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The prevalence of obesity and type 2 diabetes is growing at an alarming rate, including among pregnant women. Low-calorie sweeteners (LCSs) have increasingly been used as an alternative to sugar to deliver a sweet taste without the excessive caloric load. However, there is little evidence regarding their biological effects, particularly during development. Here, we used a mouse model of maternal LCS consumption to explore the impact of perinatal LCS exposure on the development of neural systems involved in metabolic regulation. We report that adult male, but not female, offspring from both aspartame- and rebaudioside A-exposed dams displayed increased adiposity and developed glucose intolerance. Moreover, maternal LCS consumption reorganized hypothalamic melanocortin circuits and disrupted parasympathetic innervation of pancreatic islets in male offspring. We then identified phenylacetylglycine (PAG) as a unique metabolite that was upregulated in the milk of LCS-fed dams and the serum of their pups. Furthermore, maternal PAG treatment recapitulated some of the key metabolic and neurodevelopmental abnormalities associated with maternal LCS consumption. Together, our data indicate that maternal LCS consumption has enduring consequences on the offspring's metabolism and neural development and that these effects are likely to be mediated through the gut microbial co-metabolite PAG.

Increased hepatic lipid content and decreased insulin sensitivity have critical roles in the development of cardiometabolic diseases. Therefore, our objective was to investigate the dose-response effects of consuming high fructose corn syrup (HFCS)-sweetened beverages for two weeks on hepatic lipid content and insulin sensitivity in young (18-40 years) adults (BMI 18-35 kg/m2). In a parallel, double-blinded study, participants consumed three beverages/day providing 0% (aspartame: n = 23), 10% (n = 18), 17.5% (n = 16), or 25% (n = 28) daily energy requirements from HFCS. Magnetic resonance imaging for hepatic lipid content and oral glucose tolerance tests (OGTT) were conducted during 3.5-day inpatient visits at baseline and again at the end of a 15-day intervention. During the 12 intervening outpatient days participants consumed their usual diets with their assigned beverages. Significant linear dose-response effects were observed for increases of hepatic lipid content (p = 0.015) and glucose and insulin AUCs during OGTT (both p = 0.0004), and for decreases in the Matsuda (p = 0.0087) and Predicted M (p = 0.0027) indices of insulin sensitivity. These dose-response effects strengthen the mechanistic evidence implicating consumption of HFCS-sweetened beverages as a contributor to the metabolic dysregulation that increases risk for nonalcoholic fatty liver disease and type 2 diabetes.

ContextStudies in rodents and humans suggest that high-fructose corn syrup (HFCS)-sweetened diets promote greater metabolic dysfunction than sucrose-sweetened diets.ObjectiveTo compare the effects of consuming sucrose-sweetened beverage (SB), HFCS-SB, or a control beverage sweetened with aspartame on metabolic outcomes in humans.MethodsA parallel, double-blinded, NIH-funded study. Experimental procedures were conducted during 3.5 days of inpatient residence with controlled feeding at a research clinic before (baseline) and after a 12-day outpatient intervention period. Seventy-five adults (18-40 years) were assigned to beverage groups matched for sex, body mass index (18-35 kg/m2), and fasting triglyceride, lipoprotein and insulin concentrations. The intervention was 3 servings/day of sucrose- or HFCS-SB providing 25% of energy requirement or aspartame-SB, consumed for 16 days. Main outcome measures were %hepatic lipid, Matsuda insulin sensitivity index (ISI), and Predicted M ISI.ResultsSucrose-SB increased %hepatic lipid (absolute change: 0.6 ± 0.2%) compared with aspartame-SB (-0.2 ± 0.2%, P

We aimed to determine if the newborn gut microbiota is an underlying determinant of early life growth trajectories. 132 Hispanic infants were recruited at 1-month postpartum. The infant gut microbiome was characterized using 16S rRNA amplicon sequencing. Rapid infant growth was defined as a weight-for-age z-score (WAZ) change greater than 0.67 between birth and 12-months of age. Measures of infant growth included change in WAZ, weight-for-length z-score (WLZ), and body mass index (BMI) z-scores from birth to 12-months and infant anthropometrics at 12-months (weight, skinfold thickness). Of the 132 infants, 40% had rapid growth in the first year of life. Multiple metrics of alpha-diversity predicted rapid infant growth, including a higher Shannon diversity (OR = 1.83; 95% CI: 1.07-3.29; p = .03), Faith's phylogenic diversity (OR = 1.41, 95% CI: 1.05-1.94; p = .03), and richness (OR = 1.04, 95% CI: 1.01-1.08; p = .02). Many of these alpha-diversity metrics were also positively associated with increases in WAZ, WLZ, and BMI z-scores from birth to 12-months (pall

