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A drug already in use in humans corrects obesity in mice without side effects

The obesity is a inflammatory disease, that is to say, a chronic defensive reaction of the organism before the aggression that the excess of nutrients supposes. Based on this knowledge, a team from the National Cancer Research Center (CNIO) decided to try to combat the disease by avoiding inflammation, and it has been successful in rodents.

The work, directed by Nabil djouder and published this week in Nature Metabolism, shows that a drug already in use against cardiovascular diseases, the digoxin, reduces inflammation and achieves weight loss of 40% in obese mice, no side effects.

According to the authors, digoxin completely reversed obesity: treated mice reached the same weight as healthy non-obese animals and were cured of associated metabolic disorders

What’s more, according to scientists, digoxin can completely reverse obesity. The treated mice reached the same weight as healthy non-obese animals and were cured of the metabolic disorders associated with obesity.

Digoxin works by reducing the production of a molecule, called interleukin 17A or IL-17A, which generally causes inflammation. Thus, the authors have identified this molecule as a causal element of obesity. “When IL-17A production or the signaling pathway that it activates is inhibited, there is no obesity,” explains Djouder.

Researchers have found that IL-17A acts directly on the adipose tissue, causing obesity and severe metabolic alterations associated with overweight. These pathologies are part of the so-called metabolic syndrome and are, among others, the type 2 diabetes, the hypertension and the cardiovascular diseases. Obesity also increases the risk of suffering Cancer.

“As of today, there are no effective medical treatments for obesity or metabolic syndromeHence, digoxin may represent an effective therapeutic option ”, point out the experts.

Digoxin activates basal metabolism

The animals, obese from being subjected to a hypercaloric diet, continued to eat the same food while taking digoxin. However, they showed an activation of the basal metabolism, which generates a consumption of excess fat and weightloss.

Djouder’s group observed weight loss as early as a few weeks, with no adverse effects. Profits were sustained for at least 8 months, which suggests that resistance mechanisms do not develop.

The researchers emphasize that the result is in mice, and that it requires epidemiological studies and clinical trials to be corroborated in humans.

The finding is of clinical relevance: “It is tempting to propose that obese patients take digoxin for a short period, until their weight loss stabilizes, and then follow a healthy diet“, it states Ana Teijeiro, first signatory of the work.

“The drug could also be indicated against pathologies associated with obesity, such as hypercholesterolemia, hepatic steatosis or type 2 diabetes ”, he adds.

However, the researchers emphasize that the result is in mice, and that it requires epidemiological studies and clinical trials to be corroborated in humans.

obese and drug-treated mouse adipocytes

Visualization of adipocytes from an obese mouse (left) and a lean mouse treated with digoxin (right), showing a better response to excess nutrients and fat consumption. / CNIO

First causal link between obesity and inflammation

In addition to this possible clinical relevance, the finding is of basic value because it “identifies a causal link between inflammation and weight gain,” say the authors. Thus, crucial research avenues are opened to elucidate the molecular mechanisms that make obesity an inflammatory disease.

Weight loss and systemic metabolic changes are controlled by a unique molecular mechanism, IL-17A, which acts directly on adipocytes, changing their genetic profile and their ability to respond to excess nutrients

Nabil Djouder, CNIO researcher

“Thanks to this study, we know that weight loss and systemic metabolic changes are controlled by a unique molecular mechanism, IL-17A, which acts directly on adipocytes, changing their genetic profile and their ability to respond to excess nutrients. ”Says Djouder.

“We still do not know how nutrients activate the inflammatory reaction or which cells produce interleukin 17A, this is the next thing we are going to study. A good understanding of the connection between excess nutrients, inflammation and obesity is essential to find novel approaches to treat weight gain, “he adds.

A drug already available

Digoxin has long been used to treat heart failure, and it was known to act on IL-17A. Its effect on body weight, however, had never been observed. Djouder attributes this to the fact that cardiovascular disease in patients who use it causes powerful fluid retention, which masks the ‘slimming’ effect of digoxin.

Digoxin has long been used to treat heart failure, and it was known to act on IL-17A. Its effect on body weight, however, had never been observed

In addition, the dose at which digoxin is currently used in humans is three times lower than that used in mice to combat obesity, without toxic effects. That no side effects have been reported in animals suggests that, in humans, the dose at which weight loss might be observed might not be harmful.

“Digoxin, any derivative or other inhibitors of IL-17A production could be used as anti-obesity treatments and against metabolic diseases very efficiently. They should be taken into account in clinical trials to treat these diseases ”, concludes Djouder.

Reference:

Ana Teijeiro, Amanda Garrido, Anna Ferre, Cristian Perna, Nabil Djouder. Inhibition of the IL-17A axis in adipocytes suppresses diet-induced obesity and metabolic disorders in mice. Nature Metabolism, 2021. DOI: 10.1038 / s42255-021-00371-1

This study has been funded by the Ministry of Science and Innovation, the State Research Agency co-financed with the European Regional Development Fund, the Carlos III Health Institute, the European Foundation for the Study of Diabetes and the Pfizer Foundation.

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