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Context Maternal prepregnancy body mass index (BMI) has a strong influence on gestational metabolism, but detailed metabolic alterations are unknown. Objective First, to examine the associations of maternal prepregnancy BMI with maternal early-pregnancy metabolite alterations. Second, to identify an early-pregnancy metabolite profile associated with birthweight in women with a higher prepregnancy BMI that improved prediction of birthweight compared to glucose and lipid concentrations. Design, Setting, and Participants Prepregnancy BMI was obtained in a subgroup of 682 Dutch pregnant women from the Generation R prospective cohort study. Main Outcome Measures Maternal nonfasting targeted amino acids, nonesterified fatty acid, phospholipid, and carnitine concentrations measured in blood serum at mean gestational age of 12.8 weeks. Birthweight was obtained from medical records. Results A higher prepregnancy BMI was associated with 72 altered amino acids, nonesterified fatty acid, phospholipid and carnitine concentrations, and 6 metabolite ratios reflecting Krebs cycle, inflammatory, oxidative stress, and lipid metabolic processes (P-values Conclusions A higher maternal prepregnancy BMI was associated with altered maternal early-pregnancy amino acids, nonesterified fatty acids, phospholipids, and carnitines. Using these metabolites, we identified a maternal metabolite profile that improved prediction of birthweight in women with a higher prepregnancy BMI compared to glucose and lipid concentrations.

Exclusive enteral nutrition induces remission, improves bone health and growth in paediatric Crohn's disease (CD) patients, but is highly demanding for patients. We investigated efficacy of partial enteral nutrition (PEN) on bone health, growth and course in CD patients and assessed microbial and metabolic changes induced by PEN.We performed a two centre, non-randomized controlled intervention study in quiescent CD patients aged19 years. Patients in intervention group received a liquid formula providing ~25% of daily energy for one year. At baseline, after 3, 6, 9 and 12 months, we collected data on bone, muscle (peripheral quantitative computertomography), anthropometry, disease activity (weighted paediatric CD activity index), metabolomic profile (liquid chromatography mass spectrometry), and faecal microbiome (16S rRNA gene sequencing).Of 41 CD patients, 22 received the intervention (PEN) (mean age 15.0 ± 1.9 years, 50% male), 19 served as controls (non-PEN) (12.8 ± 3.1 years, 58% male). At baseline, mean bone quality was comparable to reference population with no improvement during the intervention. Relapse rate was low (8/41, PEN 4/22 and non-PEN 4/19, ns). PEN was not associated with microbiota community changes (beta diversity) but significantly reduced species diversity. Metabolome changes with upregulation of phosphatidylcholines in PEN patients are likely related to lipid and fatty acid composition of the formula. PEN significantly improved growth in a subgroup with Tanner stage 1-3.In our cohort of paediatric CD patients, PEN did not affect bone health but improved growth in patients with a potential to grow.

Today, awareness has been raised regarding high consumption of n-6 polyunsaturated fatty acids (PUFA) in western diets. A comprehensive analysis of total and individual postprandial fatty acids profiles would provide insights into metabolic turnover and related health effects. After an overnight fast, 9 healthy adults consumed a mixed meal comprising 97 g carbohydrate and 45 g fat, of which 26.4 g was linoleic acid (LA). Nonesterified fatty acids (NEFA), phospholipid fatty acids (PL-FA) and triacylglycerol fatty acids (TG-FA) were monitored in plasma samples, at baseline and hourly over a 7-h postprandial period. Total TG-FA concentration peaked at 2 h after the meal and steadily decreased thereafter. LA from TG18:2n-6 and behenic acid from TG22:0 showed the highest response among TG-FA, with a biphasic response detected for the former. PL-FA exhibited no change. Total NEFA initially decreased to nadir at 1 h, then increased to peak at 7 h. The individual NEFA showed the same response curve except LA and some very-long-chain saturated fatty acids (VLCSFA, ≥20 carbon chain length) that markedly increased shortly after the meal intake. The similarities and dissimilarities in lipid profiles between study subjects at different time points were visualized using nonmetric multi-dimensional scaling. Overall, the results indicate that postprandial levels of LA and VLCSFA, either as NEFA or TG, were most affected by the test meal, which might provide an explanation for the health effects of this dietary lifestyle characterized by high intake of mixed meals rich in n-6 PUFA.

A high dairy protein intake in infancy, maternal pre-pregnancy BMI, and delivery mode are documented early programming factors that modulate the later risk of obesity and other health outcomes, but the mechanisms of action are not understood. The Childhood Obesity Project is a European multicenter, double-blind, randomized clinical trial that enrolled healthy infants. Participating infants were either breastfed (BF) or randomized to receive higher (HP) or lower protein (LP) content formula in the first year of life. At the ages 5.5 years (n = 276) and 8 years (n = 232), we determined plasma metabolites by liquid chromatography tandem-mass-spectrometry of which 226 and 185 passed quality control at 5.5 years and 8 years, respectively. We assessed the effects of infant feeding, maternal pre-pregnancy BMI, smoking in pregnancy, delivery mode, parity, birth weight and length, and weight gain (0–24 months) on the metabolome at 5.5 and 8 years. At 5.5 years, plasma alpha-ketoglutarate and the acylcarnitine/BCAA ratios tended to be higher in the HP than in the LP group, but no metabolite reached statistical significance (Pbonferroni>0.09). There were no group differences at 8 years. Quantification of the impact of early programming factors revealed that the intervention group explained 0.6% of metabolome variance at both time points. Except for country of residence that explained 16% and 12% at 5.5 years and 8 years, respectively, none of the other factors explained considerably more variance than expected by chance. Plasma metabolome was largely unaffected by feeding choice and other early programming factors and we could not prove the existence of a long term programming effect of the plasma metabolome.

