A phylogenetic approach to fight obesity by futile cycling

Obesity and overweight are major risk factors for several human diseases. Obesity and overweight can be the result of a high energy (high calorie) intake that exceeds energy consumption of the organism. Increasing energy consumption therefore represents an attractive strategy against obesity. We propose to enhance energy consumption (also referred to as energy expenditure) in cells of organisms by tissue-independent activation of cellular metabolism. Specifically, we will try to identify activators of so-called futile substrate cycles, which simply consume energy without generating any other net metabolic product. Examples of such cycles are known and naturally present in cells, but how and if they can be activated without metabolic counter regulation is not known. We will use a phylogenetic approach, meaning that we aim to identify pharmacological activators of cellular energy expenditure by using a yeast-based compound screening system. Yeast cells allow large-scale and cost-effective experiments. Subsequently, we will test whether our findings from yeast are conserved to higher eukaryotic organisms and thus function throughout evolution. We will test ~2000 approved drugs for their potential refurbished use against obesity. Approved drugs have an already tested safety profile from phase 1 clinical trials. Therefore, if successful in animal models, clinical translation to humans is feasible.

As part of the FWF-funded 1000 Ideas project "A phylogenetic approach to fighting obesity by futile cycling" with the aim of finding potential drug candidates against overweight/obesity, the first substance candidates were identified. A yeast cell-based screening system was successfully established, which allows the identification of active substances that intervene in the lipid or energy metabolism and thus influence the fat content of cells. At the same time, tolerability was tested by measuring the cell death and growth rates of the cells. Using the established system, over 800 substances approved for use in humans were examined for new, previously unknown effects during the course of the project. Ten substances showed a lipid-lowering effect without affecting the growth or survival capacity of the cells. Although the mechanisms of the lipid-lowering effect have not yet been elucidated, follow-up projects are planned to further investigate their mode of action and potential for treating metabolic diseases such as obesity in suitable models. In addition to substances with an effect on lipid metabolism, around 20 candidates with a cytotoxic effect have been identified. This could be relevant for the development of new antifungal strategies (e.g. treatment of human pathogenic yeast infections) and offers new starting points for associated projects, which are to be carried out in collaboration with other research groups.