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Exposure to, perception of, and response to stress have all been shown to influence appetite and dietary behaviors in non-pregnancy human and animal studies, mediated in part by the appetite stimulating hormone ghrelin. Yet, the impact of prenatal stress on biological pathways associated with appetite in the context of pregnancy is not well understood. The objective of this study was to assess the relationship between these layered dimensions of stress with fasting and postprandial plasma ghrelin concentrations among Hispanic pregnant women with overweight or obesity, a population known to experience heightened levels of stress. Thirty-three non-diabetic Hispanic women with pre-pregnancy body mass index of 25.0-34.9 kg/m2 participated in a crossover study at 28-32 weeks' gestation. At each visit, participants provided fasting blood and saliva samples, consumed a standardized mixed-meal, and completed a 15-minute task: friendly conversation (control) or the Trier Social Stress Test (experimental stress exposure). Six timed blood and saliva samples were collected up to 2 h from baseline and assayed for ghrelin and cortisol, respectively, and area-under-the-curve (AUC) values were computed. Day-to-day stress levels were assessed by the Perceived Stress Scale. Physiological and psychological stress reactivity was determined by cortisol AUC and change in self-reported affect state, respectively, during the experimental stress visit. Maternal perceived stress was positively associated with ghrelin concentrations in the fasted (β = 0.06, p = 0.02) and postprandial state (β = 0.05, p = 0.02). Mean ghrelin AUC was not significantly different following acute stress versus control. Measures of acute stress reactivity were not associated with ghrelin AUC. Contrary to our hypothesis, among Hispanic pregnant women with overweight and obesity, exposure to an acute stress induction task did not alter postprandial ghrelin concentrations, and changes in individual psychological and physiological stress reactivity did not associate with postprandial ghrelin. However, our findings suggest that maternal report of general perceived stress over the last month is associated with higher fasting and postprandial ghrelin concentrations. Differences in the effects of short-term stress exposure versus day-to-day perception of stress on appetite and food intake in pregnancy deserves further investigation.

ObjectiveThis study tested the hypothesis, in a prospective cohort study design, that maternal saturated free fatty acid (sFFA) concentration during pregnancy is prospectively associated with offspring (newborn) hypothalamic (HTH) microstructure and to explore the functional relevance of this association with respect to early-childhood body fat percentage (BF%).MethodsIn N = 94 healthy newborns (born mean 39.3 [SD 1.5] weeks gestation), diffusion-weighted magnetic resonance imaging was performed shortly after birth (25.3 [12.5] postnatal days), and a subgroup (n = 37) underwent a dual-energy x-ray absorptiometry scan in early childhood (4.7 [SD 0.7] years). Maternal sFFA concentration during pregnancy was quantified in fasting blood samples via liquid chromatography-mass spectrometry. Infant HTH microstructural integrity was characterized using mean diffusivity (MD). Multiple linear regression was used to test the association between maternal sFFA and HTH MD, accounting for newborn sex, age at scan, mean white matter MD, and image quality. Multiple linear regression models also tested the association between HTH MD and early-childhood BF%, accounting for breastfeeding status.ResultsMaternal sFFA during pregnancy accounted for 8.3% of the variation in newborn HTH MD (β-std = 0.25; p = 0.006). Furthermore, newborn HTH MD prospectively accounted for 15% of the variation in early-childhood BF% (β-std = 0.32; p = 0.019).ConclusionsThese findings suggest that maternal overnutrition during pregnancy may influence the development of the fetal hypothalamus, which, in turn, may have clinical relevance for childhood obesity risk.

The association between maternal immune activation (MIA) during pregnancy and risk for offspring neuropsychiatric disorders has been increasingly recognized over the past several years. Among the mechanistic pathways that have been described through which maternal inflammation during pregnancy may affect fetal brain development, the role of mitochondria has received little attention. In this review, the role of mitochondria as a potential mediator of the association between MIA during pregnancy and offspring brain development and risk for psychiatric disorders will be proposed. As a basis for this postulation, convergent evidence is presented supporting the obligatory role of mitochondria in brain development, the role of mitochondria as mediators and initiators of inflammatory processes, and evidence of mitochondrial dysfunction in preclinical MIA exposure models and human neurodevelopmental disorders. Elucidating the role of mitochondria as a potential mediator of MIA-induced alterations in brain development and neurodevelopmental disease risk may not only provide new insight into the pathophysiology of mental health disorders that have their origins in exposure to infection/immune activation during pregnancy but also offer new therapeutic targets.