Elective cesarean section (CS) was related to long-term adverse health effects in the offspring, but little is known about underlying mechanisms. Our study investigates the metabolic changes in both maternal and cord blood associated with CS in comparison to vaginal delivery (VD) to explore potential causal pathways. Samples obtained from PREOBE study participants were subjected to LC–MS/MS-targeted metabolomics comprising > 200 metabolites. Elective CS showed an impact on both maternal and cord blood metabolomes. In maternal blood, the CS group showed lower levels of phospholipids (PL), principally ether-linked phosphatidylcholines (aaPC), pyruvic acid, branched chain keto-acids (BCKA), and other gluconeogenic substrates, but since the CS group showed different HDL levels in comparison to the VD group, we could not exclude contribution of the latter in the findings. In cord blood, the most remarkable finding in the CS group was the high levels of Cys; conversely, the lower levels of non-esterified fatty acids (NEFA), some tricarboxylic acid (TCA) cycle metabolites, gluconeogenic substrates, markers of β-oxidation, and the sum of hexoses were lower in CS-born babies in addition to tendentially lower levels of PL. We speculate that lower levels of maternal and fetal corticosteroids in CS, due to less stressful condition, cause metabolic perturbations at birth initiating future negative health outcomes. This further supports the early programming hypothesis.

Maternal obesity is associated with adverse outcomes. Placental lipid droplets (LD) have been implicated in maternal-fetal lipid transfer but it is not known whether placental LD fat composition is modifiable. We evaluated the effects of a diet and physical activity intervention in obese pregnant women compared to routine antenatal care (UPBEAT study) on placental LD composition. LD were isolated by ultracentrifugation. Total FAs and phospholipids (phosphatidylcholines, PCs; sphingomyelins, SMs and lyso-phosphatidylcholines, Lyso-PCs) were analyzed by LC-MS/MS. Placenta MFSD2a expression was assessed by western blot. Placental LDs from obese women were comprised of predominantly saturated and monounsaturated FAs. TG and Chol composition was similar between intervention (n = 20) and control (n = 23) groups. PCs containing dihomo-ɣ-linolenic acid in LD were positively associated with gestational weight gain (P

Human milk lipids are essential for infant health. However, little is known about the relationship between total milk fatty acid (FA) composition and polar lipid species composition. Therefore, we aimed to characterize the relationship between the FA and polar lipid species composition in human milk, with a focus on differences between milk with higher or lower milk fat content. From the Norwegian Human Milk Study (HUMIS, 2002–2009), a subset of 664 milk samples were analyzed for FA and polar lipid composition. Milk samples did not differ in major FA, phosphatidylcholine, or sphingomyelin species percentages between the highest and lowest quartiles of total FA concentration. However, milk in the highest FA quartile had a lower phospholipid-to-total-FA ratio and a lower sphingomyelin-to-phosphatidylcholine ratio than the lowest quartile. The only FAs associated with total phosphatidylcholine or sphingomyelin were behenic and tridecanoic acids, respectively. Milk FA and phosphatidylcholine and sphingomyelin species containing these FAs showed modest correlations. Associations of arachidonic and docosahexaenoic acids with percentages of phosphatidylcholine species carrying these FAs support the conclusion that the availability of these FAs limits the synthesis of phospholipid species containing them.

Context Offspring exposed in utero to maternal obesity have an increased risk of later obesity; however, the underlying mechanisms remain unknown. Objective To assess the effect of an antenatal lifestyle intervention in obese women on the offspring’s cord blood metabolic profile and to examine associations of the cord blood metabolic profile with maternal clinical characteristics and offspring anthropometry at birth and age 6 months. Design Randomized controlled trial and cohort study. Setting The UK Pregnancies Better Eating and Activity Trial. Participants Three hundred forty-four mother-offspring pairs. Intervention Antenatal behavioral lifestyle (diet and physical activity) intervention. Main Outcome Measures Targeted cord blood metabolic profile, including candidate hormone and metabolomic analyses. Results The lifestyle intervention was not associated with change in the cord blood metabolic profile. Higher maternal glycemia, specifically fasting glucose at 28 weeks gestation, had a linear association with higher cord blood concentrations of lysophosphatidylcholines (LPCs) 16.1 (β = 0.65; 95% confidence interval: 0.03 to 0.10) and 18.1 (0.52; 0.02 to 0.80), independent of the lifestyle intervention. A principal component of cord blood phosphatidylcholines and LPCs was associated with infant z scores of birth weight (0.04; 0.02 to 0.07) and weight at age 6 months (0.05; 0.00 to 0.10). Cord blood insulin growth factor (IGF)-1 and adiponectin concentrations were positively associated with infant weight z score at birth and at 6 months. Conclusions Concentrations of LPCs and IGF-1 in cord blood are related to infant weight. These findings support the hypothesis that susceptibility to childhood obesity may be programmed in utero, but further investigation is required to establish whether these associations are causally related.

Objective: Noncommunicable diseases such as obesity have become a serious global public health epidemic. This study aimed to examine whether there was an association between early life factors (with a special focus on breastfeeding) BMI, waist circumference, and the metabolome in offspring at 20 years. Methods: Data from the Western Australian Pregnancy Cohort (Raine) Study were analyzed using 1,024 plasma samples from the 20-year follow-up. A liquid chromatography, tandem mass spectrometry metabolomics approach was used to measure metabolites. Multiple linear regression models were performed and adjusted for relevant confounders. Inverse probability weighting was used to adjust the 20-year data for differences in socioeconomic variables between participants and nonparticipants since the commencement of the study. Results: An inverse association between breastfeeding and BMI or waist circumference at 20 years was lost after adjusting for parental prepregnancy BMI and maternal smoking during pregnancy. There was no significant effect of breastfeeding on metabolite concentrations at 20 years. Conclusions: Although other studies have shown associations between breastfeeding, obesity, and metabolite concentrations at younger ages, this was not evident in our study in young adults. We found no association of metabolites previously associated with waist circumference at 20 years and breastfeeding in early life.

