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Background Placental signaling pathways regulate nutrient transport and fetal growth, with potential long-term consequences for offspring metabolic health. Most prior human studies have focused on individual placental markers, limiting insight into the role of coordinated activity across multiple pathways in relation to offspring outcomes. Our objective was to identify patterns across placental nutrient signaling pathways and assess whether the latent placental signaling patterns were associated with early childhood adiposity, and secondarily, explore associations of adiposity-associated patterns with metabolic biomarkers. Methods Among 108 mother-child pairs from the Healthy Start cohort, we quantified 33 placental signaling proteins and their phosphorylated-to-total protein ratios involved in nutrient sensing, insulin/growth factor signaling, stress/inflammation, and mitochondrial biogenesis using Simple Western assays of term placental villus tissue. We applied unsupervised methods to identify latent patterns and LASSO regression was used to select patterns associated with %fat mass at age 4. Multivariable linear regression was used to estimate associations adjusting for offspring age, sex, and maternal pre-pregnancy BMI. These same models were used in exploratory analysis of fasting levels of adiponectin, leptin, insulin, glucose, and lipids at age 4. Results We identified two placental signaling patterns associated with %fat mass. The insulin-mTOR-energy sensing pattern was associated with lower childhood %fat mass (β = −2.46, 95% CI − 4.84, − 0.09) and adiponectin, and the stress-inflammatory MAPK pattern was associated with higher %fat mass (β = 1.28, 95% CI 0.05, 2.51), leptin, and triglycerides; however, the FDR p-values ranged from 0.06 to 0.13. Conclusion Two placental signaling patterns were associated with childhood %fat mass and metabolic markers. These findings indicate that capturing placental activity across several signaling pathways may yield insights into early origins of adiposity and metabolic health.

Healthy dietary patterns may promote kidney health and prevent adverse renal outcomes. Although reviews have summarized the findings from studies on dietary patterns for chronic kidney disease (CKD) management, less is known about dietary patterns for maintaining kidney health prior to CKD development. The current review summarized the results from observational studies from March 2009 to March 2019 investigating associations between dietary patterns and renal outcomes in the general population. The main renal outcome assessed was CKD (estimated glomerular filtration rate < 60 mL/min/1.73 m2). A total of twenty-six research articles met the inclusion criteria. Adherence to the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets were significantly associated with a decreased risk of CKD in the majority of the studies. Furthermore, a posteriori “unhealthy” dietary patterns were associated with an increased risk of CKD. In conclusion, the findings from this review suggest that adherence to DASH and Mediterranean dietary patterns may be useful in promoting kidney health and preventing CKD in the general population. More studies, in particular among minorities, are warranted to investigate the role of diet, a potentially modifiable factor, in promoting kidney health.

IntroductionSeveral adipokines are implicated in the pathophysiology of gestational diabetes mellitus (GDM), however, longitudinal data in early pregnancy on many adipokines are lacking. We prospectively investigated the association of a panel of adipokines in early and mid-pregnancy with GDM risk.Research design and methodsWithin the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons cohort (n=2802), a panel of 10 adipokines (plasma fatty acid binding protein-4 (FABP4), chemerin, interleukin-6 (IL-6), leptin, soluble leptin receptor (sOB-R), adiponectin, omentin-1, vaspin, and retinol binding protein-4) were measured at gestational weeks (GWs) 10–14, 15–26, 23–31, and 33–39 among 107 GDM cases (ascertained on average at GW 27) and 214 non-GDM controls. Conditional logistic regression was used to estimate ORs of each adipokine and GDM, controlling for known GDM risk factors including pre-pregnancy body mass index.ResultsThroughout pregnancy changes in chemerin, sOB-R, adiponectin, and high-molecular-weight adiponectin (HMW-adiponectin) concentrations from 10–14 to 15–26 GWs were significantly different among GDM cases compared with non-GDM controls. In early and mid-pregnancy, FABP4, chemerin, IL-6 and leptin were positively associated with increased GDM risk. For instance, at 10–14 GWs, the OR comparing the highest versus lowest quartile (ORQ4–Q1) of FABP4 was 3.79 (95% CI 1.63 to 8.85). In contrast, in both early and mid-pregnancy adiponectin (eg, ORQ4–Q1 0.14 (0.05, 0.34) during 10–14 GWs) and sOB-R (ORQ4–Q1 0.23 (0.11, 0.50) during 10–14 GWs) were inversely related to GDM risk. At 10–14 GWs a model that included conventional GDM risk factors and FABP4, chemerin, sOB-R, and HMW-adiponectin improved the estimated prediction (area under the curve) from 0.71 (95% CI 0.66 to 0.77) to 0.77 (95% CI 0.72 to 0.82).ConclusionsA panel of understudied adipokines including FABP4, chemerin, and sOB-R may be implicated in the pathogenesis of GDM with significant associations detected approximately 10–18 weeks before typical GDM screening.