ContextHispanic women are at elevated risk of gestational glucose intolerance and postpartum type 2 diabetes compared with non-Hispanic White women. Identification of potentially modifiable factors contributing to this trajectory of beta-cell dysfunction is warranted.ObjectiveWe aimed to determine the association between rate of gestational weight gain (rGWG) and glucose-insulin metabolism in Hispanic pregnant women with overweight and obesity.MethodsThis cross-sectional, observational study, conducted from 2018-2020 at the clinical research center at University of California, Irvine, included 33 nondiabetic Hispanic pregnant women at 28 to 30 weeks' gestation with pre-pregnancy body mass index (BMI) 25.0 to 34.9 kg/m2. Participants consumed a standardized liquid mixed meal after an overnight fast. Serial blood samples were collected at fasting and up to 2 hours postprandial. The glucose and insulin area under the curve (AUC), insulin sensitivity index (ISI) and insulin secretion sensitivity index (ISSI)-2 were computed.ResultsAverage rGWG (0.36 ± 0.22 kg/week) was classified as excessive in 60% of women. While rGWG was not associated with the glucose or insulin AUC or ISI, it accounted for 13.4% of the variance in ISSI-2 after controlling for covariates (maternal age, parity, and pre-pregnancy BMI); for each 1 unit increase in rGWG, ISSI-2 decreased 2.1 units (P = 0.015).ConclusionEven in the absence of gestational diabetes, rGWG was inversely associated with beta-cell function in a high-risk population of Hispanic pregnant women with overweight and obesity. Beta-cell decline is an established risk factor for transition to type 2 diabetes, and these cross-sectional findings highlight rGWG as a potentially modifiable contributor to this process.

BackgroundMaternal inflammation during pregnancy can alter offspring brain development and influence risk for disorders commonly accompanied by deficits in cognitive functioning. We therefore examined associations between maternal interleukin 6 (IL-6) concentrations during pregnancy and offspring cognitive ability and concurrent magnetic resonance imaging-based measures of brain anatomy in early childhood. We further examined newborn brain anatomy in secondary analyses to consider whether effects are evident soon after birth and to increase capacity to differentiate effects of pre- versus postnatal exposures.MethodsIL-6 concentrations were quantified in early (12.6 ± 2.8 weeks), mid (20.4 ± 1.5 weeks), and late (30.3 ± 1.3 weeks) pregnancy. Offspring nonverbal fluid intelligence (Gf) was assessed at 5.2 ± 0.6 years using a spatial reasoning task (Wechsler Preschool and Primary Scale of Intelligence-Matrix) (n = 49). T1-weighted magnetic resonance imaging scans were acquired at birth (n = 89, postmenstrual age = 42.9 ± 2.0 weeks) and in early childhood (n = 42, scan age = 5.1 ± 1.0 years). Regional cortical volumes were examined for a joint association between maternal IL-6 and offspring Gf performance.ResultsAverage maternal IL-6 concentration during pregnancy was inversely associated with offspring Gf performance after adjusting for socioeconomic status and the quality of the caregiving and learning environment (R2 = 13%; p = .02). Early-childhood pars triangularis volume was jointly associated with maternal IL-6 and childhood Gf (pcorrected < .001). An association also was observed between maternal IL-6 and newborn pars triangularis volume (R2 = 6%; p = .02).ConclusionsThese findings suggest that the origins of variation in child cognitive ability can, in part, trace back to maternal conditions during the intrauterine period of life and support the role of inflammation as an important component of this putative biological pathway.

High levels of early emotionality (of either negative or positive valence) are hypothesized to be important precursors to early psychopathology, with attention-deficit/hyperactivity disorder (ADHD) a prime early target. The positive and negative affect domains are prime examples of Research Domain Criteria (RDoC) concepts that may enrich a multilevel mechanistic map of psychopathology risk. Utilizing both variable-centered and person-centered approaches, the current study examined whether levels and trajectories of infant negative and positive emotionality, considered either in isolation or together, predicted children's ADHD symptoms at 4 to 8 years of age. In variable-centered analyses, higher levels of infant negative affect (at as early as 3 months of age) were associated with childhood ADHD symptoms. Findings for positive affect failed to reach statistical threshold. Results from person-centered trajectory analyses suggest that additional information is gained by simultaneously considering the trajectories of positive and negative emotionality. Specifically, only when exhibiting moderate, stable or low levels of positive affect did negative affect and its trajectory relate to child ADHD symptoms. These findings add to a growing literature that suggests that infant negative emotionality is a promising early life marker of future ADHD risk and suggest secondarily that moderation by positive affectivity warrants more consideration.

