Sci. Signal., 12 March 2013
Pharmacology Old Drug, New Purpose for Obesity
Leslie K. Ferrarelli
Science Signaling, AAAS, Washington, DC 20005, USA
Chronic inflammation, obesity, and insulin resistance appear to be linked by an uncharacterized mechanism involving nuclear factor B (NF-B). NF-B is activated when its inhibitory regulator IB (inhibitor of B) is inactivated by the IB kinase (IKK) complex through phosphorylation mediated by the IKK-α or IKK-β subunits. Reilly et al. found that an anti-inflammatory drug, amlexanox, currently used to treat asthma, allergic rhinitis, and canker sores, rapidly reduced weight and insulin resistance in obese mice by inhibiting the IKK family kinases TBK1 [TRAF family member–associated NF-B activator (TANK)–binding kinase 1] and IKK-. The abundance and kinase activity of both TBK1 and IKK- increased in the liver and adipose tissue of mice fed high-fat diets. Their increase correlated with the onset of inflammatory macrophage infiltration in these tissues, and both macrophage infiltration and the increase in the activities of the two kinases were inhibited by treatment of the mice with amlexanox. In vitro pharmacological induction of inflammatory signaling also increased TBK1 and IKK-. In vivo, agonists of the transcription factor peroxisome proliferator–activated receptor- (PPAR-), which reduces inflammation and insulin resistance, reduced the abundance of TBK1 and IKK-. Amlexanox had no effect on the in vitro activity of IKK-α, IKK-β, or a large panel of other kinases. In vitro, amlexanox inhibited TBK1 and IKK- in a manner competitive with ATP, supporting molecular simulation studies, which predicted that amlexanox bound TBK1 at the ATP-binding site. Physiologically, amlexanox prevented weight gain in mice fed high-fat diets and induced reversible weight loss, reduced adipose tissue mass, and improved glucose tolerance and insulin sensitivity in mice with either genetic or dietary-established obesity without affecting food intake. Energy expenditure, assessed by various metabolic parameters, was increased in amlexanox-treated diet-induced obese mice but was unchanged in amlexanox-treated mice fed a normal diet. Double-knockout Tbk1 and Ikbke mouse embryonic fibroblasts (MEFs) were unresponsive to amlexanox, whereas single-knockout MEFs and Ikbk-–/– mice were responsive, indicating that TBK1 and IKK- may be functionally redundant. Together, the findings suggest that amlexanox elicits its metabolic effects through inhibition of both TBK1 and IKK- and that this drug may be repurposed to treat obesity.
S. M. Reilly, S.-H. Chiang, S. J. Decker, L. Chang, M. Uhm, M. J. Larsen, J. R. Rubin, J. Mowers, N. M. White, I. Hochberg, M. Downes, R. T. Yu, C. Liddle, R. M. Evans, D. Oh, P. li, J. M. Olefsky, A. R. Saltiel, An inhibitor of the protein kinases TBK1 and IKK- improves obesity-related metabolic dysfunctions in mice. Nat. Med. 19, 313–321 (2013). [PubMed]
Citation: L. K. Ferrarelli, Old Drug, New Purpose for Obesity. Sci. Signal. 6, ec62 (2013).
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