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META-GROWTH Report Summary

Project ID: 322605
Funded under: FP7-IDEAS-ERC
Country: Germany

Mid-Term Report Summary - META-GROWTH (Metabolic regulation of growth and body composition: key modulators of long-term health)

The ERC META-GROWTH project started in October 2013 to study key modulators of early programming mechanisms of infant growth and body composition. A strong team of post-doc researchers, statisticians, study nurses, technicians, PhD students and support staff has been established. A strong spirit of team work, enthusiasm and dedication to the scientific goals and the work has been created. The required methodology is achieved and works well. A large number of data, as well as important and exciting results have been obtained, of which a number have already been published whereas other publications are prepared. So far, 32 peer reviewed journal articles were published based on the ERC funded work.
First, we examined the impact of infant nutrition on body composition in the Childhood Obesity Project (CHOP). Mixed longitudinal piecewise linear spline modelling revealed that higher formula protein supply during the first year induces increased tissue fat deposition throughout the first six years of life. Comparing higher to lower protein fed infants at the age of six years fat mass index was increased by 0.17 kg/m² (0.06-0.27, P=0.002). The difference in fat mass gain of about 3g per month induced by the higher protein formula intake leads to an increased risk for later overweight/obesity of about 6%. Comparing both formula groups to the breastfed group the difference of 7 g might be extrapolated to a risk increase of 15%.
To understand the mechanisms how environmental factors in the first 1000 days of life influence later growth and adiposity, we have applied and will continue to apply targeted metabolomics and genom-wide epigenetic analyses of a variety of cohort studies and intervention trials. Our high-throughput metabolomic platform based on LC-MS/MS methodology is well established and provides reproducible and quantitatively reliable data. Work on expansion of the method spectrum is ongoing. We measured 600 cord blood samples from the UPBEAT trial, 691 plasma samples of the Childhood Obesity Project (CHOP), 385 cord blood and 432 blood samples withdrawn at the age of 8years in children prospectively followed in the Ulm Birth Cohort Study (UBSC), and plasma samples of 1279 children of the 10 and 15 year follow-up visits of the GINI-LISA cohort. Metabolomic analysis of the plasma samples collected at the 6, 8, and 11 years follow up is still ongoing and the measurement of samples of pregnant women of the ROLO trial will be completed within the first half of 2016.
In the CHOP trial, we found that higher protein intake results in elevated levels of branched-chain amino acids (BCAA) and their degradation products, the short-chain acylcarnitines. For the first time, our data indicated a limited capacity for BCAA to be degraded in infants in vivo. We defined the plasma concentrations above which the capacity of catabolism is exceeded. We conclude that a high supply of BCAA inducing plasma concentration exceeding the breakpoint may induce a more marked increase of BCAA concentrations in plasma and tissues. This seems especially critical for leucine, which is a potent stimulator of insulin secretion and stimulates the mammalian Target Of Rapamycin (mTOR). We also detected indication for a suppression of ß-oxidation of long-chain fatty acids by the high protein supply. Thereby, high protein intakes in infants appears to block oxidation of dietary fat and shift a great proportion of fat intake to tissue deposition. This provides a metabolic explanation for our finding that children provided higher protein intakes in infancy have an increased body fat content and FMIat both 2 and 6 years of age. Additionally, we identified a metabolite named lysophosphatidylcholines (LPC) 14:0, which is strongly related to both rapid weight gain in infancy and to overweight/obesity at school age in the CHOP trial, suggesting that LPCaC14:0 levels reflect a metabolic programming mechanism in infancy. We aim at exploring this question further by potential replication in other studies. Relating growth parameter at birth with cord blood metabolites in the UBSC, we found positive associations of LPC (namely, C16:1, C18:1, C16:0, and C14:0) with birth weight. Concerning the outcomes early weight gain 0-2yrs or zBMI-Score at 8yr, neither a single metabolite nor their ensemble had predictive power. For both outcomes, cord blood metabolites explained 0% of variance.
Data analysis of the all measured samples will give us further inside in programming mechanism from pregnancy throughout childhood in the second period of this ERC project.
For epigenetic analyses, 600 cord blood samples of LIMIT trial and 384 samples of children of the CHOP trial at the age of 6 years, and 436 samples of children at age 11 years were analysed. We applied genome-wide methylation analysis using the Illumina 450k chip with DNA extracted. Epigenome-Wide-Association-Studies (EWAS) of children’s DNA-methylation with several predictors or phenotypes related to foetal and postnatal development, including maternal smoking during pregnancy, child’s body composition, breastfeeding, maternal BMI, age or stress in pregnancy were performed. EWAS to assess stability in methylation from 6 to 11 years involving also food intake and metabolic measurements will start soon. We published that maternal smoking during pregnancy impacts on DNA-methylation in children at age 5.5, years. Methylation levels at five HM450K probes showed differential methylation. Thereby, our study replicates previous findings on the epigenetic effects of maternal smoking in children ages 3 to 5, 7 and 17 and confirms the postnatal stability of MYO1G, CNTNAP2 and FRMD4A differential methylation. The role of this differential methylation in mediating childhood phenotypes, previously associated with maternal smoking, requires further investigation.
Additional EWAS to study prospectively the postnatal stability of methylation profiles in children and adolescents in association with various phenotypes prospectively over time and by integrating GWAS data as well as metabolic markers and nutritional data are planned and work is progressing very well.

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