BackgroundThe effects of breastfeeding (BF) on metabolic syndrome (MetS) and diabetes mellitus in children exposed to gestational diabetes mellitus (GDM) in utero have rarely been evaluated.ObjectiveThis study assessed BF and GDM in relation to the prevalence of prediabetes and MetS in Hispanic children and adolescents (8-19 y).MethodsThis is a longitudinal study with 229 Hispanic children (8-13 y) with overweight/obesity, family history of diabetes, and an average of four annual visits (AV). Participants were categorized as follows: never (negative for prediabetes/MetS at all AVs), ever (positive for prediabetes/MetS at any visit), intermittent (positive for prediabetes/MetS at 1-2 AVs), and persistent (positive for prediabetes/MetS at greater than or equal to 3 AVs).ResultsCompared with GDM offspring who were not BF (referent), GDM offspring who were BF had lower odds of persistent prediabetes (OR = 0.18; 95% CI, 0.04-0.82; P = 0.02) and MetS (OR = 0.10; 95% CI, 0.02-0.55; P = 0.008). Compared with referent group, non-GDM offspring who were BF, and non-GDM offspring not BF had lower odds of persistent prediabetes (OR = 0.10; 95% CI, 0.03-0.39; P = 0.001; OR = 0.05; 95% CI, 0.01-0.11; P

Metabolic dysfunction‐associated steatotic liver disease (MASLD) is the most common paediatric liver disease. Latinos have high MASLD risk due to 50% prevalence of GG genotype of PNPLA3. Our primary aim was to evaluate associations between dietary carbohydrates/sugars and liver stiffness in Latino adolescents with obesity. Our secondary aim was to examine effect modification by (a) PNPLA3 genotype or (b) liver disease severity. Data were obtained from 114 Latino adolescents with obesity involved in two prior studies. No associations were seen between dietary carbohydrates/sugars and liver stiffness in the group as a whole. In subjects with GG genotype of PNPLA3, total sugar, fructose, sucrose, and glucose were associated with liver stiffness. Positive relationships between carbohydrate, total sugar, and sucrose and liver stiffness were stronger in those with MASLD and fibrosis compared to those with healthy livers and MASLD without fibrosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous and has been associated with an increased risk of several cardiometabolic diseases. However, the metabolic pathways linking PFAS exposure and human disease are unclear. OBJECTIVE: We examined associations of PFAS mixtures with alterations in metabolic pathways in independent cohorts of adolescents and young adults. METHODS: Three hundred twelve overweight/obese adolescents from the Study of Latino Adolescents at Risk (SOLAR) and 137 young adults from the Southern California Children's Health Study (CHS) were included in the analysis. Plasma PFAS and the metabolome were determined using liquid-chromatography/high-resolution mass spectrometry. A metabolome-wide association study was performed on log- transformed metabolites using Bayesian regression with a g-prior specification and g-computation for modeling exposure mixtures to estimate the impact of exposure to a mixture of six ubiquitous PFAS (PFOS, PFHxS, PFHpS, PFOA, PFNA, and PFDA). Pathway enrichment analysis was performed using Mummichog and Gene Set Enrichment Analysis. Significance across cohorts was determined using weighted Z-tests. RESULTS: In the SOLAR and CHS cohorts, PFAS exposure was associated with alterations in tyrosine metabolism (meta- analysis p = 0.00002) and de novo fatty acid biosynthesis (p = 0.03), among others. For example, when increasing all PFAS in the mixture from low (~ 30th percentile) to high (~ 70th percentile), thyroxine (T4), a thyroid hormone related to tyrosine metabolism, increased by 0.72 standard deviations (SDs; equivalent to a standardized mean difference) in the SOLAR cohort (95% Bayesian credible interval (BCI): 0.00, 1.20) and 1.60 SD in the CHS cohort (95% BCI: 0.39, 2.80). Similarly, when going from low to high PFAS exposure, arachidonic acid increased by 0.81 SD in the SOLAR cohort (95% BCI: 0.37, 1.30) and 0.67 SD in the CHS cohort (95% BCI: 0.00, 1.50). In general, no individual PFAS appeared to drive the observed associations. DISCUSSION: Exposure to PFAS is associated with alterations in amino acid metabolism and lipid metabolism in adolescents and young adults. https:// doi.org/10.1289/EHP11372, Introduction Per- and polyfluoroalkyl substances (PFAS) make up a prevalent class of persistent organic pollutants with endocrine and metabolism disrupting properties. (1,2) PFAS are used in a broad range of [...]

