Researchers at the University of Michigan’s Life Sciences Institute have found that amlexanox, an off-patent drug used to treat asthma and canker sores, can also reduce obesity, diabetes and fatty liver disease in mice.
The team led by Life Sciences Institute director, Alan Saltiel, focused on the impact that the drug amlexanox has on the genes IKKE and TBK1 in mice. This followed on from research the Saltiel lab published in Cell Magazine in 2009 suggesting a link between the genes, obesity, insulin resistance and diabetes. Saltiel maintains IKKE and TBK1 play a crucial role maintaining "metabolic balance."
Professor Saltiel explains that IKKE and TBK1 are part of a process of inflammation linked to obesity and insulin resistance, the condition that precedes Type 2 diabetes.
“The basic story is that IKKE and TBK1 are elevated in obesity due to the generation of inflammation, and in turn are involved in repressing adaptive energy expenditure and producing insulin resistance,’’ Professor Saltiel told Gizmag.
“Thus, we think that these genes play a "counter-inflammatory" role, keeping inflammation at a low grade, sustained level, without allowing resolution, and preserving energy storage in fat and liver.”
Saltiel says this might explain why some people struggle to lose weight. “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’.’’
Based on that research, the next step was to find compounds that would inhibit the expression of IKKE and TBK1. After some high-throughput chemical screening at the Institute’s Center for Chemical Genomics, Saltiel and his team identified amlexnox – a drug that has been used to treat asthma in Japan for the last 25 years and to treat canker sores in the United States.
They tested the drug on both genetic and dietary-induced obese mice, finding that it elevated energy expenditure in the mice, increasing the heat in their bodies and producing weight loss. In addition to treading obesity, it reversed related metabolic problems such as diabetes and fatty liver.
“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," says Saltiel.
Saltiel is now working with University of Michigan clinical trial specialists to test whether the drug will have the same impact on obese and diabetic humans as it did on mice. Clinical studies are planned for later this year.
“I have no idea whether or not it will work in patients, but we'll find out,’’ says Saltiel.
There is however room for optimism as amlexanox has been found to be safe for patients, and humans also have the same genetic pathways as mice. Saltiel is also working with medicinal chemists at the university to develop a new compound based on the drug that would optimize its formula.
The research was supported by the National Institutes of Health, the Michigan Diabetes Research and Training Center, the Michigan Institute for Clinical and Health Research, and the Nathan Shock Center in the Basic Biology of Aging.
The findings have been published in the journal Nature Medicine
Source: University of Michigan
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