Researchers in Europe and Australia have developed an anti-obesity “chemical cigarette” that exploits the body’s natural responses to both cold exposure and smoking. The new approach uses two chemicals to boost energy expenditure and fat burning, while simultaneously dampening appetite, improving lipid metabolism, and reversing glucose intolerance.

Tested in obese mice, the weight-loss approach couples treatment using a compound called icilin that stimulates a target (TRPM8) involved in the regulation of cold sensing—and so mimic the thermogenesis-stimulating effects of cold exposure—with another compound,  dimethylphenylpiperazinium (DMPP), which activates receptors in the brain to recapitulate the appetite-suppressant effects of smoking. Obese mice given the combination therapy lost about 12% of their body weight within 20 days. And while nicotine has adverse effects on the body’s metabolism, the combination of icilin and DMPP also improved dyslipidemia and glucose tolerance. The team concludes that their experiments support the “compelling potential” to target both pathways for treating obesity, type 2 diabetes, and fatty liver disease.

It was the combination of icilin and DMPP that achieved “what you might call a synergy effect on body weight,” comments Christoffer Clemmensen, Ph.D., who is an associate professor at the University of Copenhagen Faculty of Health and Medical Sciences, and corresponding author of the researchers’ paper in Nature Communications. “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.”

The researchers report their experiments and results in a paper titled, “Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes.”

Obesity is a global epidemic in the western world, and half of the adult population in Denmark is classed as moderately overweight to obese. Scientists have been investigating the potential use of drugs to stimulate metabolic rate and burn fat, since before the mid-20th century, but the side effects have probably contributed to diverting anti-obesity research towards appetite suppressants as another approach, the authors write.

Over the last decade, however, the discovery that brown adipose tissue (BAT) or brown fat, in humans generates heat in response to cold exposure has “reinvigorated” research on BAT thermogenesis, and the potential to develop therapeutic strategies against obesity that increase energy expenditure.

Working with colleagues in Germany, Denmark, Australia, and the Netherlands, the University of Copenhagen team developed a combination drug-based approach to weight loss that combines two different mechanisms. One of the drugs is designed to stimulate the body’s cold-sensing circuits and so increases energy expenditure by turning up fat burning. “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,” notes Dr. Clemmensen. “We found a cold receptor—TRPM8—and identified the substance icilin which can activate it.”

The authors acknowledge that targeting TRPM8 to increase energy expenditure as a means to combat obesity has previously been suggested. But because triggers that increase energy expenditure tend to stimulate increased appetite, the researchers also looked for another drug that could be administered at the same time to switch on appetite suppressant pathways that are triggered by smoking, through the nicotinic acetylcholine receptor (nAChR) subtype α3β4 in the brain.

“… we hypothesized that additional pharmacology concurrently targeting central satiety circuits would complement TRPM8-based pharmacology to achieve greater weight loss,”  the researchers continue. α3β4 seemed to be an ideal target as stimulating α3β4 also acts to increase lypolysis and “somewhat paradoxically” they note, nAChR activation, in addition, acts to lower body temperature.“Inspired by the efficiency of two canonical environmental modulators of human energy metabolism—tobacco smoking and cold exposure—to suppress appetite and increase energy expenditure, respectively, we here explored a novel pharmacological strategy in which we aimed to simultaneously mimic the metabolic benefits of both phenomena through a “biochemical cigarette”.

The team first tested each half of the combination therapy alone, in a diet-induced obese mouse model. Treating animals for 14 days using the TRPM8 agonist icilin to mimic the effects of cold exposure resulted in dose-dependent weight loss and fat mass reduction as a result of increased energy expenditure. But while the treatment didn’t appear to affect appetite, it also didn’t have enough of an effect on energy turnover to suggest that it would be clinically effective in humans.

Moreover, the cold receptor isn’t present in brown fat so, icilin doesn’t appear to directly stimulate brown fat. Rather it seems that the cold receptor on the surface of the skin signals the brain to activate the brown fat via nerve connectors, Dr. Clemmensen continues. “’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. 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.”

Encouragingly, tests in the same diet-induced mouse model of obesity showed that DMPP monotherapy led to dose-dependent reductions in body weight, in a similar manner to nicotine, by suppressing food intake, but unlike nicotine DMPP also benefited metabolism.  “… in contrast to nicotine, DMPP markedly improved diet-induced glucose intolerance, even at doses with negligible effect on body weight change,” the authors write. “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,” Dr. Clemmensen notes.

When the researchers then tested both compounds together, the combination therapy worked synergistically to lower body weight, reduce food intake, and increase energy expenditure, and also correct diet-induced glucose intolerance. “ … long-term glycemic benefits were further improved when DMPP and icilin were coadministered,” the authors write.  And while each compound administered as monotherapy improved diet-induced non-alcoholic fatty liver disease, “the combination of DMPP and icilin was superior to the monotherapies with respect to improving NAFLD and NASH,” the team comments.

“In summary, we report that stimulation of TRPM8 represents a novel strategy to pharmacologically mimic the benefits of cold exposure on energy metabolism,” they conclude. “The ability of the potent TRPM8 agonist icilin to induce a negative energy state is substantially potentiated by coordinated activation of nAChRs by DMPP. The combination of DMPP and icilin engages central satiety circuits and increases BAT thermogenesis, which ultimately improves diet-induced obesity, glucose intolerance, and hepatic steatosis in mice. Conclusively, these data support the compelling potential in the coordinated targeting of TRPM8 and α3β4-nAChRs for the treatment of the related epidemics of obesity, type 2 diabetes, and fatty liver disease.”

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