Body composition and metabolism associated withgenetic factors, nutrition and metabolomics datain adults

The human health status is co-determined by the interplay of body composition, metabolism, and energy balance. In turn, these factors are influenced by genetic predispositions, a multitude of environmental factors such as nutritional habits or physical activity, and interactive effects between these parameters. Malnutrition and obesity reflect extreme phenotypes of body composition, and lead to disturbances in metabolism. Especially obesity as a prominent health problem in industrialised countries is linked to an increased risk of morbidity and mortality. Important regulators of energy balance and metabolism are thyroid hormones and disturbances of their homoeostasis are associated with serious health problems. Metabolomics is an evolving field which has the ability to represent a snapshot of the current metabolic state. Disturbances of pathways can be captured and the utilisation of closely connected metabolites ratios provides proxies for enzymatic reactions. In this doctoral thesis, three projects are presented exploring the interplay of body composition,metabolism, and energy homeostasis by focusing on gene–nutrition interactions and their effect on obesity risk, the relationship between fat free mass and the serum metabolite profile of adults, and the influence of thyroid hormones on the metabolism in euthyroid adult participants. The first project aims at improving the understanding of inter-individual variance and susceptibility towards obesity. Common obesity is the result of a genetic predisposition in combination with nowadays modern environment which encourages a sedentary lifestyle and often leads to an imbalance in energy intake and expenditure, subsequently followed by weight gain. To this end, adjusted logistic regression models are used to analyse the interaction effects between single nucleotide polymorphisms (SNPs) of different candidate genes for obesity and polyunsaturated fatty acids (PUFAs) analysed in erythrocyte membranes, which are valid biomarkers for PUFA intake, on the obesity risk in adults participating in a crosssectional population-based study. Several significant SNP–PUFA interactions are identified, indicating regulatory effects of PUFAs by gene variants of interleukin (IL)-2, IL-6, IL-18,tumour necrosis factor receptor superfamily (TNFRSF) member 1B and 21, leptin receptor (LEPR), and adiponectin (ADIPOQ). Due to the limited statistical power of this study, these results have to be reproduced in a sufficiently sized prospective study. If replicated, our results would indicate a beneficial effect of high PUFA supply for a substantial proportion of the population with respect to obesity risk. Aspiration of the second project is to provide a comprehensive picture of fat free mass induced effects on the metabolite profile in blood samples of adults. Further, it is hypothesised that a sedentary lifestyle leads to derangements in skeletal muscle metabolism, e.g., favouring the development of obesity. Thus, the associations between the fat free mass index (FFMI) and up to 190 serum metabolite concentrations - with a focus on amino acids, acylcarnitines, phosphatidylcholines (PCs), and sphingomyelins - and all intra-class metabolite ratios are investigated by means of adjusted linear regression models in cross-sectional analyses of a cohort study. These analyses reveal 339 significant associations between FFMI and various metabolites and metabolite ratios. Among the most prominent associations with higher FFMI are increasing concentrations of the branched-chain amino acids (BCAAs), ratios of BCAAs to glucogenic amino acids, and carnitine concentrations. These findings are in agreement with the expected metabolic situation in fasted participants. Most of these results are replicated in the follow-up survey of the analysed baseline study. In order to draw a comprehensive picture of the FFMI effects, Gaussian graphical models (GGMs) are computed. These models have previously been shown to reveal the true relationships among metabolites. Further, genetic aspects are investigated. To this end, the relationships between SNPs described to be associated with anthropometric characteristics and the metabolite variables are analysed; however, no significant association is revealed. Sensitivity and stratified analyses are carefully performed. Most interestingly, almost all associations which are found for the entire sample are largely missing in the obese subgroup supporting our hypothesis that the accumulation of body fat tissue may be accompanied by a derangement in skeletal muscle metabolism. The aim of the third project is to identify thyroid hormone related changes on metabolism of fasting euthyroid participants in a cross-sectional analysis of a cohort study. To this end, the associations between free tyroxine (FT4), thyrotropin (TSH), and 151 metabolites as well as their pairwise intra-class metabolite ratios are analysed in adjusted linear regression models. Increased serum FT4 levels are associated with an overall enhanced transport to the mitochondria and beta-oxidation of fatty acids which is reflected by significantly increased serum acylcarnitine concentrations and decreased PC concentrations. Further, these findings are largely stable as they could be reproduced in different subsets of the population, including obese versus non-obese participants. No significant associations are found between the metabolite variables and the TSH concentrations. In summary, this doctoral thesis provides indication of a beneficial effect of high PUFA supply for specific genotype carriers with respect to obesity risk. An extensive image of FFMI effects in a data-driven metabolic network is revealed and high body fat accumulation is linked to a derangement in skeletal muscle metabolism. Further, this thesis broadens our knowledge of FT4 triggered pathways in euthyroid participants. Thus, this thesis contributes deeper insight into the interplay of body composition, metabolism, and energy balance.