“Obesity is the biggest risk factor in the development of type 2 diabetes and cardiovascular diseases,” says Professor Matthias H. Tschöp, who was recently appointed CEO of the Helmholtz Zentrum München and also holds the Chair of Metabolic Diseases at TUM. Previously he was Director of the Institute for Diabetes and Obesity (IDO) at the Center. “Unfortunately, diet alone is obviously not sufficient to solve the ever-rising obesity problem, which is why drug-based therapeutic approaches are urgently required,” he adds. Along with Dr. Timo Müller (Acting Director of the IDO), Dr. Christoffer Clemmensen (formerly IDO, now at the University of Copenhagen) and Sigrid Jall (PhD student at the IDO), he therefore developed a new strategy*. Using a novel combined therapy, the scientists succeeded in reducing excess adipose tissue by suppressing the appetite and at the same time increasing energy expenditure.
Drug simulates the effects of cold
The new combined therapy takes its cue from nature. “It has long been known that our energy expenditure increases in cold surroundings. This is how the body attempts to maintain a constant temperature,” Clemmensen notes. Mammals, including humans, have special fat cells for this purpose – so-called brown fat cells, which specialize in converting energy into heat. A key mechanism in this process is based on the fact that, when activated, special cold receptors (TRPM8 channels) transmit the cold signal to the brown fat. One of the components of the new treatment strategy is icilin, a cold- mimicking molecule that triggers precisely this effect. “Icilin activates TRPM8 channels and thus boosts our metabolic rate, but importantly without a cold environment,” Sigrid Jall explains. Drug-induced activation of TRPM8 in obese mice stimulated brown adipose tissue, resulting in an increase in energy expenditure and a reduction in body weight.
The fight against hunger pangs
The second component in the new treatment aims to curb the appetite and thus reduce food intake. Here the researchers used a molecule which, like nicotine, activates so-called nicotinic acetylcholine receptors (nAChRs) in the brain. These receptors are found in special nerve cells in the hypothalamus. When they are activated, this generates a greater feeling of fullness and the appetite wanes. In their experiments, however, the researchers did not use the rather toxic nicotine, but instead the less harmful and considerably more specific dimethylphenylpiperazinium (DMPP). In obese mice, DMPP not only lead to a reduction in food intake but significantly improved glucose metabolism.
In the course of their experiments the scientists made one particularly important discovery, namely that combining icilin and DMPP lowered body weight and improved glucose metabolism to a much greater degree than the added single effects of individual treatment with icilin and DMPP. Monotherapy with icilin or DMPP only had a minor impact on body weight. “However, if both treatments are combined in a single therapy, body weight and glucose metabolism improve sustainably. We have thus gained important knowledge that can help us to develop new therapeutic approaches in the treatment of obesity and diabetes”, Matthias Tschöp says.
The researchers will now conduct further experiments to discover why a combination of the two molecules is so much more effective than each substance on its own. “The results of these studies can provide important new insights into molecules and how they mutually enhance their effect, which could have a major impact on the development of future therapies,” Timo Müller concludes.
* At Helmholtz Zentrum München, the Institute of Diabetes and Regeneration Research (IDR), the Core Facility Pathology & Tissue Analytics and the Institute for Biological and Medical Imaging were also involved in the project.
Clemmensen, C. & Jall, S. et al. (2018): Coordinated Targeting of Cold and Nicotinic Receptors Synergistically Improves Obesity and Type 2 Diabetes. Nature Communications, DOI: 10.1038/s41467-018-06769-y