Amlexanox Abolishes Consequences of Obesity in a Mouse Model

This kinase enzyme complex is part of the upstream NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) signal transduction cascade. The serine/threonine-protein kinase TBK1 (TANK-binding kinase 1) is similar to the I-kappaB kinases and can mediate NF-KappaB activation in response to certain growth factors. For example, the protein can form a complex with the I-kappaB protein TANK and TRAF2 and release the NF-kappaB inhibition caused by TANK.

NF-kappaB is a protein complex that controls the transcription of DNA. As such, it is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-kappaB plays a key role in regulating the immune response to infection, and incorrect regulation of NF-kappaB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development.

Results of a study published in the February 10, 2013, online edition of the journal Nature Medicine revealed that high-throughput screen had identified the well-known drug amlexanox as an inhibitor of the IKKE and TBK1 kinases. Amlexanox (trade name Aphthasol) has antiallergic and anti-inflammatory effects. It is prescribed for the topical treatment of canker sores and as oral tablets (trade name Solfa) for treatment of bronchial asthma.

Treatment of both genetic and dietary-induced obese mice with amlexanox elevated energy expenditure by increasing thermogenesis, which produced weight loss, improved insulin sensitivity and decreased steatosis.

"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 senior author Dr. Alan Saltiel, professor of internal medicine and molecular and integrative physiology at the University of Michigan. "By releasing the brake, amlexanox seems to free the metabolic system to burn more, and possibly store less, energy. 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. Amlexanox seems to tweak the metabolic response to excessive calorie storage in mice. 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."

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