BackgroundThe distribution of adverse pregnancy, birth and subsequent child developmental and health outcomes in the U.S. is characterized by pronounced racial (particularly Black-white) disparities. In this context, chronic stress exposure represents a variable of considerable importance, and the immune/inflammatory system represents a leading candidate biological pathway of interest. Previous pregnancy studies examining racial disparities in immune processes have largely utilized circulating cytokine levels, and have yielded null or mixed results. Circulating cytokines primarily represent basal secretion and do not necessarily represent functional features of immune responsivity and regulation. Thus, in order to conduct a more in-depth characterization of racial differences in functional immune properties during pregnancy, we utilized an ex vivo stimulation assay, a dynamic measure of immune function at the cellular level, to investigate Black-white racial differences in in mid- and late-gestation in i) pro-inflammatory (IL-6) responsivity of leukocytes to antigen [lipopolysaccharide (LPS)] challenge, and ii) regulation (dampening) of this pro-inflammatory response by glucocorticoids.Method177 women (N = 42 Black (24%), n = 135 white (76%)) with a singleton, intrauterine pregnancy provided 20 mL venous blood in mid- (16.6 ± 2.4 wks) and late (33.3 ± 1.1 wks) pregnancy. Maternal pro-inflammatory responsivity of leukocytes was quantified by assessing the release of the pro-inflammatory cytokine IL-6 in response to LPS stimulation, and regulation of the pro-inflammatory response was quantified by assessing the suppression of the stimulated IL-6 response after co-incubation with progressively increasing levels of dexamethasone [10-7, 10-6, 10-5 M] (i.e., glucocorticoid receptor resistance (GRR)). A priori model covariates included maternal age, parity, SES (socioeconomic status), and pre-pregnancy BMI.ResultsMaternal pro-inflammatory responsivity (LPS-stimulated IL-6) and GRR increased significantly across mid- and late gestation (adjusted β = 0.157, p = 0.007; β = 0.627, p

ProblemThe immune system represents a leading pathway of interest in the pathophysiology of preterm birth. The majority of human clinical studies interrogating this pathway have utilized circulating immune biomarkers; however, these concentrations typically reflect only basal production but not key functional properties of the immune system, particularly variation in the pro-inflammatory response to antigen challenge and the regulation of this response. Thus, in this study, we utilized an ex vivo stimulation protocol that quantifies these processes, and we examined their prospective association with the gestation length and risk of preterm birth.Method of studyImmune responsiveness and regulation were assessed in 128 pregnant women in mid-gestation using an ex vivo stimulation protocol. Maternal pro-inflammatory responsivity of leukocytes was quantified by assessing the release of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β in response to antigen stimulation, and regulation of the pro-inflammatory response was quantified by assessing the suppression of stimulated cytokine response upon co-incubation with increasing dexamethasone concentrations (ie, glucocorticoid receptor resistance; GRR).ResultsHigher maternal GRR, indicating impaired regulation of the pro-inflammatory response, was significantly and independently associated with shorter gestational length (β = -0.42, p = .0091) and a 3.0-fold increase in risk for preterm birth (OR = 3.01, 95% CI = 1.17-7.70, p = .0218). Basal circulating IL-6 and TNF-α were not associated with either outcome.ConclusionThe association of maternal GRR with length of gestation and preterm birth risk suggests that the processes represented by this measure-maternal pro-inflammatory propensity and immune regulation-may provide further mechanistic insight into the pathophysiology of preterm birth.

Research on mechanisms underlying the phenomenon of developmental programming of health and disease has focused primarily on processes that are specific to cell types, organs and phenotypes of interest. However, the observation that exposure to suboptimal or adverse developmental conditions concomitantly influences a broad range of phenotypes suggests that these exposures may additionally exert effects through cellular mechanisms that are common, or shared, across these different cell and tissue types. It is in this context that we focus on cellular bioenergetics and propose that mitochondria, bioenergetic and signalling organelles, may represent a key cellular target underlying developmental programming. In this review, we discuss empirical findings in animals and humans that suggest that key structural and functional features of mitochondrial biology exhibit developmental plasticity, and are influenced by the same physiological pathways that are implicated in susceptibility for complex, common age-related disorders, and that these targets of mitochondrial developmental programming exhibit long-term temporal stability. We conclude by articulating current knowledge gaps and propose future research directions to bridge these gaps.