Food intake is essential for maintaining homeostasis, which is necessary for survival in all species. However, food intake also impacts multiple biochemical processes that influence our behavior. Here, we investigate the causal relationship between macronutrient composition, its bodily biochemical impact, and a modulation of human social decision making. Across two studies, we show that breakfasts with different macronutrient compositions modulated human social behavior. Breakfasts with a high-carbohydrate/protein ratio increased social punishment behavior in response to norm violations compared with that in response to a low carbohydrate/protein meal. We show that these macronutrient-induced behavioral changes in social decision making are causally related to a lowering of plasma tyrosine levels. The findings indicate that, in a limited sense, "we are what we eat" and provide a perspective on a nutrition-driven modulation of cognition. The findings have implications for education, economics, and public policy, and emphasize that the importance of a balanced diet may extend beyond the mere physical benefits of adequate nutrition.

(1) Background: Little is known on impacts of ready-to-use therapeutic food (RUTF) treatment on lipid metabolism in children with severe acute malnutrition (SAM). (2) Methods: We analyzed glycerophospholipid fatty acids (FA) and polar lipids in plasma of 41 Pakistani children with SAM before and after 3 months of RUTF treatment using gas chromatography and flow-injection analysis tandem mass spectrometry, respectively. Statistical analysis was performed using univariate, multivariate tests and evaluated for the impact of age, sex, breastfeeding status, hemoglobin, and anthropometry. (3) Results: Essential fatty acid (EFA) depletion at baseline was corrected by RUTF treatment which increased EFA. In addition, long-chain polyunsaturated fatty acids (LC-PUFA) and the ratio of arachidonic acid (AA)/linoleic acid increased reflecting greater EFA conversion to LC-PUFA, whereas Mead acid/AA decreased. Among phospholipids, lysophosphatidylcholines (lyso.PC) were most impacted by treatment, in particular, saturated lyso.PC decreased. Higher child age and breastfeeding were associated with great decrease in total saturated FA (&Sigma, SFA) and lesser decrease in monounsaturated FA and total phosphatidylcholines (&Sigma, PC). Conclusions: RUTF treatment improves EFA deficiency in SAM, appears to enhance EFA conversion to biologically active LC-PUFA, and reduces lipolysis reflected in decreased &Sigma, SFA and saturated lyso.PC. Child age and breastfeeding modify treatment-induced changes in &Sigma, SFA and &Sigma, PC.

The physiology of how prelabour caesarean section (PCS) and induction of labour (IOL) in comparison to spontaneous vaginal delivery (SVD) has not been fully clarified yet. We measured 201 cord blood (CB) phospholipids and energy metabolites via LC/MS-MS in 109 newborns from the ROLO Kids study; metabolites were compared across the three parturition groups via linear mixed models with correction for multiple testing. In comparison to SVD, PCS babies had lower non-esterified fatty acids (NEFA), including sum of NEFA (p

Childhood obesity prevalence is rising in countries worldwide. A variety of etiologic factors contribute to childhood obesity but little is known about underlying biochemical mechanisms. We performed an individual participant meta-analysis including 1,020 pre-pubertal children from three European studies and investigated the associations of 285 metabolites measured by LC/MS-MS with BMI z-score, height, weight, HOMA, and lipoprotein concentrations. Seventeen metabolites were significantly associated with BMI z-score. Sphingomyelin (SM) 32:2 showed the strongest association with BMI z-score (P = 4.68 × 10 −23 ) and was also closely related to weight, and less strongly to height and LDL, but not to HOMA. Mass spectrometric analyses identified SM 32:2 as myristic acid containing SM d18:2/14:0. Thirty-five metabolites were significantly associated to HOMA index. Alanine showed the strongest positive association with HOMA (P = 9.77 × 10 −16 ), while acylcarnitines and non-esterified fatty acids were negatively associated with HOMA. SM d18:2/14:0 is a powerful marker for molecular changes in childhood obesity. Tracing back the origin of SM 32:2 to dietary source in combination with genetic predisposition will path the way for early intervention programs. Metabolic profiling might facilitate risk prediction and personalized interventions in overweight children., SCOPUS: ar.j, info:eu-repo/semantics/published

Lymphocytes circulate through lymph nodes (LN) in search for antigen in what is believed to be a continuous process. Here, we show that lymphocyte migration through lymph nodes and lymph occurred in a non-continuous, circadian manner. Lymphocyte homing to lymph nodes peaked at night onset, with cells leaving the tissue during the day. This resulted in strong oscillations in lymphocyte cellularity in lymph nodes and efferent lymphatic fluid. Using lineage-specific genetic ablation of circadian clock function, we demonstrated this to be dependent on rhythmic expression of promigratory factors on lymphocytes. Dendritic cell numbers peaked in phase with lymphocytes, with diurnal oscillations being present in disease severity after immunization to induce experimental autoimmune encephalomyelitis (EAE). These rhythms were abolished by genetic disruption of T cell clocks, demonstrating a circadian regulation of lymphocyte migration through lymph nodes with time-of-day of immunization being critical for adaptive immune responses weeks later.

Background and aims Moderately reduced maternal nutrient availability during pregnancy has adverse effects on the fetuses' growth and metabolism during and after pregnancy. The aim of this study was to explore effects of maternal nutrition restriction (MNR) on key metabolites of the fetal energy metabolism, particularly amino acids (AA), nonesterified fatty acids (NEFA), acylcarnitines and phospholipids. These effects may reflect mechanisms relating MNR to later adverse outcomes. Methods and results Plasma and liver samples of fetal baboons, whose mothers were fed ad libitum (CTR) or MNR (70% of CTR), were collected at 0.5 and 0.9 gestation (G – term 184 days). Metabolites were measured with liquid chromatography coupled to mass spectrometry. In both, CTR and MNR, fetal metabolic profiles changed markedly between 0.5G and 0.9G. Fetal liver glucose concentrations were strongly increased. Hepatic levels of NEFA, sphingomyelins, and alkyl-linked phospholipids increased while plasma NEFA and acyl-linked phospholipids levels decreased with progression of gestation. At 0.5G, MNR fetal plasma levels of short- and medium-chain acylcarnitines were elevated, but did no longer differ between groups at 0.9G. At 0.9G, plasma levels of methionine and threonine as well as hepatic threonine levels were lower in the MNR group. Conclusion Small differences in the concentrations of plasma and liver metabolites between MNR and CTR fetuses reflect good adaptation to MNR. Fetal liver metabolic profiles changed markedly between the two gestation stages, reflecting enhanced liver glucose and lipid levels with advancing gestation. Decreased concentrations of AA suggest an up-regulation of gluconeogenesis in MNR.

