Common Heart Disease Drug reverses obesity by targeting inflammation in mice

It has long been known that obesity is an inflammatory disease, which is the body’s chronic defensive response to stress caused by excess nutrients.

Based on this knowledge, a group of researchers led by Nabil Djouder, head of the Growth Factors, Nutrients and Cancer Group at the Spanish National Cancer Research Center (CNIO), decided to try and fight obesity by preventing inflammation – and they succeeded.

Their article, published this month in Nature Metabolism, shows that digoxin, a drug already used for heart disease, reduces inflammation and results in 40% weight loss in obese mice with no side effects.

Digoxin completely reverses obesity, according to the CNIO. Treated mice had the same weight as healthy, non-obese animals. The mice were also cured of metabolic disorders associated with obesity.

Digoxin reduces the production of a molecule called interleukin 17A (IL-17A) that generally causes inflammation. The study identifies it as a causal factor in obesity: “If you inhibit the production of IL-17A or the signaling pathway that this molecule activates, you are not obese,” says Djouder.

The Madrid researchers found that IL-17A acts directly on adipose tissue, causing obesity and severe metabolic changes associated with weight gain, called metabolic syndrome, which includes type 2 diabetes, high blood pressure and cardiovascular disease.

“In the absence of effective treatments for obesity and metabolic syndrome, digoxin may be an effective therapeutic option,” they wrote in the Nature Metabolism article.

Same food – but the metabolism accelerated

The animals that were obese from a high calorie diet continued to eat as they did before when they took digoxin. However, they showed an activation of their basic metabolism, which leads to the burning of excess fat and weight loss.

Obese mice (left) and lean mice treated with digoxin (right) show improved metabolism and improved fat / CNIO burning

Djouder’s group at the CNIO observed weight loss within a few weeks without any adverse effects. The benefits persisted for at least eight months, suggesting that mechanisms of resistance are not developing.

These results are therefore clinically relevant: “It is tempting to suggest that obese patients take digoxin for short periods of time until weight loss stabilizes and then eat healthily,” says Ana Teijeiro, lead author of the paper. “The drug could also be indicated in obesity-related conditions such as hypercholesterolemia, liver steatosis and type 2 diabetes,” added Teijeiro.

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However, the researchers also emphasize that the results were obtained in mice and that epidemiological studies and clinical studies are needed to confirm them in humans.

The “First Causal Link Between Obesity and Inflammation”

In addition to this potential clinical relevance, the finding has fundamental value in that it “identifies a causal relationship between inflammation and weight gain,” according to the authors. It opens new avenues for important research to elucidate the molecular mechanisms that make obesity an inflammatory disease.

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

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“We still don’t know how nutrients trigger the inflammatory response or which cells produce interleukin 17A, and that’s what we’re going to investigate next,” reveals Djouder. “Understanding the relationship between excess nutrients, inflammation and obesity is important in finding new approaches to treating weight gain,” he adds.

Defined by the authors of the paper as “excessive fat accumulation normally caused by chronic overeating and / or inadequate physical activity,” obesity today has no effective treatment.

“Current options are limited and have not improved in the last 20 years, largely due to insufficient understanding of the pathophysiology of obesity and the mechanisms that control fat accumulation,” the team wrote.

Therapies based on lifestyle changes – changes in diet and physical activity – achieve a weight reduction of approximately 10%, and drugs that target appetite or fat absorption typically result in a weight loss of between 2% and 7%.

This study offers a possible therapeutic strategy based on a novel approach: combating obesity by targeting its inflammatory component.

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The team started this line of research five years ago when they observed mice lose weight in another study of inflammation and liver cancer, so they postulated that blocking the production of IL-17A with digoxin would decrease the effects of IL-. 17A and thus reduce the weight of the mice. “We saw that straight away,” says Djouder.

An already available drug

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

In addition, the dose at which digoxin is currently used in humans is three times lower than that in mice to combat obesity with no toxic effects. The fact that no side effects have been observed in animals suggests that in humans the dose at which weight loss has been observed may not be harmful.

This study was funded by the Spanish Ministry of Science and Innovation, the government research agency co-funded by the European Regional Development Fund, the Carlos III Health Institute, the European Foundation for the Study of Diabetes and the Pfizer Foundation.

Source: CNIO

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