New findings in the onset of diabetes

(Vienna, 2nd May 2011) Already one year ago Vienna’s scientists were describing the hedgehog signalling pathway as a “molecular switch” for the formation of body fat. In extensive research projects researchers of the Medical University of Vienna have now encountered an important mechanism in the onset of type 2 diabetes.

Obesity alone does not always lead to diabetes. Obese people mostly start suffering from diabetes when the fat cells cannot multiply sufficiently. As a result the existing fat cells become ever larger. These large fat cells die off and attract scavenger cells (macrophages), which eliminate the dead and diseased fat cells. However, they also cause a chronic inflammation in the fat, which leads to liver and muscle fatty degeneration. The consequence of which is diabetes.

More fat cells instead of diabetes
As Jelena Todoric from Harald Esterbauer’s study group from the Medical University of Vienna has now found out, certain defence cells (cell-toxic T-cells) can have a positive effect in the fat tissue on the onset and course of diabetes. They distribute Interferon gamma (IFNg) in large amounts which promotes the multiplication of fat cells and thereby directly prevents the existent cells from becoming very enlarged.

The target in this mechanism is the “hedgehog signalling pathway”, which Harald Esterbauer together with Andrew Pospisilk and Josef Penninger had already identified one year ago as a molecular “switch” in the formation of body fat. If this signalling pathway is overactivated, this leads to an almost complete loss of white fat tissue. Interferon gamma (IFNg) acts though as a “jammer” and blocks the hedgehog signal transfer. The fat cells can multiply and new small and healthy fat cells are produced on which the excess body fat is distributed. Through this the dangerous fat inflammation and the consequences of diabetes, muscle and liver fatty degeneration is also reduced.

New possibilities for cancer research?
“The blocking of the hedgehog signalling pathway by Interferon gamma discovered by Jelena Todoric has opened up a new door in research. The hedgehog is significantly involved as an important regulator in many processes. With the new findings, targeted influence can now be exerted on regulation”, says study leader Harald Esterbauer about the new findings. The direct interference of the hedgehog signalling pathway through the IFNg, which could be clearly evidenced both in cell cultures as well as in human tissue, could also play a role in cancers. Namely the particularly long-living and dangerous tumour stem cells are also supplied via hedgehog. As a result, the consideration is to interrupt this supply through IFNg and thereby to “starve out” the tumour stem cells.

The study groups of Mathias Müller (VetMedUni Vienna), Wolfgang Patsch (Paracelsus University of Salzburg) as well as of Andrew Pospisilik from the Max Planck Institute in Freiburg have made important contributions to this study. Esterbauer states, “We are now working together to further improve our understanding of how communication between hedgehog and Interferon gamma takes place. We suspect that this signalling pathway also plays an important role in the energy utilisation and sugar burning of fat and cancer cells. That would be a completely new approach to treatments of obesity, diabetes and cancer."

Authors:
Lead author: Dr. Jelena Todoric,
Study leader: Dr. Harald Esterbauer,
both: Clinical Department for Medical-Chemical Laboratory Diagnostics of the MedUni Vienna

Publication
The research paper appears in the June edition of the international leading journal “Diabetes”:
» Cross-Talk Between Interferon-g and Hedgehog Signaling Regulates Adipogenesis
Jelena Todoric, Birgit Strobl, Alexander Jais, Nicole Boucheron, Martina Bayer, Sabine Amann, Josefine Lindroos, Raffaele Teperino, Gerhard Prager, Martin Bilban, Wilfried Ellmeier, Franz Krempler, Mathias Müller, Oswald Wagner, Wolfgang Patsch, J. Andrew Pospisilik, and Harald Esterbauer;
DOI: 10.2337/db10-1628