Background/Objectives: Pregnant people with HIV (PWH) are more likely to experience systemic inflammation than pregnant people without HIV (PWoH), which may contribute to adverse outcomes in HIV-exposed uninfected (HEU) infants; however, the underlying mechanisms are not well studied. This study examined associations between maternal inflammatory markers during pregnancy and cord blood inflammatory markers and metabolomic signatures. Methods: Between 2011 and 2025, pregnant PWH and PWoH were enrolled at 24–28 weeks of gestational age. Maternal plasma was analyzed for inflammatory markers [interleukin (IL)-6, high-sensitivity C-reactive protein (hsCRP), soluble TNF-α receptor 1 (sTNFR1) and 2 (sTNFR2), soluble CD163 (sCD163), soluble CD14 (sCD14)]. At delivery, cord blood was collected for measurement of IL-6, TNF-α, IFN-γ, and IL-10 and for targeted metabolomics by ultra-performance liquid chromatography–mass spectrometry. Spearman correlation, linear regression, and weighted correlation network analysis (WGCNA) were used to evaluate associations, stratified by HIV exposure. Results: This study included 22 PWH and 47 PWoH and their infants. Among HEU infants, but not HUU infants, maternal IL-6 correlated with cord blood TNFα (r = 0.443, p < 0.05) and maternal sTNFR1 correlated with both cord blood TNFα (r = 0.617, p < 0.05) and IFNγ (r = −0.517, p < 0.05). WGCNA identified five metabolomic modules. In the HEU group, naternal sCD14 was positively associated with a metabolomic module characterized by lysophosphotidylecholines in the HEU group. Conclusions: We identified distinct patterns in the relationships between maternal inflammation and infant immune–metabolic profiles by HIV exposure status. These findings suggest that HIV infection, even with viral suppression, may alter the maternal–fetal inflammatory interface and influence early metabolic programming.

Fetal growth restriction (FGR) is associated with inhibition of placental mTOR signaling and amino acid transport. mTOR is a positive regulator of amino acid transport mediated by controlling the plasma membrane trafficking of SNAT2, a System A amino acid transporter isoform, and LAT1 an isoform involved in System L amino acid transport. Inhibition of mTOR complex 1 decreases SNAT2 and LAT1 plasma membrane trafficking by activating of Nedd4-2, an E3 ubiquitin ligase, and inhibition of mTOR Complex 2 decreases the protein expression of Cdc42 which limits transporter trafficking to the plasma membrane. We isolated human primary trophoblast (PHT) cells from FGR placentas and demonstrate that they maintain the in vivo FGR phenotype with increased expression of DEPTOR, an endogenous inhibitor of mTOR, reduced mTOR signaling, increased Nedd4-2 expression, lower expression of Cdc42, and decreased SNAT2 and LAT 1 protein expression in the plasma membrane, and decreased System A and L activity. We silenced DEPTOR in FGR PHT cells using siRNA and found normalized mTOR signaling, Nedd4-2 and Cdc42 protein expression, SNAT2 and LAT1 plasma membrane trafficking and System A and L amino acid transport activity. We also show that hypoxia induces DEPTOR upregulation in PHT cells. In the Healthy Start Study, a longitudinal pre-birth cohort, placental DEPTOR expression was correlated with lower birth weight percentile and with higher systolic and diastolic blood pressure in children at 4–6 years of age. Together, our studies provide mechanistic and translational insight into how placental DEPTOR may serve as potential mediator of fetal growth and long-term health risk. We identify a mechanistic link between increased trophoblast DEPTOR expression in FGR and decreased placental mTOR signaling and amino acid transport. Intervention strategies aimed at normalizing trophoblast mTOR signaling may be effective to improve trophoblast nutrient transport and fetal growth in FGR.

Fetal overnutrition predisposes offspring to increased metabolic risk. The current study used metabolomics to assess sustained differences in serum metabolites across childhood and adolescence among youth exposed to three typologies of fetal overnutrition: maternal obesity only, gestational diabetes mellitus (GDM) only, and obesity + GDM. We included youth exposed in utero to obesity only (BMI ≥ 30; n = 66), GDM only (n = 56), obesity + GDM (n = 25), or unexposed (n = 297), with untargeted metabolomics measured at ages 10 and 16 years. We used linear mixed models to identify metabolites across both time-points associated with exposure to any overnutrition, using a false-discovery-rate correction (FDR) <0.20. These metabolites were included in a principal component analysis (PCA) to generate profiles and assess metabolite profile differences with respect to overnutrition typology (adjusted for prenatal smoking, offspring age, sex, and race/ethnicity). Fetal overnutrition was associated with 52 metabolites. PCA yielded four factors accounting for 17–27% of the variance, depending on age of measurement. We observed differences in three factor patterns with respect to overnutrition typology: sphingomyelin-mannose (8–13% variance), skeletal muscle metabolism (6–10% variance), and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF; 3–4% variance). The sphingomyelin-mannose factor score was higher among offspring exposed to obesity vs. GDM. Exposure to obesity + GDM (vs. GDM or obesity only) was associated with higher skeletal muscle metabolism and CMPF scores. Fetal overnutrition is associated with metabolic changes in the offspring, but differences between typologies of overnutrition account for a small amount of variation in the metabolome, suggesting there is likely greater pathophysiological overlap than difference.

