Lymphocyte Circadian Clocks Control Lymph Node Trafficking and Adaptive Immune Responses.

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.

Plasma Sphingomyelins and Carnitine Esters of Infants Consuming Whole Goat or Cow Milk-Based Infant Formulas or Human Milk.

BACKGROUND: Infant formulas are typically manufactured using skimmed milk, whey proteins, and vegetable oils, which excludes milk fat globule membranes (MFGM). MFGM contains polar lipids, including sphingomyelin (SM). OBJECTIVE: The objective of this study was comparison of infant plasma SM and acylcarnitine species between infants who are breastfed or receiving infant formulas with different fat sources. METHODS: In this explorative study, we focused on SM and acylcarnitine species concentrations measured in plasma samples from the TIGGA study (ACTRN12608000047392), where infants were randomly assigned to receive either a cow milk-based infant formula (CIF) with vegetable oils only or a goat milk-based infant formula (GIF) with a goat milk fat (including MFGM) and vegetable oil mixture to the age ≥4 mo. Breastfed infants were followed as a reference group. Using tandem mass spectrometry, SM species in the study formulas and SM and acylcarnitine species in plasma samples collected at the age of 4 mo were analyzed. RESULTS: Total SM concentrations (∼42 µmol/L) and patterns of SM species were similar in both formulas. The total plasma SM concentrations were not different between the formula groups but were 15 % (CIF) and 21% (GIF) lower in the formula groups than in the breastfed group. Between the formula groups, differences in SM species were statistically significant but small. Total carnitine and major (acyl) carnitine species were not different between the groups. CONCLUSIONS: The higher total SM concentration in breastfed than in formula-fed infants might be related to a higher SM content in human milk, differences in cholesterol metabolism, dietary fatty acid intake, or other factors not yet identified. SM and acylcarnitine species composition in plasma is not closely related to the formula fatty acid composition. This trial was registered at Australian New Zealand Clinical Trials Registry as ACTRN12608000047392.

Impact of infant protein supply and other early life factors on plasma metabolome at 5.5 and 8 years of age: a randomized trial.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A population-based resource for intergenerational metabolomics analyses in pregnant women and their children: the Generation R Study.

INTRODUCTION: Adverse exposures in early life may predispose children to cardio-metabolic disease in later life. Metabolomics may serve as a valuable tool to disentangle the metabolic adaptations and mechanisms that potentially underlie these associations. OBJECTIVES: To describe the acquisition, processing and structure of the metabolomics data available in a population-based prospective cohort from early pregnancy onwards and to examine the relationships between metabolite profiles of pregnant women and their children at birth and in childhood. METHODS: In a subset of 994 mothers-child pairs from a prospective population-based cohort study among pregnant women and their children from Rotterdam, the Netherlands, we used LC-MS/MS to determine concentrations of amino acids, non-esterified fatty acids, phospholipids and carnitines in blood serum collected in early pregnancy, at birth (cord blood), and at child's age 10 years. RESULTS: Concentrations of diacyl-phosphatidylcholines, acyl-alkyl-phosphatidylcholines, alkyl-lysophosphatidylcholines and sphingomyelines were the highest in early pregnancy, concentrations of amino acids and non-esterified fatty acids were the highest at birth and concentrations of alkyl-lysophosphatidylcholines, free carnitine and acyl-carnitines were the highest at age 10 years. Correlations of individual metabolites between pregnant women and their children at birth and at the age of 10 years were low (range between r = - 0.10 and r = 0.35). CONCLUSION: Our results suggest that unique metabolic profiles are present among pregnant women, newborns and school aged children, with limited intergenerational correlations between metabolite profiles. These data will form a valuable resource to address the early metabolic origins of cardio-metabolic disease.

Impact of nutrition on social decision making.

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.

Plasma metabolomic profiling of amino acids and polar lipids in Iranian obese adults.

