The researchers suggest that their study offers up a possible therapeutic strategy based on a novel approach: fighting obesity by targeting its inflammatory component. Study lead Nabil Djouder, PhD, head of the Growth Factors, Nutrients and Cancer Group at the CNIO, commented, “When you inhibit the production of IL-17A or the signaling pathway that this molecule activates, you don’t have obesity … Digoxin, an already available drug, any derivative of it, or other inhibitors of IL-17A production could be very efficient anti-obesity and metabolic disease treatments.” Djouder, and colleagues describe their studies in Nature Metabolism, in a paper titled, “Inhibition of the IL-17A axis in adipocytes suppresses diet-induced obesity and metabolic disorders in mice.”
Obesity is a major global health problem that demonstrates what the authors call an “increasingly alarming incidence.” The team cites WHO figures estimating that globally, there are some 1.9 billion overweight adults, and 600 million obese adults. “… 51% of the global population is predicted to be obese by 2030,” the team further noted.
While obesity occurs through “excessive fat accumulation usually caused by chronic overfeeding and/or inadequate physical activity,” the investigators wrote, there is currently no effective treatment. “Current options are limited and have not improved in the last 20 years, mainly due to insufficient knowledge about the pathophysiology of obesity and the mechanisms governing fat accumulation.” Treatment 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 loss of body weight between 2% and 7%.
It is well recognized that obesity is an inflammatory disease, effectively a chronic defensive reaction of the body to stress caused by excess nutrients. Based on this knowledge, the team led by Djouder considered a potential therapeutic approach to obesity that would prevent inflammation. Djouder’s group at the CNIO started this line of research five years ago, when, in another study on inflammation and liver cancer, they observed that mice were losing weight. Evidence from other studies has previously indicated that nutrients can induce inflammation through a process mediated by IL-17A, the key component of inflammation. “A growing body of evidence indicates that nutrients are inflammatory by themselves and increase IL-17A levels, which depend on the activation of the transcription factor retinoic-acid-receptor (RAR)-related orphan receptor (ROR) γ thymus (RORγt) … These findings suggest possible links among nutrient overload, the IL-17A axis, obesity and metabolic diseases, but mechanisms of action remain unknown,” the team commented.
Digoxin has long been used to treat heart failure, and is known to act on IL-17A. The researchers postulated that using digoxin to block the production of IL-17A by immTo test this out they treated diet-induced obese (DIO) mice using various doses of digoxin. “We explored the potential therapeutic value of inhibiting IL-17A signaling in obesity and associated metabolic disorders by simultaneously treating C57BL/6 mice with a high-fat diet (HFD) and varying doses of digoxin in their drinking water.”
The results confirmed that even while the obese animals continued to eat their high fat diet, digoxin administration was associated with dramatic weight loss, and metabolic improvements, which started within just a week of initiating treatment. “… digoxin treatment for 1 week simultaneously reduces body weight and improves metabolic dysfunction,” the investigators noted “ …Digoxin-treated obese C57BL/6 mice gradually, but strikingly, lost 41% of their body weight after 1 month of treatment, eventually reaching the basal body weight of normal diet (ND)-fed mice,” the team wrote. Importantly, at the higher dose level, digoxin therapy completely restored glucose homeostasis, indicating that digoxin dose-dependently reduces features of metabolic syndrome, they further noted.
The benefits of digoxin administration to the HFD-fed mice were maintained for at least eight months, suggesting that treatment doesn’t lead to the development of resistance mechanisms. “ … digoxin-induced body weight loss was maintained until the treatment ended, suggesting that chronic treatment does not induce resistance,” they stated. But when digoxin therapy was withdrawn, the animals started to put weight back on. “… removal of digoxin from drinking water after after 3 months of treatment (digoxin OFF) progressively but completely reversed body weight loss.” Interestingly, administering recombinant IL-17A to the digoxin-treated high-fat diet-fed obese mice also led to weight gain, “…supporting that digoxin effects are mediated through the inhibition of RORγt and subsequent reduction of IL-17A production,” the scientists commented.
While the weight loss effects of digoxin on obese mice were dramatic, similar effects of digoxin on weight loss in humans haven’t previously been noted, the authors acknowledged. Djouder credited this to the fact that cardiovascular disease of patients using digoxin causes high liquid retention, which masks the weight-loss effect of digoxin.
“This lack of effects on body weight loss in humans can be explained by the huge liquid retention (>20 L) in individuals with heart failure, most likely interfering with body weight measurements, and possibly influencing the final data,” the team stated.
It might also be possible that it might be necessary to increase the digoxin dose in humans to induce weight loss. “Indeed, according to current recommendations for dose conversion, digoxin doses used to treat humans are approximately sixfold lower than the doses used to treat mice (1–2 mg/kg body weight), suggesting that they are suboptimal for weight loss,” the scientists pointed out. And the fact that no side effects were observed in animals suggests that, in humans, the dose at which weight loss could be observed may not be harmful.
The findings could have key clinical relevance, the authors suggest. “It is tempting to propose that obese patients could take digoxin for a short period until weight loss stabilizes, and then follow a healthy diet,” noted Ana Teijeiro, PhD, first author of the paper. Independently of weight loss, the drug could also be used to improve insulin sensitivity and/or hypercholesterolemia, the tea noted. “The drug could also be indicated for obesity-related pathologies, such as hypercholesterolemia, hepatic steatosis and type 2 diabetes,” Teijeiro added.
The researchers acknowledged that their results were obtained in mice, and that epidemiological studies and clinical trials are required to corroborate them in humans. Nevertheless, they concluded, “These findings reveal an unanticipated role for IL-17A in adipocyte biology, in which its direct action pathogenically reprograms adipocytes, promoting DIO and metabolic syndrome.” Targeting the IL-17A axis could thus represent an efficient antiobesity strategy. “Since no effective medical treatments for obesity and metabolic syndrome are available, and development of new drugs may be time-consuming and costly, analogues of digoxin or other RORγt–IL-17A axis inhibitors may represent metabolically potent and effective therapeutic options.”
They further noted that in addition to the potential clinical relevance of their findings, the study has added value in that it identifies a causal link between inflammation and weight gain. This opens new avenues for crucial 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, which acts directly on adipocytes and changes their genetic profile and responsiveness to excess nutrients,” Djouder said.
“We still don’t know how nutrients trigger the inflammatory reaction or which cells produce interleukin 17A, and that is what we are going to study next. Understanding the connection between nutrient excess, inflammation and obesity is essential to find novel approaches to treat weight gain.” he added.