Elevated prepregnancy body mass index (pBMI) and excess gestational weight gain (GWG) constitute important prenatal exposures that may program adiposity and disease risk in offspring. The objective of this study is to investigate the influence of pBMI and GWG on the maternal metabolomic profile across pregnancy, and to identify associations with birth weight. This is a longitudinal prospective study of 167 nondiabetic women carrying a singleton pregnancy. Women were recruited between March 2011 and December 2013 from antenatal clinics affiliated to the University of California, Irvine, Medical Center. Seven women were excluded from analyses because of a diagnosis of diabetes during pregnancy. A total of 254 plasma metabolites known to be related to obesity in nonpregnant populations were analyzed in each trimester using targeted metabolomics. The effects of pBMI and GWG on metabolites were tested through linear regression and principle component analysis, adjusting for maternal sociodemographic factors, diet, and insulin resistance. A Bonferroni correction was applied for multiple comparison testing. pBMI was significantly associated with 40 metabolites. Nonesterified fatty acids (NEFA) showed a strong positive association with pBMI, with specificity for mono-unsaturated and omega-6 NEFA. Among phospholipids, sphingomyelins with two double bonds and phosphatidylcholines containing 20:3 fatty acid chain, indicative of omega-6 NEFA, were positively associated with pBMI. Few associations between GWG, quality and quantity of the diet, insulin resistance and the maternal metabolome throughout gestation were detected. NEFA levels in the first and, to a lesser degree, in the second trimester were positively associated with birth weight percentiles. Preconception obesity appears to have a stronger influence on the maternal metabolic milieu than gestational factors such as weight gain, dietary intake and insulin resistance, highlighting the critical importance of preconception health. NEFA in general, as well as monounsaturated and omega-6 fatty acid species in particular, represent key metabolites for a potential mechanism of intergenerational transfer of obesity risk.

Obesity and related diseases have become a global public health burden. Identifying biomarkers will lead to a better understanding of the underlying mechanisms associated with obesity and the pathways leading to insulin resistance (IR) and diabetes.This study aimed to identify the lipidomic biomarkers associated with obesity and IR using plasma samples from a population-based cohort of young adults.The Western Australian Pregnancy Cohort (Raine) study enrolled 2900 pregnant women from 1989 to 1991. The 20-year follow-up was conducted between March 2010 and April 2012. Participants and Samples: Plasma samples from 1176 subjects aged 20 years were analyzed using mass spectrometry-based metabolomics.Associations of analytes with markers of obesity and IR including body mass index, waist circumference, homeostasis model assessment (HOMA-IR), and insulin were examined. Analyses were stratified by body mass index and adjusted for lifestyle and other factors.Waist circumference was positively associated with seven sphingomyelins and five diacylphosphatidylcholines and negatively associated with two lysophosphatidylcholines. HOMA-IR was negatively associated with two diacylphosphatidylcholines and positively with one lysophosphatidylcholine and one diacylphosphatidylcholine. No significant association was found in the obese/overweight group of the HOMA-IR model. In the normal-weight group, one lysophosphatidylcholine was increased.A possible discriminative effect of sphingomyelins, particularly those with two double bonds, and lysophosphatidylcholines was identified between subjects with normal weight and obesity independent of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol concentrations. Our results suggest weight status-dependent mechanisms for the development of IR with lysophosphatidylcholine C14:0 as a key metabolite in nonobese IR.

Offspring of mothers suffering from obesity and/or gestational diabetes mellitus (GDM) were reported to be at risk of higher birth weight (BW), later obesity and diabetes. We hypothesize that infant anthropometry changes related to maternal pathological status are due to dysregulated infant metabolism. First, we inspected differences in BMI z-scores (z-BMI) between three infant groups: born to normal weight (NW; n = 49), overweight/obese (OV/OB; n = 40) and GDM mothers (n = 27) at birth and 1 year. Then, we inspected associations between cord blood metabolites and 1-year Δ z-BMI in the three infant groups at birth and 1 year. No statistically significant difference was detected in z-BMI between the study groups at birth; however, GDM was associated with heavier infants at 1 year. Regarding the associations between the metabolites and z-BMI, phospholipids, especially those containing polyunsaturated fatty acids, were the species most impacted by the maternal metabolic status, since numerous phosphatidylcholines–PUFA were positively associated with z-BMI in NW but negatively in OV/OB and GDM groups at birth. Conversely, the sum of lysophosphatidylcholines was only positively associated with z-BMI in NW at birth but of no relation in the other two groups. At 1 year, most of the associations seen at birth were reversed in NW and lost in OV/OB and GDM groups. In the NW group, PC-PUFA were found to be negatively associated with Δ z-BMI at 1 year in addition to some medium-chain acylcarnitines, tricarboxylic acid metabolites, Asp and Asn-to-Asp ratio. In OV/OB and GDM groups, the non-esterified fatty acid (NEFA26:0) and His correlated with Δ z-BMI at 1 year in negative and positive directions, respectively. GDM was associated with overweight in offspring at 1 year, independent of the BW with lack of evidence on existing correlation of this finding with metabolic alterations detected in cord blood metabolome. Associations were found between cord blood metabolites and infant anthropometry at birth and were influenced by maternal OB and GDM. However, an extension of the findings monitored at birth among the three groups was not detected longitudinally showing a lack of predictive power of cord blood metabolome for later development at least 1 year.

