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Feb 11, 2013

Old Drug Plays New Tricks on Diabetes and Obesity

  • Amlexanox, an off-patent drug currently prescribed for the treatment of asthma and other uses, also reverses obesity, diabetes, and fatty liver in mice, according to researchers at the University of Michigan’s Life Sciences Institute (LSI).

    Different formulations of amlexanox are currently prescribed to treat asthma in Japan—where it has been on the market for more than 25 years—and canker sores in the U.S. Alan R. Saltiel, Ph.D., the Mary Sue Coleman director of the Life Sciences Institute, is teaming up with clinical-trial specialists at U-M to test whether amlexanox will be useful for treating obesity and diabetes in humans. He is also working with medicinal chemists at U-M to develop a new compound based on the drug that optimizes its formula.

    “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,” he explains. “Amlexanox seems to tweak the metabolic response to excessive calorie storage in mice.

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

    Using high-throughput chemical screening at LSI’s Center for Chemical Genomics to search for compounds that inhibit IKK-ε and TBK1, the researchers hit upon an approved off-patent drug: amlexanox. They then demonstrated that amlexanox had profound beneficial effects in both genetic and dietary-induced obese mice. The chemical lowered the weight of obese mice and reversed related metabolic problems such as diabetes and fatty liver.

    “These studies tell us that, at least in mice, the IKK-ε/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,” Dr. Saltiel says.

    However, the researchers don’t yet know if humans respond with the same pathway, or if the discovery of amlexanox’ effectiveness in mice can lead to a compound that is safe and effective for treating obesity and diabetes in humans. “We will be working hard on that,” Dr. Saltiel assures.

    The study, titled “An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice”, was published online yesterday in Nature Medicine.


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