Investigation of Fto as a major contributor to obesity

Coordinator:		Prof. Dr. Ulrich Rüther
Institution:		Universität Düsseldorf, Institut  für Entwicklungs- und Molekularbiologie der Tiere
Homepage:		www.biologie.uni-duesseldorf.de

The FTO gene was identified by a genome wide association study as a risk factor for the development of obesity. With the goal to understand the molecular action of FTO we started a functional analysis using genetic and biochemical methods.

Mice without FTO display a minimal accumulation of fat, however accompanied by massive alterations such as dwarfism, increased adrenaline levels and a behavioural dysfunction. It will be essential for the development of an anti-FTO therapy to discriminate between the basic function of FTO and the function in obesity development. We investigated this organ specific function by the analysis of FTO deficient mice in combination with FTO overexpressing mice. In addition we analysed the interaction of FTO with other molecules to get a good idea how to influence FTO activity directly or indirectly.

Here are our current results:

1.The analysis of FTO deficient mice gave clear evidence that FTO is participating in quantitative terms in the development of obesity.

2.FTO-overexpressing mice are healthy. They express about 3% of wildtype FTO expression which is sufficient to rescue the FTO-negative phenotype.

3.Leptin-deficient mice eat permanently and become extremely fat. As a consequence their develop the metabolic syndrome (hyperglycemia and insulin resistance). This can lead to different diseases such as type 2 diabetes or cardiovascular dysfunctions. Combination of FTO-deficiency with Leptin-deficiency revealed a normalisation of body weight and equally important normalisation of metabolic factors.

4.Several candidates for FTO interaction have already been rescreened.