This project received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 633595

Maternal obesity and gestational diabetes mellitus (GDM) were frequently reported to be risk factors for obesity and diabetes in offspring. Our goal was to study the impact of maternal prepregnancy BMI (pBMI) and GDM on both maternal and cord blood metabolic profiles. We used LC–MS/MS to measure 201 metabolites comprising phospholipids (PL), amino acids, non-esterified fatty acids (NEFA), organic acids, acyl carnitines (AC), and Krebs cycle metabolites in maternal plasma at delivery and cord plasma obtained from 325 PREOBE study participants. Several metabolites were associated with pBMI/GDM in both maternal and cord blood (p

Summary Background Elevated stearoyl-CoA desaturase 1 (SCD-1) activity showed associations with obesity in cross-sectional studies. In non-pregnant populations, nutrition regulates SCD-1 transcription and activity. Objective To investigate the longitudinal associations of maternal and fetal SCD-1 activity markers with infant anthropometry up to 2 years of age, and to explore how selected dietary intakes modulate SCD-1 activity in pregnancy. Methods As a secondary analysis from the ROLO intervention study, which was conducted in a population at risk for macrosomia, non-esterified fatty acids (NEFA) from maternal plasma at 13 and 28 weeks' gestation and in cord blood were measured via liquid-chromatography-mass-spectrometry. Fatty acid ratios 18:1/18:0 and 16:1/16:0 were used as markers for SCD-1 activity (‘desaturation indices’, DIs). Relationships of DIs with infant anthropometry up to 2 years of age and maternal dietary parameters during pregnancy were investigated using adjusted linear regression models and p-values correction for multiple testing. Results 18:1/18:0, but not 16:1/16:0, was associated with measures of infant anthropometry at birth (maternal and fetal markers) and up to 2 years of age (maternal markers only). Dietary intakes did not show strong associations with 18:1/18:0, but 16:1/16:0 was associated with absolute and relative dietary intakes. Conclusions In a population at risk for macrosomia, maternal SCD-1 activity measured via 18:1/18:0 was involved in the fetal programming of infant obesity, but could not be substantially modulated by short-term diet in pregnancy. Clinical trial registration ISRCTN Registration number: ISRCTN54392969 ( http://www.isrctn.com/ISRCTN54392969 ).

Growth characteristics during periods of early developmental plasticity are linked with later health outcomes and with disease risks. Infant growth is modulated by genetic and exogenous factors including nutrition. We try to explore their underlying mechanisms using targeted metabolomic profiling of small molecules in biological samples using high-performance liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) to quantify hundreds of molecules in small biosamples, e.g., 50 µL plasma. In the large German LISA birth cohort study, cord blood lysophosphatidylcholines and fatty acids were closely associated with infant birth weight, with a nonsignificant trend towards an association with infant weight gain and later BMI. Studies in infants randomized to different protein intakes in the European CHOP Study show conventional high protein intakes to markedly increase plasma-indispensable amino acids (AA), particularly branched-chain AA (BCAA), while exceeding the infant's capacity of BCAA breakdown, and an increase in the dispensable AA tyrosine previously associated with insulin resistance. In a path model analysis of the relationship of infant plasma AA, growth factors, and infant growth, AA were generally found to induce a stronger response of insulin than IGF-I although effects of individual AA were very different. We conclude that targeted improvement in nutrient supply in pregnancy and infancy may offer large opportunities for promoting desirable child growth patterns and long-term health.

Background & aims Breastfeeding is beneficial for mothers and infants. Underlying mechanisms and biochemical mediators thus need to be investigated to develop and support improved infant nutrition practices promoting the child health. We analysed the relation between maternal breast milk composition and infant metabolism. Methods 196 pairs of mothers and infants from a European research project (PreventCD) were studied. Maternal milk samples collected at month 1 and month 4 after birth were analysed for macronutrient classes, hormone, and fatty acid (FA) content. Phospholipids, acylcarnitines, and amino acids were measured in serum samples of 4-month old infants. Associations between milk components and infant metabolites were analysed with spearman correlation and linear mixed effect models (LME). P-values were corrected for multiple testing (P-LME). Results Month 1 milk protein content was strongly associated with infant serum lyso-phosphatidylcholine (LPC) 14: 0 (P-LME = 0.009). Month 1 milk insulin was associated to infant acetylcarnitine (P-LME = 0.01). There were no associations between milk protein content and serum amino acids and milk total fat content and serum polar lipids. Middle- and odd-chain FA% in breast milk at both ages were significantly related to serum LPC and sphingomyelins (SM) species in infant serum (all P-LME < 0.05), while FA% 20: 5n(-3) and 22: 6n(-3) percentages were significantly associated to serum LPC 22:6 (P-LME = 1.91x10(-4)/7.93x10(-5)) in milk only at month 4. Other polyunsaturated fatty acids and hormones in milk showed only weak associations with infant serum metabolites. Conclusions Infant serum LPC are influenced by breast milk FA composition and, intriguingly, milk protein content in early but not late lactation. LPC 14:0, previously found positively associated with obesity risk, was the serum metabolite which was the most strongly associated to milk protein content. Thus, LPC 14:0 might be a key metabolite not only reflecting milk protein intake in infants, but also relating high protein content in milk or infant formula to childhood obesity risk.

SCOPE The fetal programming paradigm posits that the origins of obesity can be traced, in part, to the intrauterine period of life. However, the mechanisms underlying fetal programming are not well understood, and few studies have measured offspring adiposity in the neonatal period. The aim of this study is to identify maternal metabolites, and their determinants, that are associated with neonatal adiposity. METHODS AND RESULTS A targeted metabolomics approach is applied to analyze plasma samples collected across gestation from a well-characterized cohort of 253 pregnant women participating in a prospective study at the University of California, Irvine. Whole-body dual X-ray absorptiometry (DXA) imaging of body composition is obtained in N = 121 newborns. Statistical models are adjusted for potential confounders and multiple testing. The authors identify six alkyl-linked phosphatidylcholines (PCae), containing fatty acid 20:4, that are significantly and negatively associated with neonatal body fat percentage. Factors indicating higher socioeconomic status, non-Hispanic ethnicity, and higher nonesterified fatty acid percentages are positively associated with these PCae. CONCLUSIONS The polyunsaturated fatty acid 20:4 contained in PCae may exert a beneficial effect with respect to future propensity for obesity development. Prepregnancy and early pregnancy factors are determinants of these PCae, highlighting the importance of addressing preconceptional conditions for fetal programming of newborn adiposity.

