The human metabolic syndrome is characterized by a heterogenic complex of symptoms, including central obesity. Obesity itself is linked to major features of the metabolic syndrome such as insulin resistance, dyslipidemia or type 2 diabetes mellitus. It has been shown that obesity risk and resulting metabolic alterations are associated with adipose tissue distribution, adipocyte size and secretion of adipocytokines, which are in turn influenced by environmental factors and genetic susceptibility. It might be assumed that currently known genetic variants associated with obesity and/or BMI (body mass index) as well as fat distribution explain up to 20 % of the variability in BMI and so, studies employing novel strategies are inevitable. In addition to the role of genetic variation, mRNA levels of several genes have been shown to be differentially expressed in subcutaneous (SC) and visceral (Vis) adipose tissue and to be correlated with obesity-related traits. It is scarcely investigated whether the obesity risk variants also might account for the variability in mRNA expression. The present thesis deals with novel obesity candidate genes, characterized by a differential mRNA expression in various fat depots. The association of genetic variants in these genes with obesity as part of the metabolic syndrome, and related traits was investigated in well characterized German cohorts. The main method used for genotyping was described in detail in a comprehensive review providing explicit troubleshooting and description of modified protocols for specific experimental needs. Further, the influence of genotypes on the gene expression levels was examined. While the differential expression for FTO could be described for the first time, the variant rs8050136 was shown to be significantly associated with obesity but not with the expression. Genetic variants in FASN were shown to be significantly associated with obesity and related traits in a cohort of European ancestry for the very first time. Moreover, one polymorphism showed effects on the ratio of Vis/SC FASN mRNA expression. While CNR1 is controversially discussed in the literature, the present work showed rather moderate effects of genetic variants on obesity. BMPR2 could be described as a novel obesity candidate gene. Amongst others, one variant was associated with obesity in a case-control design and with BMPR2 mRNA expression in Vis adipose tissue. In conclusion, the present study revealed novel genetic variants promoting obesity, and therefore a metabolic risk, which might be partly explicable through an influence of these variants on the mRNA expression levels of the genes in the adipose tissue depots. These findings contribute to better understanding of the genetic background of obesity which is essential in order to translate experimental data into diagnostic, preventive and treatment strategies.

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Die weltweite Zunahme der Adipositasprävalenz stellt eine wachsende Herausforderung für Gesundheitssysteme dar. Adipositas ist mit Begleiterkrankungen wie Diabetes melltitus Typ 2, koronarer Herzerkrankung und unter Anderen malignen Erkrankungen assoziiert. Genetische Faktoren spielen bei der Entstehung von Adipositas eine Rolle. Zur Beurteilung des mit dem kardiometabolischen Risiko verbundenen Adipositasgrads sind Maße der Fettverteilung, insbesondere das Taille-Hüft-Verhältnis (WHR) gut geeignet. Der Growth factor receptor-bound protein 14/ Cordon-bleu protein-like 1 (GRB14/COBLL)-Locus wurde in genomweiten Assoziationsstudien (GWAS) als WHR-beeinflussend identifiziert. In dieser Dissertation wurde die Rolle von GRB14 in der viszeralen Adipositas untersucht. GRB14 moduliert die Insulinrezeptoraktivität und beeinflusst die Lipogenese. In murinen Hepatozyten reduzierte ein Grb14-Knockdown die Lipogenese. Ein Knockout von GRB14 in humanen Präadipozyten verringerte Differenzierung und Lipidakkumulation. Die Dissertation beantwortet folgende Fragen: 1. Einfluss von Grb14-Expression auf Lipidakkumulation in murinen Zelllinien verschiedener Fettdepots. 2. Assoziation der Genvariante rs10195252 mit metabolischen Phänotypen. 3. Unterschiede in GRB14-mRNA-Expression in menschlichem Fettgewebe zwischen Depots und deren Einfluss auf metabolische Phänotypen. 1. In murinen Präadipozyten zeigte sich bei Grb14-Knockdown eine verringerte Lipidakkumulation in viszeralen Depots. In der German Obesity Biomaterial Bank (GOBB)-Kohorte zeigte rs10195252 Assoziationen mit Diabetes-Parametern, Triglyzeriden, Leukozytenzahl und Fettgewebs-spezifischer GRB14-Expression. 2./3. Die GRB14-Expression war im viszeralen Fettgewebe höher als im subkutanen Fettgewebe. Bei höherem BMI und Diabetes war die GRB14-Expression gesteigert. Der SNP rs10195252 zeigte einen eQTL-Effekt auf GRB14-Expression im viszeralen Fettgewebe und beeinflusste indirekt Diabetesparameter. Zusammenfassend scheinen die beobachteten Assoziationen von o.g. SNP und metabolischen Parametern zumindest teilweise durch die GRB14-Expression im viszeralen Fettgewebe vermittelt zu werden, eine Kausalität ist aufgrund der Daten jedoch nicht nachgewiesen. Weitere Studien sind zur Aufklärung der molekularen Mechanismen und möglicher Kausalitäten erforderlich.

The human metabolic syndrome is characterized by a heterogenic complex of symptoms, including central obesity. Obesity itself is linked to major features of the metabolic syndrome such as insulin resistance, dyslipidemia or type 2 diabetes mellitus. It has been shown that obesity risk and resulting metabolic alterations are associated with adipose tissue distribution, adipocyte size and secretion of adipocytokines, which are in turn influenced by environmental factors and genetic susceptibility. It might be assumed that currently known genetic variants associated with obesity and/or BMI (body mass index) as well as fat distribution explain up to 20 % of the variability in BMI and so, studies employing novel strategies are inevitable. In addition to the role of genetic variation, mRNA levels of several genes have been shown to be differentially expressed in subcutaneous (SC) and visceral (Vis) adipose tissue and to be correlated with obesity-related traits. It is scarcely investigated whether the obesity risk variants also might account for the variability in mRNA expression. The present thesis deals with novel obesity candidate genes, characterized by a differential mRNA expression in various fat depots. The association of genetic variants in these genes with obesity as part of the metabolic syndrome, and related traits was investigated in well characterized German cohorts. The main method used for genotyping was described in detail in a comprehensive review providing explicit troubleshooting and description of modified protocols for specific experimental needs. Further, the influence of genotypes on the gene expression levels was examined. While the differential expression for FTO could be described for the first time, the variant rs8050136 was shown to be significantly associated with obesity but not with the expression. Genetic variants in FASN were shown to be significantly associated with obesity and related traits in a cohort of European ancestry for the very first time. Moreover, one polymorphism showed effects on the ratio of Vis/SC FASN mRNA expression. While CNR1 is controversially discussed in the literature, the present work showed rather moderate effects of genetic variants on obesity. BMPR2 could be described as a novel obesity candidate gene. Amongst others, one variant was associated with obesity in a case-control design and with BMPR2 mRNA expression in Vis adipose tissue. In conclusion, the present study revealed novel genetic variants promoting obesity, and therefore a metabolic risk, which might be partly explicable through an influence of these variants on the mRNA expression levels of the genes in the adipose tissue depots. These findings contribute to better understanding of the genetic background of obesity which is essential in order to translate experimental data into diagnostic, preventive and treatment strategies.