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Drug discovery

Amlexanox reverses obesity and diabetes in mice

Study could lead to new treatments for diabetes and obesity

An off-patent drug currently prescribed for the treatment of asthma and other uses, also reverses obesity, diabetes and fatty liver in mice, researchers from the University of Michigan's Life Sciences Institute have reported. The study, "An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice, was published online in the journal Nature Medicine.

"One of the reasons that diets are so ineffective in producing weight loss for some people is that their bodies adjust to the reduced calories by also reducing their metabolism, so that they are defending' their body weight," said Dr Alan Saltiel, Mary Sue Coleman director of the Life Sciences Institute Saltiel. "Amlexanox seems to tweak the metabolic response to excessive calorie storage in mice."

Alan Saltiel, director of the University of Michigan's Life Sciences Institute. Image credit: Scott Soderberg, Michigan Photography.

In 2009, Saltiel and colleagues previously reported in the journal Cell that the genes IkappaB kinase epsilon and TANK-binding kinase 1 play a crucial role for maintaining metabolic balance. They are induced in liver and fat by NF-κB activation upon high-fat diet feeding and in turn initiate counter inflammation that preserves energy storage. Amlexanox is an inhibitor of these kinases.

For this latest research, they used high-throughput chemical screening to search for compounds that inhibit IKKE and TBK1. They then demonstrated that treating obese mice with amlexanox elevates energy expenditure through increased thermogenesis, producing weight loss, improved insulin sensitivity and decreased steatosis. Because of its record of safety in patients, amlexanox may be an interesting candidate for clinical evaluation in the treatment of obesity and related disorders, the authors note.

"Amlexanox appears to work in mice by inhibiting two genes - IKKE and TBK1 - that we think together act as a sort of brake on metabolism," said Saltiel. "By releasing the brake, amlexanox seems to free the metabolic system to burn more, and possibly store less, energy."

The researchers do not know if humans will respond with the same pathway, or if the discovery of amlexanox's effectiveness in mice can lead to a compound that is safe and effective for treating obesity and diabetes in humans.

Saltiel is in discussions with clinical trial specialists to test whether amlexanox will be useful for treating obesity and diabetes in humans. He is also working with medicinal chemists to develop a new compound based on the drug that optimises its formula.

"These studies tell us that, at least in mice, the IKKE/TBK1 pathway plays an important role in defending body weight by increasing storage and decreasing burning of calories, and that by inhibiting that pathway with a compound, we can increase metabolism and induce weight loss, reverse diabetes and reduce fatty liver," he said.

 

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