Research press release


Nature Medicine

Targeting inflammation to treat obesity and diabetes


肥満には軽度の炎症がともなうことが多く、それがインスリン抵抗性と2型糖尿病発症に寄与すると考えられている。Alan Saltielたちはin vitroでの大規模な化学物質スクリーニングによって、IKK-εとそれに良く類似したキナーゼTBK1とを阻害する低分子化合物を同定した。これら阻害剤の1つアンレキサノクスは、この2種類のキナーゼを比較的選択的に阻害することがわかった。またアンレキサノクスが、食餌性肥満と遺伝性肥満のマウスモデルでエネルギー消費を増加させ、体重を可逆的に減少させることも明らかになった。さらに、アンレキサノクスはこれらのマウスのインスリン感受性を改善し、脂肪肝を回復させた。これらの作用は脂肪組織の炎症の軽減をともなっており、またIKK-εとTBK1の発現に依存しているらしい。


The drug amlexanox, which is currently used to treat asthma in Japan and open sores in the mouth in the US, may be beneficial in treating obesity and type 2 diabetes in mice, according to study published this week in Nature Medicine.

Obesity is often associated with a state of low-grade inflammation, which is believed to contribute to insulin resistance and the development of type 2 diabetes. Using a large-scale in vitro chemical screen Alan Saltiel and colleagues now identify small molecule inhibitors of IKK-epsilon and a highly related kinase called TBK1. One of these inhibitors includes amlexanox, which they show is a relatively selective inhibitor of these two kinases. They also report that amlexanox produced reversible weight loss in a dietary and a genetic mouse model of obesity through an increase in energy expenditure. Further, the drug improved the insulin sensitivity and reversed fatty liver disease in these mice, even before a change in weight. These effects were associated with a reduction in adipose tissue inflammation and seemed to depend on the expression of IKK-epsilon and TBK1.

Amlexanox has a long history of use in people and with a good safety record. Although future clinical studies are needed, repurposing of the drug to treat obesity and its metabolic complications may be a valid option in the clinic.

doi: 10.1038/nm.3082


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