BACKGROUND: Obesity, widely recognized as a serious health concern, is characterized by profoundly altered metabolism. However, the intermediate metabolites involved in this change remain largely unknown. OBJECTIVE: We conducted targeted metabolomics profiling to identify moieties associated with adult obesity. METHODS: In this case-control study of Iranian adults, 200 obese patients were compared with 100 controls based on 104 metabolites profiled by a targeted metabolomic approach using liquid chromatography coupled to triple quadrupole mass spectrometry (LC-MS/MS). The analysis comprised acylcarnitines, diacyl-phosphatidylcholines (PCaa), acyl-alkyl-phosphatidylcholines (PCae), sphingomyelins (SM), lyso-phospholipids (LPC) and amino acids. We performed multivariable linear regression to identify metabolites associated with obesity, adjusting for age, sex, total energy intake, total physical activity, smoking, and alcohol consumption. The Bonferroni correction was used to adjust for multiple testing. RESULTS: A pattern of 19 metabolites was significantly associated with obesity. Branched chain amino acids, alanine, glutamic acid, proline, tyrosine LPCa C16:1, PCaa C32:1, PCaa C32:2 and PCaa C38:3 were positively, while serine, asparagine, LPCa C18:1, LPCa C18:2, LPCe C18:0, PCae C34:3, PCae C38:4 and PCae C40:6 were negatively associated with obesity (all p < 0.00048). CONCLUSIONS: A metabolomic profile containing 9 amino acids and 10 polar lipids may serve as a potential biomarker of adult obesity. Further studies are warranted to replicate these findings as well as investigate potential changes in this profile after weight reduction.

Phospholipids in lipoproteins: compositional differences across VLDL, LDL, and HDL in pregnant women.

OBJECTIVE: The aim of this study was to analyse the differences in the phospholipid composition of very low density (VLDL), low density (LDL) and high density lipoprotein (HDL) monolayers in pregnant lean and obese women. METHODS: LDL, HDL, and VLDL were isolated from plasma samples of 10 lean and 10 obese pregnant women, and their species composition of phosphatidylcholines (PC) and sphingomyelins (SM) was analysed by liquid-chromatography tandem mass-spectrometry. Wilcoxon-Mann-Whitney U test and principal component analysis (PCA) were used to investigate if metabolite profiles differed between the lean/obese group and between lipoprotein species. RESULTS: No significant differences have been found in the metabolite levels between obese and non-obese pregnant women. The PCA components 1 and 2 separated between LDL, HDL, and VLDL but not between normal weight and obese women. Twelve SM and one PCae were more abundant in LDL than in VLDL. In contrast, four acyl-alkyl-PC and two diacyl-PC were significantly higher in HDL compared to LDL. VLDL and HDL differed in three SM, seven acyl-alkyl-PC and one diacyl-PC (higher values in HDL) and 13 SM (higher in VLDL). We also found associations of some phospholipid species with HDL and LDL cholesterol. CONCLUSION: In pregnant women phospholipid composition differs significantly in HDL, LDL and VLDL, similar to previous findings in men and non-pregnant women. Obese and lean pregnant women showed no significant differences in their lipoprotein associated metabolite profile.

Investigation of the impact of birth by cesarean section on fetal and maternal metabolism.

PURPOSE: 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. METHODS: Samples obtained from PREOBE study participants were subjected to LC-MS/MS-targeted metabolomics comprising > 200 metabolites. RESULTS: 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 ß-oxidation, and the sum of hexoses were lower in CS-born babies in addition to tendentially lower levels of PL. CONCLUSIONS: 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.

Obesity-Related Metabolomic Profiles and Discrimination of Metabolically Unhealthy Obesity.

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.

Placental lipid droplet composition: Effect of a lifestyle intervention (UPBEAT) in obese pregnant women.

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 < 0.007), and lowered by the intervention. In the whole sample, PCs carrying DHA and arachidonic acid were inversely associated with placental weight. Placenta MFSD2a expression was associated with DHA cord blood metabolites and relationships were observed between LD lipids, especially DHA carrying species, and cord blood metabolites. We describe placenta LD composition for the first time and demonstrate modest, potentially beneficial effects of a lifestyle intervention on LD FAs in obese pregnant women.

Effectiveness of vitamin D therapy in improving metabolomic biomarkers in obesity phenotypes: Two randomized clinical trials.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Early Programming of Obesity Throughout the Life Course: A Metabolomics Perspective.

