Amlexanox is a medication historically used for inflammatory conditions that has recently gained attention for its potential in metabolic health and weight regulation. The drug’s journey from a topical treatment to a candidate for obesity management is an example of drug repurposing. Researchers began investigating Amlexanox after discovering a link between chronic inflammation, common in obesity, and the regulation of body weight. Preclinical findings provided a novel molecular target for addressing excess weight, insulin resistance, and related metabolic disorders. This has spurred interest in understanding the biological mechanisms that allow this existing drug to promote weight loss and improve metabolic function.
Amlexanox: Primary Medical Applications
Amlexanox is not a newly developed compound, having been used therapeutically for decades for its anti-inflammatory and anti-allergic properties. The most recognized application in the United States is as a topical paste (Aphthasol) for treating recurrent aphthous ulcers, or canker sores. This formulation helps reduce pain and accelerate the healing time of these mouth lesions.
The drug has a broader history of systemic use in other countries, particularly in Japan, where it has been available in tablet form since the 1980s. Its original indications there included treating allergic conditions like bronchial asthma and allergic rhinitis. Amlexanox functions by inhibiting the release of inflammatory mediators, such as histamine and leukotrienes, which drive allergic and inflammatory responses. This established track record provided a foundation for its later investigation into metabolic disorders.
Molecular Mechanism Linking Amlexanox to Weight Loss
Interest in Amlexanox as a weight loss agent began with the discovery that obesity creates a state of chronic, low-grade inflammation within fat tissue and the liver. This inflammation leads to the increased activity of two specific protein kinases: IKK-epsilon (IKK\(\epsilon\)) and TANK-binding kinase 1 (TBK1). These kinases are thought to promote energy conservation, helping sustain energy storage despite insulin resistance.
Amlexanox was identified as a small-molecule inhibitor capable of selectively blocking the activity of both IKK\(\epsilon\) and TBK1. By inhibiting these two kinases, the drug interferes with cellular programming that favors fat storage and reduced energy expenditure. In preclinical studies using diet-induced obese mice, Amlexanox administration resulted in weight loss, which was not attributed to reduced food intake.
The mechanism of weight reduction was found to be an increase in the animal’s energy expenditure, meaning they burned more calories. This effect is primarily achieved through thermogenesis, the biological production of heat. Amlexanox was shown to promote the “browning” of white adipose tissue (WAT), the body’s primary form of fat storage.
White fat cells typically store energy, but Amlexanox stimulates them to take on characteristics similar to brown adipose tissue (BAT), which specializes in heat generation. This transformation is marked by the induction of uncoupling protein 1 (UCP1). UCP1 allows fat cells to dissipate energy as heat instead of storing it as fat, and this increase is a hallmark of enhanced thermogenesis.
Further research revealed that this thermogenic effect depends on the synthesis of Fibroblast Growth Factor 21 (FGF21) in the fat cells. FGF21 acts as a hormone regulating energy metabolism and is necessary for the long-term weight loss effects of Amlexanox treatment. The inhibition of IKK\(\epsilon\) and TBK1 also leads to higher levels of cyclic adenosine monophosphate (cAMP) in fat cells, which further increases the rate at which they burn fat.
In addition to weight loss through enhanced calorie burning, Amlexanox improves insulin sensitivity and reduces fat accumulation in the liver (hepatic steatosis). This improvement in metabolic health is partly due to the drug’s ability to trigger the release of Interleukin-6 (IL-6) from fat cells. IL-6 travels to the liver, signaling the organ to suppress glucose production and helping to lower overall blood sugar levels.
Current Clinical Status and Safety Profile for Weight Management
Despite encouraging findings in animal models, Amlexanox is not currently approved by regulatory bodies like the U.S. Food and Drug Administration (FDA) as a treatment for obesity or Type 2 diabetes. Its application in metabolic disorders remains investigational, meaning its efficacy and safety for these new uses are still being studied in humans. This is distinct from its historical use for conditions like canker sores, which involved topical application or systemic use at different doses.
Preliminary human trials, often called proof-of-concept studies, have evaluated the drug’s potential in obese patients with Type 2 diabetes. One randomized, double-blind, placebo-controlled study involved 42 obese patients who received Amlexanox for three months. The results showed a statistically significant reduction in hemoglobin A1c, a measure of long-term blood glucose control.
The human trials indicated that a specific subset of patients, those who began the trial with higher levels of inflammation in their fat tissue, exhibited a more favorable response. These responders showed improvements in insulin sensitivity and a reduction in liver fat. This correlated with changes in gene expression consistent with increased energy expenditure, suggesting Amlexanox may be most effective in patients whose obesity is linked to a specific inflammatory profile.
When considering the safety profile for off-label use in weight management, it is necessary to consider the known side effects from its use in other applications. Amlexanox has a relatively favorable safety record, especially at the doses used for topical treatment. Systemic administration, such as the oral tablets used for asthma in Japan, revealed a non-serious adverse event profile.
Known side effects include a temporary stinging or burning sensation at the application site for the oral paste, and potential for nausea or diarrhea with systemic use. In the human metabolic trials, no serious adverse events were reported, but a few patients experienced a perivascular inflammatory rash that resolved with local treatment. The use of any drug for an unapproved indication (“off-label” use) carries inherent risks, and patients should only use Amlexanox for weight management within a clinical trial.
The current scientific data suggest that Amlexanox operates through a novel metabolic pathway. However, more extensive and larger-scale human trials are required to confirm its long-term safety and efficacy for the broader population of patients with obesity and metabolic disorders. For now, it remains a promising drug candidate that is providing scientists with a deeper understanding of the inflammatory link between obesity and metabolic dysfunction.