Growing evidence indicates that human milk oligosaccharides (HMOs) are important bioactive compounds that enhance health and developmental outcomes in breastfed babies. Maternal dietary intake likely contributes to variation in HMO composition, but studies identifying diet–HMO relationships are few and inconsistent. This study aimed to investigate how the maternal intake of macronutrients and micronutrients—specifically proteins, fats, vitamins, and minerals—associated with HMOs at 1 month (n = 210), 6 months (n = 131), and 12 months postpartum (n = 84). Several associations between maternal dietary factors and HMO profiles were identified utilizing partial correlation analysis. For example, maternal free sugar (rho = −0.02, p < 0.01), added sugar (rho = −0.22, p < 0.01), and sugary sweetened beverage (rho = −0.22, p < 0.01) intake were negatively correlated with the most abundant HMO, 2′-fucosyllactose (2′-FL), at 1 month, suggesting that higher sugar consumption was associated with reduced levels of 2′-FL. Further, vitamins D, C, K, and the minerals zinc and potassium were positively correlated with 2′-FL at 1 month (pAll < 0.05). For the longitudinal analysis, a mixed-effects linear regression model revealed significant associations between maternal vitamin intake and HMO profiles over time. For example, for each unit increase in niacin intake, there was a 31.355 nmol/mL increase in 2′-FL concentration (p = 0.03). Overall, the results provide additional evidence supporting a role for maternal nutrition in shaping HMO profiles, which may inform future intervention strategies with the potential of improving infant growth and development through optimal HMO levels in mothers' milk. [ABSTRACT FROM AUTHOR]

BackgroundEvidence linking breastfeeding to reduced risk of developing childhood obesity is inconclusive, yet previous studies have not considered variation in specific components of breast milk that may affect early development.ObjectiveWe examined whether differences in the composition of human milk oligosaccharides (HMOs) correlate with infant growth and body composition at 1 and 6 mo of age.DesignTwenty-five mother-infant dyads were recruited from the University Hospital at the University of Oklahoma Health Sciences Center. Infants were breastfed for 6 mo. Breast-milk and infant measures were obtained at 1 and 6 mo of infant age. HMO composition was analyzed by high-pressure liquid chromatography, and infant growth (length and weight) and body composition (percentage fat, total fat, lean mass) were measured by dual-energy X-ray absorptiometry. Relations between HMOs and infant growth and body composition were examined by using multiple linear regression. A priori covariates included maternal prepregnancy body mass index, pregnancy weight gain, and infant age and sex.ResultsHigher HMO diversity and evenness at 1 mo were associated with lower total and percentage fat mass at 1 mo. At 1 mo, each 1-μg/mL increase in lacto-N-fucopentaose (LNFP) I was associated with a 0.40-kg lower infant weight (P = 0.03). At 6 mo, each 1-μg/mL increase in LNFPI was associated with a 1.11-kg lower weight (P = 0.03) and a 0.85-g lower lean mass (P = 0.01). At 6 mo, each 1-μg/mL increase in LNFPI was associated with a 0.79-g lower fat mass (P = 0.02), whereas disialyl-lacto-N-tetraose and LNFPII were associated with a 1.92-g (P = 0.02) and 0.42-g (P = 0.02) greater fat mass, respectively. At 6 mo, each 1-μg/mL increase in fucosyl-disialyl-lacto-N-hexaose and lacto-N-neotetraose was associated with 0.04% higher (P = 0.03) and 0.03% lower (P < 0.01) body fat, respectively.ConclusionThese findings support the hypothesis that differences in HMO composition in mother's milk are associated with infant growth and body composition. This trial was registered at clinicaltrials.gov as NCT02535637.

