Stimulating the body’s cold and nicotine receptors burns energy, suppresses appetite, and may lead to weight loss, a study with mice shows.
Inspired by everyday life, researchers wondered whether they could pharmacologically imitate some of the effects from winter swimming and smoking.
The result was an increase in the energy turnover which may happen in cold environments and decreased appetite like that seen with nicotine. First, researchers investigated how they could activate the so-called cold receptors found, for example, 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,” says Christoffer Clemmensen, associate professor at the University of Copenhagen.
“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.”
“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,” Clemmensen says.
“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 optimize the medical product,” he explains.
“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.”
So, the researchers began to look for something they could combine with the icilin treatment and focused on the so-called nicotinic receptor. The receptor is named after nicotine, because it is one of the substances that can activate the receptor which decreases 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 nicotine, which has a poor effect on fat in the liver and insulin sensitivity,” Clemmensen says.
“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,” he says.
In the tests, mice experienced a weight loss of about 12 percent over a period of 20 days when they received the combination treatment. Their metabolism was improved and glucose intolerance disappeared.
Several studies are still needed to determine if the combination will have the same effect on humans, the researchers say.
The study appears in Nature Communications.
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 funded the work.
Source: University of Copenhagen
