Director of MPI for Metabolism Research
Brüning’s group explores how the central nervous system regulates food intake and influences energy availability in the body. Altered metabolism can trigger diseases like obesity and diabetes mellitus. The team of scientists led by Prof. Dr. Brüning has succeeded in identifying groups of nerve cells in the brain that control energy homeostasis and in revealing the role of the FTO gene, which is strongly associated with obesity. The group’s goal for the future is to deepen our understanding of the control processes the brain uses to integrate the complex impulses that govern our eating behavior.
Our research: Depending on the body’s energy stores, the brain regulates nutrient intake as well as energy and sugar metabolism in the body. It coordinates processes in adipose tissue, skeletal muscle, liver and pancreas, that together form a complex system. Dysregulation of this system can trigger diseases like obesity and diabetes, highly relevant to today’s society by virtue of their prevalence.
The group led by Prof. Brüning is currently pursuing two research approaches in this area. The team is aiming to understand the neuronal control of the regulatory mechanisms by exploring both the connections between neurocircuits in the brain, and the effect their activity has on human eating behavior and motivation. In addition, the scientists are exploring how these processes deregulated patients who already suffer from a metabolic disorder. The working group hopes to thus decode the fundamental mechanisms behind the normal control as well as alteration in energy homeostasis.
Our successes: In recent years, Prof. Brüning and his team have made a considerable contribution to identifying the neurocircuits in the brain that regulate energy balance. This not only opens up new insights into the regulation of the cells activity in a physiological state, but also enables the scientists to identify signals that lead to the dysregulation of behavior in overweight people.
Additionally, the working group has succeeded in decoding the function of the so-called FTO gene. Variations in the FTO gene are strongly associated with obesity in human beings. Experiments have shown that this gene controls the regulation of reward behavior in mice. The researchers’ new findings indicate that the gene variations that trigger obesity in humans also produce a change in reward behavior and the regulatory nerve cells.
Our goals: The long-term goal of Prof. Brüning and his scientific team is to understand in detail how fundamental regulatory principles for food intake in the brain are linked to higher brain functions like emotions, or the smell and appearance of a particular food. The integration of all this information leads to the decision about when one eats – and what one eats – and as such whether one becomes overweight. These findings could have a decisive influence on developing new therapeutic approaches to obesity and diabetes mellitus.
Our methods/techniques: Prof. Brüning’s group uses mouse models in its basic research to unravel the regulatory mechanisms. The ultimate goal is to translate their findings to humans. Model organisms allow targeted neurocircuits to be stimulated, so scientists can observe the effects on behavioral patterns and metabolic processes. Researchers also use the animal models to validate imaging techniques such as MRI (magnetic resonance imaging) and PET (positron emissions tomography). These non-invasive methods can then be used in the next step: designing clinical trials.
Figure 1: Fluorescent staining of a marker for dopaminergic neurons and Fto. Midbrain dopaminergic neurons were stained in Fto∆DAT/∆ and Fto+/+ mice using an antibody directed against the tyrosine hydroxylase (TH, green), a marker for dopaminergic neurons in the midbrain. Further labeling of FTO (red) revealed the absence of FTO in dopamine neuron restricted Fto knock out mice.
Figure 2: Effect of cocaine on control and Fto∆DAT DA neurons.
Figure 3: Reversible N6-methyladenosine modification. FTO demethylates N6-methyladenosine (m6A) in mRNA (Gerken et al., 2007), thereby presumably playing a role in mRNA processing.
Figure 4: Genome wide association studies link FTO to obesity. A cluster of single nucleotide polymorphisms (SNPs) within the first intron of the human FTO gene is significantly associated with increased BMI. Figure adapted from Willer et al.