ObjectiveSalsalate treatment has well-known effects on improving glycemia, and the objective of this study was to examine whether the mechanism of this effect was related to changes in adipose tissue.MethodsA randomized double-blind and placebo-controlled trial in obese Hispanics (18-35 years) was conducted. The intervention consisted of 4 g day(-1) of salsalate (n = 11) versus placebo (n = 13) for 4 weeks. Outcome measures included glycemia, adiposity, ectopic fat, and adipose tissue gene expression and inflammation.ResultsIn those receiving salsalate, plasma fasting glucose decreased by 3.4% (P < 0.01), free fatty acids decreased by 42.5% (P = 0.06), and adiponectin increased by 27.7% (P < 0.01). Salsalate increased insulin AUC by 38% (P = 0.01) and HOMA-B by 47.2% (P < 0.01) while estimates of insulin sensitivity/resistance were unaffected. These metabolic improvements occurred without changes in total, abdominal, visceral, or liver fat. Plasma markers of inflammation/immune activation were unchanged following salsalate. Salsalate had no effects on adipose tissue including adipocyte size, presence of crown-like structures, or gene expression of adipokines, immune cell markers, or cytokines downstream of NF-κB with the exception of downregulation of IL-1β (P < 0.01).ConclusionsFindings suggest that metabolic improvements in response to salsalate occurred without alterations in adiposity, ectopic fat, or adipose tissue gene expression and inflammation.

Summary: Background: Non‐alcoholic fatty liver disease (NAFLD) is on the rise among youth. Identifying biomarkers of NAFLD progression/risk can aid in prevention efforts. Aims: This pilot study investigated associations of two endotoxin biomarkers—lipopolysaccharide‐binding protein (LBP) and anti‐endotoxin core immunoglobulin G (EndoCab)—with markers of NAFLD among 99 Latino/Latina adolescents (11–19 years) with obesity. Materials & Methods: We used linear regression to examine associations of each endotoxin biomarker (per 1‐SD) with hepatic fat fraction (HFF), liver volume, and liver stiffness. Results: We found positive associations of LBP with HFF and liver volume. Each 1‐SD increment in LBP corresponded with 2.35% (95% CI: 0.46%, 4.23%) higher HFF and 0.14 (0.06, 0.23) L greater liver volume after adjusting for age, sex, and maternal education. Accounting for abdominal adiposity and Tanner stage did not change results. Excluding 72 participants with NAFLD attenuated associations of LBP with HFF but associations with liver volume persisted (0.11 [0.01, 0.21] L). EndoCab was not associated with any liver outcomes. Neither endotoxin biomarker predicted liver stiffness. Discussion/conclusion: While additional research is warranted, our results support LBP as a biomarker of NAFLD risk/progression in high‐risk youth. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Prediabetes in young people is an emerging epidemic that disproportionately impacts Hispanic populations. We aimed to develop a metabolite-based prediction model for prediabetes in young people with overweight/obesity at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS: In independent, prospective cohorts of Hispanic youth (discovery; n = 143 without baseline prediabetes) and predominately Hispanic young adults (validation; n = 56 without baseline prediabetes), we assessed prediabetes via 2-h oral glucose tolerance tests. Baseline metabolite levels were measured in plasma from a 2-h postglucose challenge. In the discovery cohort, least absolute shrinkage and selection operator regression with a stability selection procedure was used to identify robust predictive metabolites for prediabetes. Predictive performance was evaluated in the discovery and validation cohorts using logistic regression. RESULTS: Two metabolites (allylphenol sulfate and caprylic acid) were found to predict prediabetes beyond known risk factors, including sex, BMI, age, ethnicity, fasting/2-h glucose, total cholesterol, and triglycerides. In the discovery cohort, the area under the receiver operator characteristic curve (AUC) of the model with metabolites and known risk factors was 0.80 (95% CI 0.72–0.87), which was higher than the risk factor-only model (AUC 0.63 [0.53–0.73]; P = 0.001). When the predictive models developed in the discovery cohort were applied to the replication cohort, the model with metabolites and risk factors predicted prediabetes more accurately (AUC 0.70 [95% CI 40.55–0.86]) than the same model without metabolites (AUC 0.62 [0.46–0.79]). CONCLUSIONS: Metabolite profiles may help improve prediabetes prediction compared with traditional risk factors. Findings suggest that medium-chain fatty acids and phytochemicals are early indicators of prediabetes in high-risk youth. [ABSTRACT FROM AUTHOR]