Summary: By stimulating cold and nicotine receptors, researchers successfully improved metabolism in mice, helping them to lose weight. Further studies will investigate whether the same results can be achieved in humans.
Source: University of Copenhagen.
Obesity is an increasing problem in the western world, and half of the adult population in Denmark falls into the categories of moderately overweight to obese. Researchers from, among others, the Faculty of Health and Medical Sciences, University of Copenhagen have now found a method to fight this problem with a new treatment. The treatment, which has been tested on mice, burns more energy, suppresses the appetite and produces weight loss.
The researchers have found inspiration in everyday life and investigated whether pharmacologically, they were able to imitate some of the effects from winter swimming and smoking. The result – which the researchers would like to achieve – was an increase in the energy turnover which may happen in cold environments and decreased appetite as you see in connection with uptake of nicotine. First, they investigated how they could activate the so-called cold receptors found e.g. in connection with winter swimming. The cold receptors activate the body’s so-called brown fat which burns energy.
‘We tried to find the molecular mechanisms for the way in which cold increases the burning of energy in order to duplicate them in a medical product. We found a cold receptor – TRPM8 – and identified the substance icilin which can activate it. However, the cold receptor is not found on brown fat. It seems that the cold receptor on the surface of the skin sends a signal to the brain that subsequently activates the brown fat via nerve connectors,’ says Associate Professor Christoffer Clemmensen, CBMR, University of Copenhagen.
‘The mice became slimmer when they were given icilin because it increased their energy turnover. This confirmed our idea. However, the effect we saw was not sufficiently strong to have any actual effect for patients, even if we could optimise the medical product. If you want to change people’s body weight, it is not enough to target the energy turnover alone. To really create a negative energy balance, you also have to make people eat less,’ says Christoffer Clemmensen.
A Synergy Effect on Body Weight
The researchers therefore began to look for something they could combine with icilin treatment. It led them to investigate the so-called nicotinic receptor. The receptor is named after nicotine, because this is one of the substances that can activate the receptor which e.g. decreases the appetite. Following a wide range of tests of various pharmacological substances that could activate nicotinic receptors, researchers discovered dimethylphenylpiperazinium (DMPP).
‘DMPP not only suppresses the appetite, it also has a huge positive effect on glucose metabolism as opposed to e.g. nicotine, which has a poor effect on fat in the liver and insulin sensitivity. We therefore combined icilin and DMPP and achieved what you might call a synergy effect on body weight. This means that two plus two add up to more than four. On their own, they do not produce any particular weight loss, but when we give them together, we see a big weight loss’, explains Associate Professor Christoffer Clemmensen.
In the tests, the mice experienced a weight loss of about 12 per cent over a period of 20 days when they received the combination treatment. Their metabolism was improved and glucose intolerance disappeared. The test results are described in a new study just published in the scientific journal Nature Communications. However, it will require several studies to determine if the combination treatment has the same effect on humans.
Funding: The study is funded by the Alfred Benzon Foundation, the Lundbeck Foundation, the Novo Nordisk Foundation, the European Research Council, the Alexander von Humboldt Foundation, the Hemholtz Alliance ICEMED, the Initiative and Networking Fund of the Hemholtz Association, the Helmholtz Initiative Personalized Medicine iMed and the Helmholtz’ Cross-Program ‘Metabolic Dysfunction’.
Source: Cecilie Krabbe – University of Copenhagen
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to University of Copenhagen.
Original Research: Open access research for “Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes” by Christoffer Clemmensen, Sigrid Jall, Maximilian Kleinert, Carmelo Quarta, Tim Gruber, Josefine Reber, Stephan Sachs, Katrin Fischer, Annette Feuchtinger, Angelos Karlas, Stephanie E. Simonds, Gerald Grandl, Daniela Loher, Eva Sanchez-Quant, Susanne Keipert, Martin Jastroch, Susanna M. Hofmann, Emmani B. M. Nascimento, Patrick Schrauwen, Vasilis Ntziachristos, Michael A. Cowley, Brian Finan, Timo D. Müller & Matthias H. Tschöp in Nature Communications. Published October 23 2018.
Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes
Pharmacological stimulation of brown adipose tissue (BAT) thermogenesis to increase energy expenditure is progressively being pursued as a viable anti-obesity strategy. Here, we report that pharmacological activation of the cold receptor transient receptor potential cation channel subfamily M member 8 (TRPM8) with agonist icilin mimics the metabolic benefits of cold exposure. In diet-induced obese (DIO) mice, treatment with icilin enhances energy expenditure, and decreases body weight, without affecting food intake. To further potentiate the thermogenic action profile of icilin and add complementary anorexigenic mechanisms, we set out to identify pharmacological partners next to icilin. To that end, we specifically targeted nicotinic acetylcholine receptor (nAChR) subtype alpha3beta4 (α3β4), which we had recognized as a potential regulator of energy homeostasis and glucose metabolism. Combinatorial targeting of TRPM8 and nAChR α3β4 by icilin and dimethylphenylpiperazinium (DMPP) orchestrates synergistic anorexic and thermogenic pathways to reverse diet-induced obesity, dyslipidemia, and glucose intolerance in DIO mice.