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.

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]

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]

Background: Lifetime physical activity (PA) is associated with decreased breast cancer (BC) risk; reports suggest that PA during adolescence contributes strongly to this relationship. PA lowers production of sex hormones, specifically estradiol, or decreases insulin resistance (IR), thereby lowering risk. Overweight Latina adolescents are insulin resistant and exhibit low levels of PA, potentially increasing their future BC risk. Methods: 37 obese Latina adolescents (15.7 ± 1.1 yrs) provided measures of PA using accelerometry; plasma follicular phase estradiol, sex-hormone binding globulin, total and free testosterone, dehydroepiandrosteronesulfate (DHEAS); IR using HOMA-IR; and body composition via DEXA. Partial correlations and stepwise linear regressions assessed cross-sectional relationships between sex hormones, IR and PA. Body composition, and age were included a priori as covariates. Results: Estradiol was negatively associated with accelerometer counts per minute (CPM; r = --0.4; P = .02), percent time spent in moderate PA (%MPA; r = -0.5; P = .006), and percent time in moderate or vigorous PA (%MVPA; r = -0.5; P = .007). DHEAS was positively associated with CPM (r = .4, P = .009), %MPA (r = .3, P = .04), and %MVPA (r = .3, P = .04). Other sex hormones and IR were not associated with PA measures. Conclusion: This study is the first to show that higher habitual PA was inversely associated with estradiol in obese adolescents. [ABSTRACT FROM AUTHOR]

Objective To investigate the impact of eating frequency on dietary intake, physical activity (PA), metabolic, and adiposity measures in minority youth. Methods This analysis included 185 overweight (≥85th BMI percentile) Hispanic and African-American youth (8-18 years) with the following cross-sectional measures: height, weight, BMI, dietary intake, body composition, metabolic parameters, PA, visceral adipose tissue (VAT), and subcutaneous adipose tissue. Each eating occasion (EO) was defined as ≥50 calories and ≥15 minutes from any previous EO. Participants were dichotomized based on EOs per 24-h into meal skippers <3 EO (MS; n = 27) or normal/frequent eaters ≥3 EO (NFE; n = 158). ANCOVAs were used to assess dietary intakes, metabolic outcomes, adiposity, and PA between eating frequency groups. Results MS compared to NFE consumed 24% fewer calories per 24-h ( P ≤ 0.01), 21% more calories per EO ( P ≤ 0.01), ate 40% less often ( P ≤ 0.01), had 18% higher triglycerides ( P = 0.03), and 26% more VAT ( P = 0.03), with no differences in PA. Conclusions Although meal skipping was associated with decreased energy intake, it was linked to increased calories per EO and higher triglycerides and VAT, which are strong indicators of deleterious metabolic profiles. These findings elucidate that meal skipping may be associated with increased VAT and related metabolic diseases in high-risk minority youth. [ABSTRACT FROM AUTHOR]

Objective Cortisol has been associated with preferential visceral adipose tissue (VAT) deposition; however, findings in humans are mixed, which may be clarified when diet is considered. Design and Methods Participants included 165 African-American and Latino, overweight adolescents (BMI% 97.2±3.2%, ages 13-18, 67% Latino, 66% female). Body composition was determined by dual energy X-ray absorptiometry, abdominal fat depots [VAT, subcutaneous (SAT)] by multiple-slice MRI, time-controlled serum sample to measure cortisol, and 2-day multi-pass 24-hour dietary recall. Linear regression analysis examined the cross-sectional relationship between cortisol, and the interaction of diet and cortisol on adiposity measures. Sex, race, age, and total body fat were a priori covariates. Results There was a significant interaction between cortisol and sugar (total and added) in the prediction of VAT ( Pinteraction ≤ 0.05). Amongst participants with high total or added-sugar intake, cortisol was significantly associated with VAT (ß = 0.031 P < 0.001; ß = 0.026 P < 0.001), with no relationship in low consumers of total or added-sugar. Conclusion Dietary sugar may play an important role in modifying the relationship between cortisol and VAT, such that cortisol is significantly associated with elevated VAT under conditions of high sugar intake. [ABSTRACT FROM AUTHOR]

