Metabolic Pathway Discovered Has Implications for Diabetes, Obesity, Cancer Therapy

A newly discovered hedgehog-signaling pathway has been found to be a primary regulator of cellular energy metabolism and to include insulin-independent glucose uptake.

Scientists from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg (Freiburg, Germany) and the Medical University of Vienna (Vienna, Austria) together with an international research team have jointly resolved this pathway, which also involves the known activation of Smo upon binding of Sonig Hedgehog (Shh) to its membrane receptor Patched (Ptch). Smo controls the previously known hedgehog pathway through transcription factors, whereas it controls the newly discovered, must faster, alternative hedgehog pathway through calcium-dependent activation of an AMP-kinase. This rewires metabolism so that the cell can now rapidly absorb large quantities of glucose, rebalancing anabolism and catabolism. Further, rather than promoting efficient energy metabolism through mitochondria, this pathway promotes the much less efficient lactic acid fermentation, the process cancer cells use to acquire their energy anaerobically, as in the Warburg effect.

The US Food and Drug Administration approved the first hedgehog inhibitor, Vismodegib, for treatment of cancer this year. There are presently at least six further agents being tested in clinical studies. Surprisingly, the first patient cohorts receiving Vismodegib have shown serious side effects, such as weight loss and muscle cramps, to the extent that more than half of the participants discontinued use. “Activation of the AMP-kinase and increased catabolism could explain the exaggerated weight loss of the participants in the clinical studies. More importantly though, the influx of calcium into muscle cells leads to instant contraction, and must be triggering the cramps,” explained Prof. Andrew Pospisilik from the Max Planck Institute in Freiburg. Hedgehog inhibitors do not have to lead to these side effects. “We targeted the Smo protein with various substances and found out that there are inhibitors that do not evoke an increase in calcium or glucose values, and, critically, these same inhibitors fail to cause muscle cells to contract in culture," said Prof. Pospisilik.

The scientists also found that cultured fat cells dramatically increase the glucose quantity they can absorb – without relying on insulin. This finding was confirmed by glucose-tolerance tests on mice treated with the classic hedgehog inhibitor cyclopamine, which showed correspondingly lower blood glucose than untreated mice. “Agents that only activate the Smo-calcium/AMP-kinase hedgehog signaling pathway are therefore candidates as medications for treating excess body weight, as well as type-1 and type-2 diabetes. Similar to the broad hedgehog inhibitors, they possess the potential to induce muscle cramps. Thanks to our findings, we now know that a new agent must first be tested on muscle cells before it is used on humans,” said Prof. Harald Esterbauer of the Medical University of Vienna.

The study was published October 12, 2012, in the journal Cell.


Related Links:
Max Planck Institute of Immunobiology and Epigenetics in Freiburg
Medical University of Vienna