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.

Long-Term Health Impact of Early Nutrition: The Power of Programming.

The Power of Programming conference 2016 at Ludwig-Maximilians-Universität Munich brought together about 600 researchers and other stakeholders from around the world who reviewed the recent evidence on the lasting health impact of environment and nutrition during early life, from pre-pregnancy to early childhood. The conference was hosted by the Early Nutrition Project, a multidisciplinary research collaboration funded by the European Commission with collaborating researchers from 35 institutions in 15 countries in Europe, the United States and Australia. The project explores the early origins of obesity, adiposity and associated non-communicable diseases, underlying mechanisms and opportunities for prevention. The project also proactively supports translational application of research findings. In fact, some existing evidence has already been rapidly adopted into policy, regulatory standards and practice. Further, broad dissemination of findings is achieved through the established digital eLearning platform of the Early Nutrition eAcademy, video clip-based learning and graphically supported messaging to consumers. The project demonstrated powerful effects of early metabolic programming on later health. Compared to other common prevention strategies, modifying risk trajectories in early life can achieve a much larger risk reduction and be more cost-effective. While some effective prevention strategies have been promptly implemented in policy and guidelines, legislation and practice, in other areas, the uptake is limited by a paucity of quality human intervention trials and insufficient evaluation of the feasibility of implementation and econometric impact. This needs to be strengthened by future collaborative research work.

Investigating the early metabolic fingerprint of celiac disease - a prospective approach.

OBJECTIVES AND STUDY: In the development of Celiac Disease (CD) both genetic and environmental factors play a crucial role. The Human Leukocyte Antigen (HLA)-DQ2 and HLA-DQ8 loci are strongly related to the disease and are necessary but not sufficient for the development of CD. Therefore, increasing interest lies in examining the mechanisms of CD onset from the early beginning. Differences in serum and urine metabolic profiles between healthy individuals and CD patients have been reported previously. We aimed to investigate if the metabolic pathways were already altered in young, 4 month old infants, preceding the CD diagnosis. METHODS: Serum samples were available for 230 four month old infants of the PreventCD project, a multicenter, randomized, double-blind, dietary intervention study. All children were positive for HLA-DQ2 and/or HLA-DQ8 and had at least one first-degree relative diagnosed with CD. Amino acids were quantified after derivatization with liquid chromatography - tandem mass spectrometry (MS/MS) and polar lipid concentrations (acylcarnitines, lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins) were determined with direct infusion MS/MS. We investigated the association of the metabolic profile with (1) the development of CD up to the age of 8 years (yes/no), (2) with HLA-risk groups, (3) with the age at CD diagnosis, using linear mixed models and cox proportional hazards models. Gender, intervention group, and age at blood withdrawal were included as potential confounder. RESULTS: By the end of 2014, thirty-three out of the 230 children (14%) were diagnosed with CD according to the ESPGHAN criteria. Median age at diagnosis was 3.4 years (IQR, 2.4-5.2). Testing each metabolite for a difference in the mean between healthy and CD children, we (1) could not identify a discriminant analyte or a pattern pointing towards an altered metabolism (Bonferroni corrected P > 0.05 for all). Metabolite concentrations (2) did not differ across the HLA-risk groups. When investigating the age at diagnosis using (3) survival models, we found no evidence for an association between the metabolic profile and the risk of a later CD diagnosis. CONCLUSION: The metabolic profile at 4 months of age was not predictive for the development of CD up to the age of 8 years. Our results suggest that metabolic pathways reflected in serum are affected only later in life and that the HLA-genotype does not influence the serum metabolic profile in young infants before introduction of solid food.

Dietary Effects on Plasma Glycerophospholipids.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Metabolomic biomarkers for obesity in humans: a short review.

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 ß-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.

Regulation of early human growth: impact on long-term health.