Objective This study examined the contribution of subcutaneous adipose tissue (SAT) 11βHSD1 to obese African Americans' (AA) elevated metabolic risk, despite a protective obesity phenotype of reduced visceral adipose tissue (VAT) and hepatic fat fraction (HFF) relative to obese Hispanics with similar metabolic risk. Design and Methods Obese AA and Hispanic adults ( N = 36(16AA); BMI 35.2 ± 0.6 kg/m2, 18-25y) participated, with VAT, SAT, and HFF measured by MRI, SAT gene expression measured by HT-12 microarray and insulin sensitivity (SI), disposition index (DI) by IVGTT. Multiple linear regression examined relationships/interactions of ethnicity and 11βHSD1 expression on outcomes (covariates: age, sex, total fat mass), with standardized β (stβ) reported. Results SAT 11βHSD1 expression significantly associated with insulin parameters and this varied by ethnicity ( Pinteraction<0.1). In AA, 11βHSD1 negatively associated with SI (stβ = -0.58, P = 0.03), DI (stβ = −0.62, P = 0.03) and positively associated with fasting insulin (stβ = 0.54, P = 0.04), with no significant relationship in Hispanics. SAT 11βHSD1 associated with HFF in the combined sample (stβ = 0.42, P = 0.008), with no difference between ethnicites ( Pinteraction>0.1). After controlling for HFF, 11βHSD1 associations with metabolic risk in AA became nonsignificant. Conclusions These results suggested that in AA and not Hispanics, SAT 11βHSD1 is associated with SI and DI, and may be mediated by HFF. [ABSTRACT FROM AUTHOR]

This study assessed the changes in time spent in moderate to vigorous physical activity (MVPA) on fat depots, insulin action, and inflammation. Longitudinal data were generated from 66 Hispanic adolescents (15.6±1.1 yr; BMI percentile 97.1±3.0) who participated in a 16-wk nutrition or nutrition+exercise intervention. There were no effects of the intervention on PA, but there were inter-individual changes in PA. For purposes of this analysis, all intervention groups were combined to assess how changes in PA during 16 wk affected changes in adiposity, insulin action, and markers of inflammation. MVPA was assessed by 7-day accelerometry, total body fat via DXA, liver fat by MRI, and insulin, glucose and HOMA-IR via a fasting blood draw. A repeated measures ANCOVA was used to assess the effect of MVPA on fat depots, insulin action, and inflammatory markers. Sixty-two percent of participants increased MVPA (mean increase, 19.7±16.5 min/day) and 38% decreased MVPA (mean decrease, 10.7±10.1 min/day). Those who increased MVPA by as little as 20 min per day over 16 wk, compared to those who decreased MVPA, had significant reductions in liver fat (-13% vs. +3%; P=0.01), leptin levels (-18% vs. +4%; P=0.02), and fasting insulin (-23% vs. +5%; P=0.05). These findings indicate that a modest increase in MVPA can improve metabolic health in sedentary overweight Hispanic adolescents. [ABSTRACT FROM AUTHOR]

Our objective was to interrogate mesenchymal stem cell (MSC) lipid metabolism and gestational exposures beyond maternal body mass that may contribute to child obesity risk. MSCs were cultured from term infants of mothers with obesity (n = 16) or normal weight (n = 15). In MSCs undergoing myogenesis in vitro, we used lipidomics to distinguish phenotypes by unbiased cluster analysis and lipid challenge (24-hour excess fatty acid [24hFA]). We measured MSC AMP-activated protein kinase (AMPK) activity and fatty acid oxidation (FAO), and a composite index of maternal glucose, insulin, triglycerides, free fatty acids, TNF-α, and high-density lipoprotein and total cholesterol in fasting blood from mid and late gestation (~17 and ~27 weeks, respectively). We measured child adiposity at birth (n = 29), 4-6 months (n = 29), and 4-6 years (n = 13). Three MSC clusters were distinguished by triacylglycerol (TAG) stores, with greatest TAGs in Cluster 2. All clusters increased acylcarnitines and TAGs with 24hFA, although Cluster 2 was more pronounced and corresponded to AMPK activation and FAO. Maternal metabolic markers predicted MSC clusters and child adiposity at 4-6 years (both highest in Cluster 3). Our data support the notion that MSC phenotypes are predicted by comprehensive maternal metabolic milieu exposures, independent of maternal BMI, and suggest utility as an at-birth predictor for child adiposity, although validation with larger longitudinal samples is warranted.