Body composition and metabolism associated with genetic factors, nutrition and metabolomics data in 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.