A particular subgroup of obese adults, considered as metabolically healthy obese (MHO), has a reduced risk of metabolic complications. However, the molecular basis contributing to this healthy phenotype remains unclear. The objective of this work was to identify obesity-related metabolite patterns differed between MHO and metabolically unhealthy obese (MUHO) groups and examine whether these patterns are associated with the development of cardiometabolic disorders in a sample of Iranian adult population aged 18-50 years. Valid metabolites were defined as metabolites that passed the quality control analysis of the study. In this case-control study, 104 valid metabolites of 107 MHO and 100 MUHO patients were separately compared to those of 78 normal-weight metabolically healthy (NWMH) adults. Multivariable linear regression was used to investigate all potential relations in the study. A targeted metabolomic approach using liquid chromatography coupled to triple quadrupole mass spectrometry was employed to profile plasma metabolites. The study revealed that, after Bonferroni correction, branched-chain amino-acids, tyrosine, glutamic acid, diacyl-phosphatidylcholines C32:1 and C38:3 were directly and acyl-carnitine C18:2, acyl-lysophosphatidylcholines C18:1 and C18:2, and alkyl-lysophosphatidylcholines C18.0 were inversely associated with MHO phenotype. The same patterns were observed in MUHO patients except for the acyl-carnitine and lysophosphatidylcholine profiles where acyl-carnitine C3:0 and acyl-lysophosphatidylcholine C16:1 were higher and acyl-lysophosphatidylcholines C18:1, C18:2 were lower in this phenotype. Furthermore, proline, and diacyl-phosphatidylcholines C32:2 and C34:2 were directly and serine, asparagines, and acyl-alkyl-phosphatidylcholine C34:3 were negatively linked to MUHO group. Factors composed of amino acids were directly and those containing lysophosphatidylcholines were inversely related to cardiometabolic biomarkers in both phenotypes. Interestingly, the diacyl-phosphatidylcholines-containing factor was directly associated with cardiometabolic disorders in the MUHO group. A particular pattern of amino acids and choline-containing phospholipids may aid in the identification of metabolic health among obese patients.

Background/aim Maternal diet before and during pregnancy can contribute to an offspring’s mental and physical health. Moreover, maternal food intake can modulate overweight or obesity issues and the development of adverse metabolic related outcomes/diseases later in life. Thus, this study aims to evaluate the association of maternal diet during pregnancy with the metabolite profile in cord blood. Methods An analysis of maternal diet was conducted to study diet variability and patterns and to derive a set of factors, which would then be used in association analyses with cord blood metabolites. These analyses were done in the German LISA birth cohort (n~650 with information available on maternal diet and cord blood metabolome). Maternal food intake during the last 4 weeks of pregnancy was assessed by using a semi-quantitative food-frequency questionnaire (FFQ) comprising of 45 food items administered shortly after childbirth. Glycerophospholipid fatty acids (GPL-FA), polar lipids, non-esterified fatty acids (NEFA), and amino acids were analysed with gas chromatography (GPL-FA) or targeted liquid chromatography-tandem mass spectrometry based metabolomics platforms. Results Factor analysis shows ten factors accounting for 28% of the total variance that could be classified into different dietary patterns. Some of the categories are ‘meat-eaters’, ‘healthy/vegetable-eaters’ and ‘sweet-eaters’ additionally a seasonal pattern in some maternal diets has emerged. A regression score is used in an effort to provide the highest correlations between the factor and its score. Finally, a linear regression for association with cord blood metabolites, adjusted for relevant confounders, will complete the investigation. Conclusion A good classification of the different maternal diets has been identified which allows for the characterisation of associations between maternal diet and cord blood metabolites. We conclude that maternal diet modulates metabolic status of the fetus which may be relevant for fetal growth and development.

Die fruhe Ernahrung von der Konzeption bis zum Kleinkindalter hat pragende oder programmierende Wirkungen auf die spatere Gesundheit und auf Krankheitsrisiken. Eine rasche Gewichtszunahme in Fetalzeit und fruher Kindheit erhoht das spatere Risiko fur Adipositas, Diabetes und andere nichtubertragbare Krankheiten. In Kohortenstudien ist eine rasche Gewichtszunahme zwischen Geburt und dem Alter von 2 Jahren mit erhohtem Adipositasrisiko bis ins Erwachsenenalter verbunden. Stillen geht mit einer geringeren mittleren Gewichtszunahme als konventionelle Sauglingsnahrung einher. Verschiedene Metaanalysen zeigen durch Stillen ein spater um 12–24 % geringeres Adipositasrisiko. Wir untersuchten die „Fruhe-Protein-Hypothese“, nach der eine hohe Eiweiszufuhr im Sauglingsalter zu erhohten Konzentrationen an insulinfreisetzenden Aminosauren, den Wachstumsfaktoren Insulin und „insulin-like growth factor-1“ (IGF-1) sowie zu erhohter fruher Gewichtszunahme und spaterer Adipositas fuhrt. In einer doppelblinden randomisierten Studie erhielten 1678 reifgeborene Sauglinge im ersten Lebensjahr Sauglings- und Folgenahrungen mit konventionell hohem oder reduziertem Proteingehalt. Die verminderte Proteinzufuhr reduzierte Gewicht, Gewicht-fur-Lange und Body-Mass-Index (BMI) bis zum Alter von 2 Jahren sowie Adipositas mit 6 Jahren um das 2,4- bis 2,9-Fache, verglichen mit konventioneller Flaschenernahrung. Wir folgern, dass Sauglingsernahrung starke langzeitig programmierende Wirkungen ausubt, mit starken Effektgrosen auf Adipositas im fruhen Schulalter. Stillen sollte aktiv gefordert, geschutzt und unterstutzt werden. Nicht voll gestillte Sauglinge sollten eine Flaschennahrung mit niedrigem Proteingehalt bekommen. Unveranderte Kuhmilch, die 3‑mal so viel Protein wie Muttermilch enthalt, sollte im ersten Lebensjahr nicht als Getrank angeboten werden.

