Identification and characterization of obesity genes, gene-gene and diet gene interactions involved in polygenic obesity in mice

Coordinator:		Prof. Dr. Annette Schürmann
Institution:		Deutsches Institut für Ernährungsforschung Potsdam Rehbrücke
Homepage:		www.dife.de

Obesity (morbid overweight) is the most important symptom of the metabolic syndrome, which also comprises insulin resistance, dyslipoproteinemia (abnormal concentrations of plasma lipoproteins), and hypertension (high blood pressure). The polygenic predisposition (numerous variant genes) of obesity is characterized by a complex interaction of different gene variants with each other and with exogenic factors (such as a fat-enriched diet). The major goal of our project was to identify candidate genes for human obesity in order to allow therapeutic intervention and to define gene-gene and gene-diet interactions. Based on results of genome-wide studies performed in a polygenic mouse model we located 16 chromosomal regions (QTL, quantitative trait loci) that are associated with the metabolic syndrome and carry gene variants. The combination of parallel strategies led to the identification and functional characterization of several obesity genes (Tbc1d1, Zfp69, Nmu2R, Abcg1, and Ifi202b). For the Ifi202b gene, which is destroyed in the lean mouse by a microdeletion we could demonstrate that it upregulates the expression of an enzyme producing cortisol specifically in the adipose tissue and thereby participating in the development of the visceral adiposity.  Two members of the corresponding human Ifi family (IFI16 and MNDA) exhibited an elevated level in the visceral adipose tissue of obese subjects, an effect that was associated with lager adipocytes.  This finding indicates that this novel adiposity gene also plays a role for the human disease. Beside the effect on body weight our mouse studies demonstrated that the Ifi202b locus also has an impact on the behavior, especially on voluntary activity, exploration and anxiety.  However, currently we do not know if this phenotype is induced by Ifi202b alone or by an altered expression of other genes that are located in close proximity to the microdeletion.