insulin in early childhood. Results: MSC‐TG was positively associated with in vivo child adiposity at birth, age 4 to 6 months, and age 4 to 6 years. MSC‐TG was associated with fasting glucose, but not insulin, at 4 to 6 years. Importantly, MSC‐TG explained an additional 13% variance in child adiposity at 4 to 6 years, after accounting for other established birth predictors (weight and percent fat mass at birth) and other established covariates related to child adiposity (e.g., breastfeeding exposure, physical activity). Conclusions: This work demonstrates the strength of the MSC model for predicting offspring metabolic phenotype into childhood, even when considering the important contribution of other early life risk factors. [ABSTRACT FROM AUTHOR]

High dietary fat intake leads to insulin resistance in skeletal muscle, and this represents a major risk factor for type 2 diabetes and cardiovascular disease. Mitochondrial dysfunction and oxidative stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the [H.sub.2][O.sub.2]-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial [H.sub.2][O.sub.2] emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial [H.sub.2][O.sub.2] emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity., Introduction Obesity has become a worldwide epidemic, the consequences of which represent a major health care challenge in the 21st century. A decrease in the sensitivity of skeletal muscle to [...]

Obesity is associated with a decrement in the ability of skeletal muscle to oxidize lipid. The purpose of this investigation was to determine whether clinical interventions (weight loss, exercise training) could reverse the impairment in fatty acid oxidation (FAO) evident in extremely obese individuals. FAO was assessed by incubating skeletal muscle homogenates with [1-[sup.14]C]palmitate and measuring [sup.14]C[O.sub.2] production. Weight loss was studied using both cross-sectional and longitudinal designs. Muscle FAO in extremely obese women who had lost weight (decrease in body mass of--50 kg) was compared with extremely obese and lean individuals (BMI of 22.8 [+ or -] 1.2, 50.7 [+ or -] 3.9, and 36.5 [+ or -] 3.5 kg/[m.sup.2] for lean, obese, and obese after weight loss, respectively). There was no difference in muscle FAO between the extremely obese and weight loss groups, and FAO was depressed (-45%; P [less than or equal to] 0.05) compared with the lean subjects. Muscle FAO also did not change in extremely obese women (n = 8) before and 1 yr after a 55-kg weight loss. In contrast, 10 consecutive days of exercise training increased (P [less than or equal to] 0.05) FAO in the skeletal muscle of lean (+ 1.7-fold), obese (+ 1.8-fold), and previously extremely obese subjects after weight loss (+2.6-fold). mRNA content for PDK4, CPT I, and PGC-l[alpha] corresponded with FAO in that there were no changes with weight loss and an increase with physical activity. These data indicate that a defect in the ability to oxidize lipid in skeletal muscle is evident with obesity, which is corrected with exercise training but persists after weight loss. extreme obesity; fat oxidation; gastric bypass surgery; mitochondria; physical activity

Maternal obesity increases the risk for pediatric obesity; however, the molecular mechanisms in human infants remain poorly understood. We hypothesized that mesenchymal stem cells (MSCs) from infants born to obese mothers would demonstrate greater potential for adipogenesis and less potential for myogenesis, driven by differences in β-catenin, a regulator of MSC commitment. MSCs were cultured from the umbilical cords of infants born to normal-weight (prepregnancy [pp] BMI 21.1 ± 0.3 kg/m(2); n = 15; NW-MSCs) and obese mothers (ppBMI 34.6 ± 1.0 kg/m(2); n = 14; Ob-MSCs). Upon differentiation, Ob-MSCs exhibit evidence of greater adipogenesis (+30% Oil Red O stain [ORO], +50% peroxisome proliferator-activated receptor (PPAR)-γ protein; P < 0.05) compared with NW-MSCs. In undifferentiated cells, total β-catenin protein content was 10% lower and phosphorylated Thr41Ser45/total β-catenin was 25% higher (P < 0.05) in Ob-MSCs versus NW-MSCs (P < 0.05). Coupled with 25% lower inhibitory phosphorylation of GSK-3β in Ob-MSCs (P < 0.05), these data suggest greater β-catenin degradation in Ob-MSCs. Lithium chloride inhibition of GSK-3β increased nuclear β-catenin content and normalized nuclear PPAR-γ in Ob-MSCs. Last, ORO in adipogenic differentiating cells was positively correlated with the percent fat mass in infants (r = 0.475; P < 0.05). These results suggest that altered GSK-3β/β-catenin signaling in MSCs of infants exposed to maternal obesity may have important consequences for MSC lineage commitment, fetal fat accrual, and offspring obesity risk. [ABSTRACT FROM AUTHOR]