Molecular mechanisms in obesity

Major goal of the network “Molecular mechanisms in obesity” is the identification of genes/alleles predisposing to obesity and their subsequent evaluation in epidemiological, developmental, clinical, functional and therapeutic terms.
Genome wide association studies (GWA) are already leading to the identification of novel obesity genes. Hence, the extension and subsequent maintenance of our successful research pipeline (figure 1) established during NGFN1&2 is vital for the network. Using GWA data based on more than 5,000 subjects - including data encompassing 487 extremely obese and 442 healthy lean individuals (Hinney et al., 2007) and of 424 obesity trios (extremely obese index patient and both parents) – we have already identified novel polygenes (Workblock (WB) 1: “Gene identification”); parallel studies will be continued in rodents. As a third and new approach, we included the subproject “Proteomics” in workblock 1. We will validate the respective findings and assess the relevance of detected alleles in relationship to different developmental stages in epidemiological samples in workblock 2 (Epidemiology). Functional studies in workblock 3 will focus on the implications of the detected genetic variation using in vitro and in vivo models. The analysis of Fto knock out mice will facilitate the analysis of the obesity polygene with the largest effect size currently known. Within workblock 4 “Therapy” we address implications of molecular findings for treatment of obesity, validated alleles are to be tested in obese subjects, who differ in magnitude and rate of weight loss during conventional treatment programs. We will initiate systemic studies using in vivo models to examine negative side effects of therapeutically induced weight loss at the molecular level.