Two-pronged approach -- Novel combined therapy tackles excess fatty tissue

October 26, 2018

"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.

Two-pronged approach

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.
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Further information

* 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.

Original Publication:

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

https://www.nature.com/articles/s41467-018-06769-y

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus, allergies and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. https://www.helmholtz-muenchen.de/

The Institute of Diabetes and Obesity (IDO) studies the diseases of the metabolic syndrome by means of systems biological and translational approaches on the basis of cellular systems, genetically modified mouse models and clinical intervention studies. It seeks to discover new signaling pathways in order to develop innovative therapeutic approaches for the personalized prevention and treatment of obesity, diabetes and their concomitant diseases. IDO is part of the Helmholtz Diabetes Center (HDC). https://www.helmholtz-muenchen.de/ido | https://www.helmholtz-muenchen.de/hdc

The Technical University of Munich (TUM) is one of Europe's leading research universities, with around 550 professors, 41,000 students, and 10,000 academic and non-academic staff. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, combined with economic and social sciences. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with the TUM Asia campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany.https://www.tum.de/nc/en/homepage/

The German Center for Diabetes Research (DZD) is a national association that brings together experts in the field of diabetes research and combines basic research, translational research, epidemiology and clinical applications. The aim is to develop novel strategies for personalized prevention and treatment of diabetes. Members are Helmholtz Zentrum München - German Research Center for Environmental Health, the German Diabetes Center in Düsseldorf, the German Institute of Human Nutrition in Potsdam-Rehbrücke, the Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Medical Center Carl Gustav Carus of the TU Dresden and the Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard-Karls-University of Tuebingen together with associated partners at the Universities in Heidelberg, Cologne, Leipzig, Lübeck and Munich. https://www.dzd-ev.de/

Helmholtz Zentrum München - German Research Center for Environmental Health

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