Obesity: Teaching an Old Drug New Tricks—Amlexanox Targets

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RESEARCH HIGHLIGHTS Nature Reviews Endocrinology 9, 185 (2013); published online 26 February 2013; doi:10.1038/nrendo.2013.42 © iStockphoto/Thinkstock

OBESITY Teaching an old drug new tricks—amlexanox targets inflammation to improve metabolic dysfunction mlexanox, an anti-inflammatory were already obese: to leptin-deficient of obesity or type 2 diabetes mellitus is medication used to treat mouth ob/ob mice, to test the drug’s effects on bound to generate a vast amount of interest. Aulcers and asthma, could have some genetic obesity, and to diet-induced “The specific action of amlexanox is benefit for the treatment of obesity and obese mice. Body weights of both groups remarkable,” comments Michael I. Goran type 2 diabetes mellitus, a study published returned to almost normal, and the weight (Keck School of Medicine, Childhood in Nature Medicine shows. Moreover, the loss was maintained for as long as the drug Obesity Research Center, University of findings shed light on how energy balance was administered. Southern California, Los Angeles, CA, is regulated by inflammation. To elucidate the mechanism underlying USA), who is not affiliated with the study. Myriad studies in animals and in the effects of amlexanox, the investigators “This very targeted approach to reduce humans implicate inflammation in the performed a detailed assessment of inflammation might cause less serious development of obesity-associated insulin metabolic parameters, including insulin adverse effects compared with blunting a resistance. “We have been studying sensitivity (by hyperinsulinaemic whole arm of the inflammation pathway,” inflammatory links between obesity and euglycaemic clamp studies), energy points out Goran, “and could potentially insulin resistance for some time, with expenditure (by indirect calorimetry), avoid a trade-off between improving a particular focus on macrophages in phosphorylation patterns and in vivo and metabolic health and the potential adverse adipose tissue,” recounts senior study in vitro changes in energy disposition. effect of immunocompetence that can arise investigator Alan R. Saltiel (University “The answer is that amlexanox restores the when using general anti-inflammatories to of Michigan, Ann Arbor, MI, USA). ability of mice to adapt to increased caloric address adipose tissue inflammation.” “Our discovery of macrophage subtype intake by subsequently increasing energy Saltiel and his team plan to build switching during obesity led us to search expenditure through on their findings and elucidate the NH for genes involved in this O N 2 thermogenesis,” mechanisms underlying IKK-ε and TBK1 process, and we learned explains Saltiel. activity. “We have some leads on the that expression of the Importantly, the kinase substrates and are also looking at noncanonical O findings by Saltiel gene expression patterns over time in mice IκB kinases and colleagues treated with amlexanox,” says Saltiel. “At IKK-ε and TBK1 further elucidate the the same time, we are planning clinical was elevated O OH mechanisms through trials in patients with obesity and type 2 in obesity and insulin resistance.” In a which inflammation diabetes mellitus and nonalcoholic fatty previously published study, Saltiel and modulates energy balance. “We suspect liver disease, which we hope to start soon.” colleagues found that mice lacking IKK-ε that obesity-related inflammation The outcome of these human studies who were fed a high-fat diet gained produces not only insulin resistance but will determine the actual impact that less weight and developed less insulin also catecholamine resistance, in such a the findings by Saltiel and co-workers resistance and fatty liver disease than way that fat cells (and possibly liver cells) will have on clinical practice. Given control mice. This finding prompted become metabolically inflexible and are that data on long-term drug effects in the investigators to search for chemical unable to respond to either anabolic or large patient populations are lacking, inhibitors of the two kinases. catabolic signals,” says Saltiel. In other enthusiasm for this old drug’s new tricks Saltiel’s team screened 150,000 chemical words, the results suggest that IKK-ε and should be coupled with caution. “As this compounds, including drugs already on TBK1 are part of a counterinflammatory drug is capable of modulating immune the market and chemicals derived from process that sustains energy storage activation, it is critical to determine what natural sources, and identified amlexanox, in the presence of insulin resistance. unintended consequences treatment could an approved small-molecule therapeutic, The authors speculate that the reduced have in the face of pathogen exposure,” as a high-affinity inhibitor of IKK-ε. The inflammation observed with amlexanox concludes Goran. researchers then fed mice a high-fat diet treatment is an indirect effect of improved and treated one group with amlexanox. metabolic disease or, perhaps, the result Linda Koch Whereas untreated mice became of elimination of a feedback loop that obese, animals treated with amlexanox maintains inflammation at low levels. maintained their body weight. In a second Amlexanox has been in clinical use for Original article Reilly, S. M. et al. An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic experiment, Saltiel and co-workers more than 25 years, and the possibility that dysfunctions in mice. Nat. Med. doi:10.1038/nm.3082 administered amlexanox to mice that it might be repurposed for the treatment