Since 1980 worldwide obesity has doubled in incidence to 52 % of people being overweight or obese. Obesity causes various comorbidities such as cardiovascular diseases, type II diabetes, dyslipidemia and several cancer types, making it one of the biggest challenges in worldwide health care systems. It is well known that obesity is highly heritable by either monogenetic causes or multifactorial interactions of different genes that superimpose on environmental factors and behavior. To answer questions in understanding mechanisms of obesity and/or associated metabolic pathways, mouse models have been a powerful tool. Several approaches in characterizing genes involved in obesity development through mouse engineering have been implemented, with the Cre/loxP system emerging as one of the most informative and widespread techniques. Using this approach, promoter-dependent temporal and tissue-specific regulated recombination can be achieved by Tamoxifen administration. To investigate effects of Tamoxifen on adipocyte biology in vivo, we characterized 12 weeks old male C57BL/6NTac mice after Tamoxifen treatment. We found that Tamoxifen treatment caused transient body composition changes, increased HbA1c, triglyceride and free fatty acid serum concentrations as well as smaller adipocytes in combination with browning of subcutaneous adipose tissue. Therefore, we suggest considering these effects when using Tamoxifen as a tool to induce conditional transgenic mouse models and to treat control mice in parallel. Another methodology used to identify genes involved in obesity related traits is QTL mapping in combination with congenic and subcongenic strains of mice or rats. One candidate gene that was previously identified on rat chromosome 4 is replication initiator 1 (Repin1 ). This gene was first described as a 60 kDa zinc finger protein involved in replication activation of the Chinese hamster dihydrofolate reductase (dhfr ) gene. Moreover, a triplet repeat (TTT) in the 3’UTR is associated with facets of the metabolic syndrome, including body weight, serum insulin, cholesterol and triglyceride levels. In vitro studies in 3T3-L1 cells revealed that Repin1 regulates adipocyte size, glucose transport and lipid metabolism. In this thesis functional analyses of Repin1 were performed using different Repin1 deficient mouse models. In the first study we generated a whole body Repin1 deficient db/db double knockout mouse (Rep1−/−x db/db) and systematically characterized the consequences of Repin1 deficiency. Our study provided evidence that loss of Repin1 in db/db mice improves insulin sensitivity and reduces chronic hyperglycemia most likely by reducing fat mass and adipose tissue inflammation. We next generated a liver-specific Repin1 knockout mouse (LRep1−/−) and could show that loss of Repin1 in liver leads to reduced body weight gain in combination with lower fat mass. Liver specific Repin1 deficient mice also show lower triglyceride content in the liver, improved insulin sensitivity and altered gene expression of genes involved in lipid and glucose metabolism. Finally, we inactivated the Repin1 gene in adipose tissue (iARep−/−) at an age of four weeks using Tamoxifen-inducible gene targeting strategies on a background of C57BL/6NTac mice. Mice lacking Repin1 in adipose tissue showed reduced body weight gain, decreased fat mass with smaller adipocytes, improved insulin sensitivity, lower LDL-, HDL- and total cholesterol serum concentrations and reduced expression of genes involved in lipid metabolism (Cd36 and Lcn2 ). In conclusion, the thesis presented here provides novel insights into Repin1 function. Moreover, the data clearly indicate that Repin1 plays a role in insulin sensitivity and lipid metabolism by regulating key genes involved in those pathways.