Aims/hypothesisLimited data exist on the association between maternal diet quality during pregnancy and metabolic traits in offspring during early childhood, which is a sensitive period for risk of obesity-related disorders later in life. We aimed to examine the association of maternal diet quality, as indicated by the Healthy Eating Index-2010 (HEI), in pregnancy with offspring metabolic biomarkers and body composition at age 4–7 years.MethodsWe used data from 761 mother–offspring pairs from the Healthy Start study to examine sex-specific associations of HEI >57 vs ≤57 with offspring fasting glucose, leptin, cholesterol, HDL, LDL, percentage fat mass, BMI z score and log-transformed insulin, 1/insulin, HOMA-IR, adiponectin, triacylglycerols, triacylglycerols:HDL, fat mass, and sum of skinfolds. Multivariable linear regression models accounted for maternal race/ethnicity, age, education, smoking habits during pregnancy and physical activity, and child’s age.ResultsDuring pregnancy, mean (SD) HEI score was 55.0 (13.3), and 43.0% had an HEI score >57. Among boys, there was an inverse association of maternal HEI with offspring glucose, insulin, HOMA-IR and adiponectin. For instance, maternal HEI >57 was associated with lower fasting glucose (−0.11; 95% CI −0.20, −0.02 mmol/l), and lower concentrations of: insulin by 15.3% (95% CI −24.6, −5.0), HOMA-IR by 16.3% (95% CI −25.7, −5.6) and adiponectin by 9.3% (95% CI −16.1, −2.0). Among girls, there was an inverse association of maternal HEI with insulin and a positive association with LDL. However, following covariate adjustment, all estimates among girls were attenuated to the null.Conclusions/interpretationGreater compliance with the USA Dietary Guidelines via the HEI may improve the maternal–fetal milieu and decrease susceptibility for poor metabolic health among offspring, particularly boys. Future studies are warranted to confirm these associations and determine the underlying mechanisms.

Background/objective: Approximately one-third of pregnant individuals in the U.S. are affected by obesity, which can adversely impact the in utero environment and offspring. This study aimed to investigate the differences in urine metabolomics between children exposed and unexposed to maternal obesity. Methods: In a study nested within a larger pregnancy cohort of women–offspring pairs, we measured untargeted metabolomics using liquid chromatography–mass spectrometry in urine samples from 68 children at 4–8 years of age. We compared metabolite levels between offspring exposed to maternal obesity (body mass index [BMI] ≥ 30.0 kg/m2) vs. unexposed (maternal BMI 18.5–24.9 kg/m2) and matched them on covariates, using two-sample t-tests, with additional sensitivity analyses based on children’s BMI. This study reports statistically significant results (p ≤ 0.05) and potentially noteworthy findings (fold change > 1 or 0.05 < p < 0.15), considering compounds’ involvement in common pathways or similar biochemical families. Results: The mean (SD) maternal age at study enrollment was 28.0 (6.3) years, the mean child age was 6.6 (0.8) years, 56% of children were male, and 38% of children had a BMI in the overweight/obese range (BMI ≥ 85th percentile). Children exposed to maternal obesity had lower levels of 5-hydroxyindole sulfate and 7-hydroxyindole sulfate and higher levels of secondary bile acids. Phenylacetic acid derivatives were lower in offspring exposed to obesity and in offspring who had a current BMI in the overweight/obese range. Exposure to maternal obesity was associated with lower levels of androgenic steroid dehydroepiandrosterone sulfate (DHEA-S). Conclusions: In this preliminary study, children exposed to maternal obesity in utero had differences in microbiome-related metabolites in urine suggestive of altered microbial catabolism of tryptophan and acetylated peptides. Some of these differences were partially attributable to the offspring’s current BMI status. This study highlights the potential of urine metabolomics to identify biomarkers and pathways impacted by in utero exposure to maternal obesity.

This study examined engagement in five health behaviors among pregnant women in the USA. Pregnant women who participated in the National Health and Nutrition Examination Survey 2007-2014 were included in this study. Five health behaviors were examined: adequate fruit and vegetable consumption, prenatal multivitamin use, physical activity, sleep and smoking. Multivariable regressions were used to estimate the odds ratio and 95% confidence interval of characteristics associated with health behaviors. Among 248 pregnant women, only 10.2% engaged in all five health behaviors and 35.4% consumed adequate fruits and vegetables. For adequate fruit and vegetable consumption, Hispanic and women of 'other' race were more likely to meet the recommendation compared to non-Hispanic white (P = 0.01 and P = 0.03, respectively); high school graduates were less likely to meet the recommendation compared to those with at least some college education or more (P = 0.04). Adequate fruit and vegetable consumption among pregnant women was poor and differed by race/ethnicity and education status. Because of the cross-sectional design, we cannot examine engagement in health behaviors continuously throughout pregnancy. Future research with longitudinal data over the course of pregnancy is needed to confirm these results.