Human milk provides a complex mixture of animal lipids, whereas the fat supply of most modern infant formula is based on vegetable oils. We studied the effects of breast-feeding and of feeding infant formula either without or with dairy goat lipids on the composition of infant plasma glycerophospholipids.Healthy-term infants were randomized double blind to feeding with infant formula based on whole goats' milk (GIF, approximately 60% milk fat and 40% vegetable oils) or a control cows' milk infant formula based on vegetable oils (VIF) from 2 weeks after birth. A reference group of fully breast-fed infants was also followed. At the age 4 months, blood samples were collected and plasma glycerophospholipids were analyzed with liquid chromatography coupled to triple quadrupole mass spectrometry.The group of breast-fed infants showed significantly higher contents of glycerophospholipid species containing sn-2 palmitic acid [PC(16:0/16:0) and PC(18:0/16:0)] and significantly higher contents of glycerophospholipid species containing long-chain polyunsaturated fatty acids than infants in both formula groups. The GIF group demonstrated significantly higher glycerophospholipid species containing myristic acid [LPC(14:0), PC(14:0/18:1), PC(16:0/14:0)] and palmitoleic acid [LPC(16:1), PC(16:0/16:1), and PC(16:1/18:1)] than the VIF group.We conclude that breast-feeding induces marked differences in infant plasma glycerophospholipid profiles compared with formula feeding, whereas the studied different sources of formula fat resulted in limited effects on plasma glycerophospholipids.

Growth characteristics during periods of early developmental plasticity are linked with later health outcomes and with disease risks. Infant growth is modulated by genetic and exogenous factors including nutrition. We try to explore their underlying mechanisms using targeted metabolomic profiling of small molecules in biological samples using high-performance liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) to quantify hundreds of molecules in small biosamples, e.g., 50 µL plasma. In the large German LISA birth cohort study, cord blood lysophosphatidylcholines and fatty acids were closely associated with infant birth weight, with a nonsignificant trend towards an association with infant weight gain and later BMI. Studies in infants randomized to different protein intakes in the European CHOP Study show conventional high protein intakes to markedly increase plasma-indispensable amino acids (AA), particularly branched-chain AA (BCAA), while exceeding the infant's capacity of BCAA breakdown, and an increase in the dispensable AA tyrosine previously associated with insulin resistance. In a path model analysis of the relationship of infant plasma AA, growth factors, and infant growth, AA were generally found to induce a stronger response of insulin than IGF-I although effects of individual AA were very different. We conclude that targeted improvement in nutrient supply in pregnancy and infancy may offer large opportunities for promoting desirable child growth patterns and long-term health.

Uncertainty remains about the effect of vitamin D therapy on biomarkers of health status in obesity. The molecular basis underlying this controversy is largely unknown. To address the existing gap, our study sought to compare changes in metabolomic profiles of obesity phenotypes (metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO)) patients with sub-optimal levels of vitamin D following vitamin D supplementation. We conducted two randomized double-blind clinical trials on participants with either of the two obesity phenotypes from Tehran province. These phenotypes were determined by the Adult Treatment Panel-III criteria. Patients in each of the MHO (n = 110) and MUHO (n = 105) groups were separately assigned to receive either vitamin D (4000 IU/d) or placebo for 4 months. Pre- and post-supplementation plasma metabolomic profiling were performed using Liquid chromatography coupled to a triple quadrupole mass spectrometry. Multivariable linear regression was used to explore the association of change in each metabolite with the trial assignment (vitamin D/placebo) across obesity phenotypes. Metabolites (n = 104) were profiled in 82 MHO and 78 MUHO patients. After correction for multiple comparisons, acyl-lysophosphatidylcholines C16:0, C18:0, and C18:1, diacyl-phosphatidylcholines C32:0, C34:1, C38:3, and C38:4, and sphingomyelin C40:4 changed significantly in response to vitamin D supplementation only in MUHO phenotype. The interaction analysis revealed that vitamin D therapy was different between the two obesity phenotypes based on acyl-lysophosphatidylcholines C16:0 and C16:1 and citrulline which were altered significantly after supplementation. Changes in metabolites were associated with changes in cardiometabolic biomarkers after the intervention. Vitamin D treatment influenced the obesity-related plasma metabolites only in adults with obesity and metabolically unhealthy phenotype. Therefore, not all patients with obesity may benefit from an identical strategy for vitamin D therapy. These findings provide mechanistic basis highlighting the potential of precision medicine to mitigate diseases in health-care settings.

At The Power of Programming 2014 Conference, researchers from multiple disciplines presented and discussed the effects of early nutrition and other environmental cues during the first thousand days of life and beyond on the lifelong risk of noncommunicable diseases. This paper aims to summarize the concepts and some of the first achievements of the EarlyNutrition research project that initiated the conference. The EarlyNutrition consortium is a multinational, multidisciplinary research collaboration of researchers from Europe, the USA, and Australia. A focus is placed on exploration of the developmental origins of obesity, adiposity, and related health outcomes. Here we report on the first findings of experimental approaches, cohort studies, randomized clinical trials, and systematic reviews of current information, as well as position papers, which have all been developed with the involvement of project partners. We conclude that the EarlyNutrition project has successfully established itself during the first 2 project years as a very strong platform for collaborative research on early programming effects. The first results, available already at this early stage of the project, point to great opportunities for health prevention strategies via the implementation of dietary and lifestyle modifications, with large effect sizes. Further results are expected which should support improved recommendations and related policies for optimized nutrition and lifestyle choices before and during pregnancy, in infancy, and in early childhood.