Growth and development are central characteristics of childhood. Deviations from normal growth can indicate serious health challenges. The adverse impact of early growth faltering and malnutrition on later health has long been known. In contrast, the impact of rapid early weight and body fat gain on programming of later disease risk have only recently received increased attention. Numerous observational studies related diet in early childhood and rapid early growth to the risk of later obesity and associated disorders. Causality was confirmed in a large, double-blind randomised trial testing the 'Early Protein Hypothesis'. In this trial we found that attenuation of protein supply in infancy normalized early growth and markedly reduced obesity prevalence in early school age. These results indicate the need to describe and analyse growth patterns and their regulation through diet in more detail and to characterize the underlying metabolic and epigenetic mechanisms, given the potential major relevance for public health and policy. Better understanding of growth patterns and their regulation could have major benefits for the promotion of public health, consumer-orientated nutrition recommendations, and the development of improved food products for specific target populations.

The Power of Programming and the EarlyNutrition project: opportunities for health promotion by nutrition during the first thousand days of life and beyond.

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.

Rapid growth and childhood obesity are strongly associated with lysoPC(14:0).

BACKGROUND: Despite the growing interest in the early-origins-of-later-disease hypothesis, little is known about the metabolic underpinnings linking infant weight gain and childhood obesity. OBJECTIVE: To discover biomarkers reflective of weight change in the first 6 months and overweight/obesity at age 6 years via a targeted metabolomics approach. DESIGN: This analysis comprised 726 infants from a European multicenter randomized trial (Childhood Obesity Programme, CHOP) for whom plasma blood samples at age 6 months and anthropometric data up to the age of 6 years were available. 'Rapid growth' was defined as a positive difference in weight within the first 6 months of life standardized to WHO growth standards. Weight change was regressed on each of 168 metabolites (acylcarnitines, lysophosphatidylcholines, sphingomyelins, and amino acids). Metabolites significant after Bonferroni's correction were tested as predictors of later overweight/obesity. RESULTS: Among the overall 19 significant metabolites, 4 were associated with rapid growth and 15 were associated with a less-than-ideal weight change. After adjusting for feeding group, only the lysophosphatidylcholine LPCaC14:0 remained significantly associated with rapid weight gain (ß = 0.18). Only LPCaC14:0 at age 6 months was predictive of overweight/obesity at age 6 years (OR 1.33; 95% CI 1.04-1.69). CONCLUSION: LPCa14:0 is strongly related to rapid growth in infancy and childhood overweight/obesity. This suggests that LPCaC14:0 levels may represent a metabolically programmed effect of infant weight gain on the later obesity risk. However, these results require confirmation by independent cohorts.

Sarcopenia: investigation of metabolic changes and its associated mechanisms.

BACKGROUND: Sarcopenia is one of the most predominant musculoskeletal diseases of the elderly, defined as age-related progressive and generalized loss of muscle mass with a simultaneous reduction in muscle strength and/or function. Using metabolomics, we aimed to examine the association between sarcopenia and the plasma metabolic profile of sarcopenic patients, measured using a targeted HPLC-MS/MS platform. METHODS: Plasma samples from 22 (17 men) hip fracture patients undergoing surgery (8 sarcopenic, age 81.4+6.3, and 14 non-sarcopenic, age 78.4±8.1) were analyzed. T test, fold change, orthogonal partial least squares discriminant analysis, and sparse partial least squares discriminant analysis were used for mining significant features. Metabolite set enrichment analysis and mediation analysis by PLSSEM were thereafter performed. RESULTS: Using a univariate analysis for sarcopenia z score, the amino acid citrulline was the only metabolite with a significant group difference after FDR correction. Positive trends were observed between the sarcopenia z score and very long-chain fatty acids as well as dicarboxylic acid carnitines. Multivariate analysis showed citrulline, non-esterified fatty acid 26:2, and decanedioyl carnitine as the top three metabolites according to the variable importance in projection using oPLS-DA and loadings weight by sPLS-DA. Metabolite set enrichment analysis showed carnitine palmitoyltransferase deficiency (II) as the highest condition related to the metabolome. CONCLUSIONS: We observed a difference in the plasma metabolic profile in association with different measures of sarcopenia, which identifies very long-chain fatty acids, Carn.DC and citrulline as key variables associated with the disease severity. These findings point to a potential link between sarcopenia and mitochondrial dysfunction and portraits a number of possible biochemical pathways which might be involved in the disease pathogenesis.