Background: The prevalence and incidence of obesity have become a major public health problem during the last decades, but the underlying biochemical and metabolic processes are not fully understood. Metabolomics, the science of small molecules of the metabolism, is helping to unravel these mechanisms via the identification of markers related to obesity. These biomarkers are used to prevent diseases in later life or for the early diagnosis of diseases. This review focuses on articles dealing with biomarkers for obesity. Key Messages: Branched-chain amino acids (BCAA), nonesterified fatty acids, organic acids, acylcarnitines, and phospholipids were identified as potential biomarkers for obesity. This indicates a relation between elevated BCAA, and other amino acids, and the obese state. Furthermore, deregulation of β-oxidation is associated with the development of obesity. The results have several limitations, including the differing ages of the subjects in the studies, the fact that all of the studies had a case-control design and therefore no causal explanatory power, and that most looked for similar metabolites and reported almost equal results. Conclusion: The strength of this review is that it gives a comprehensive overview of the current status of the knowledge on metabolomics biomarkers for obesity, but further research is needed because the methods used in the studies to date are very homogenous, e.g. most used a targeted approach and therefore analyzed almost the same group of metabolites. Moreover, prospective studies are lacking since all of the studies are either case-control or cross-sectional studies.

Docosahexaenoic acid (DHA) status is related to health and disease risk. DHA status is mainly determined by dietary DHA intake, since endogenous synthesis of DHA is limited. We aimed to investigate the changes of different molecular glycerophospholipid species containing DHA in plasma and red blood cells (RBC) in response to increased DHA intake. Thirteen healthy adults had their diet supplemented with 510 mg DHA/day for 29 days. Fasted blood samples were taken at 11 time points and glycerophospholipid species were analyzed by liquid chromatography mass spectrometry. In plasma, percentages of glycerophospholipid species containing DHA increased significantly by 64–104 % relative to baseline values during supplementation, but the relative distribution between species was not markedly altered. In RBC, phosphatidylcholine (PtdCho) species containing DHA increased to a similar extent as in plasma, while phosphatidylethanolamine and phosphatidylserine species with DHA increased by only 12–25 %, respectively, which was significantly different compared to PtdCho species (p < 0.01). Despite the high increase, the contribution of DHA PtdCho species to total DHA remained minor (14 % after supplementation). In conclusion, DHA supplementation does not alter the relative distribution of DHA among glycerophospholipid species in plasma. A majority of PtdCho species are rapidly exchanged between plasma lipoproteins and RBC membrane lipids, while there is a minor exchange of phosphatidylethanolamine and phosphatidylserine species.

Background: Over the last decades, research on early life risk factors for obesity and its comorbidities in early life has gained attention within the field of developmental origins of health and diseases. Metabolomics studies that are trying to find early life biomarker and intervention targets for the early development of obesity and associated cardiovascular diseases could help break the inter-generational cycle of obesity. Summary: Metabolomics studies in the field of early programming are scarce and causality is lacking at this stage, as most of the studies are cross-sectional. The main metabolites in the focus of obesity are branched-chain and aromatic amino acids, long-chain polyunsaturated fatty acids, lysophosphatidylcholines, and sphingomyelins. Sex and puberty have not been considered in most of the biomarker studies, but show differences in the metabolite associations to obesity. Key Messages: There is still a lot unknown about the associations between early programming exposures, metabolite concentrations, and the development of obesity. The few studies focusing on this topic find similar metabolite classes in the same age groups being associated with rapid early growth or obesity; but due to differences in the methodological and statistical approaches, the single species often differ. Therefore, more research, preferably with standardized approaches, is needed.

Background/Aims: Fetal metabolism may be changed by the exposure to maternal factors, and the route to obesity may already set in utero. Cord blood metabolites might predict growth patterns and later obesity. We aimed to characterize associations of cord blood with birth weight, postnatal weight gain, and BMI in adolescence. Methods: Over 700 cord blood samples were collected from infants participating in the German birth cohort study LISAplus. Glycerophospholipid fatty acids (GPL-FA), polar lipids, non-esterified fatty acids (NEFA), and amino acids were analyzed with a targeted, liquid chromatography-tandem mass spectrometry based metabolomics platform. Cord blood metabolites were related to growth factors by linear regression models adjusted for confounding variables. Results: Cord blood metabolites were highly associated with birth weight. Lysophosphatidylcholines C16:1, C18:1, C20:3, C18:2, C20:4, C14:0, C16:0, C18:3, GPL-FA C20:3n-9, and GPL-FA C22:5n-6 were positively related to birth weight, while higher cord blood concentrations of NEFA C22:6, NEFA C20:5, GPL-FA C18:3n-3, and PCe C38:0 were associated with lower birth weight. Postnatal weight gain and BMI z-scores in adolescents were not significantly associated with cord blood metabolites after adjustment for multiple testing. Conclusion: Potential long-term programming effects of the intrauterine environment and metabolism on later health cannot be predicted with profiling of the cord blood metabolome.

Breastfeeding induces a different metabolic and endocrine response than feeding conventional infant formula, and it has also been associated with slower weight gain and reduced disease risk in later life. The underlying programming mechanisms remain to be explored. Breastfeeding has been reported to induce lower levels of insulin, insulin-like growth factor-1 and some amino acids (AAs) than formula feeding. In the Childhood Obesity Project (CHOP), infants fed a conventional protein-rich formula had a higher BMI at 2 and 6 years than those fed a protein-reduced formula. At 6 months, higher protein intakes induced increased plasma concentrations of branched-chain AAs (BCAAs) and their oxidation products, short-chain acylcarnitines. With increasing BCAA levels, these short-chain acylcarnitines increased proportionally only until a break point was reached, after which BCAAs seemed to escape their degradation. The resulting marked elevation in BCAA levels with high-protein (HP) intakes appears to contribute to increased insulin levels and to affect β-oxidation of fatty acids. The ratios of long-chain acylcarnitines to free carnitine decreased in infants who received a HP formula, which indicates a reduced initiation of β-oxidation. We conclude that HP intakes inducing high BCAA plasma levels may inhibit fat oxidation and thereby enhance body fat deposition and adiposity.