An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice

Shannon M. Reilly; Shian Huey Chiang; Stuart J. Decker; Louise Chang; Maeran Uhm; Martha J. Larsen; John R. Rubin; Jonathan Mowers; Nicole M. White; Irit Hochberg; Michael Downes; Ruth T. Yu; Christopher Liddle; Ronald M. Evans; Dayoung Oh; Pingping Li; Jerrold M. Olefsky; Alan R. Saltiel

doi:10.1038/nm.3082

An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice

Shannon M. Reilly, Shian Huey Chiang, Stuart J. Decker, Louise Chang, Maeran Uhm, Martha J. Larsen, John R. Rubin, Jonathan Mowers, Nicole M. White, Irit Hochberg, Michael Downes, Ruth T. Yu, Christopher Liddle, Ronald M. Evans, Dayoung Oh, Pingping Li, Jerrold M. Olefsky, Alan R. Saltiel

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348 Scopus citations

Abstract

Emerging evidence suggests that inflammation provides a link between obesity and insulin resistance. The noncanonical IκB kinases IKK-Eε and TANK-binding kinase 1 (TBK1) are induced in liver and fat by NF-κB activation upon high-fat diet feeding and in turn initiate a program of counterinflammation that preserves energy storage. Here we report that amlexanox, an approved small-molecule therapeutic presently used in the clinic to treat aphthous ulcers and asthma, is an inhibitor of these kinases. Treatment of obese mice with amlexanox elevates energy expenditure through increased thermogenesis, producing weight loss, improved insulin sensitivity and decreased steatosis. Because of its record of safety in patients, amlexanox may be an interesting candidate for clinical evaluation in the treatment of obesity and related disorders.

Original language	English (US)
Pages (from-to)	313-321
Number of pages	9
Journal	Nature medicine
Volume	19
Issue number	3
DOIs	https://doi.org/10.1038/nm.3082
State	Published - Mar 2013

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Reilly, S. M., Chiang, S. H., Decker, S. J., Chang, L., Uhm, M., Larsen, M. J., Rubin, J. R., Mowers, J., White, N. M., Hochberg, I., Downes, M., Yu, R. T., Liddle, C., Evans, R. M., Oh, D., Li, P., Olefsky, J. M., & Saltiel, A. R. (2013). An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice. Nature medicine, 19(3), 313-321. https://doi.org/10.1038/nm.3082

Reilly, SM, Chiang, SH, Decker, SJ, Chang, L, Uhm, M, Larsen, MJ, Rubin, JR, Mowers, J, White, NM, Hochberg, I, Downes, M, Yu, RT, Liddle, C, Evans, RM, Oh, D, Li, P, Olefsky, JM & Saltiel, AR 2013, 'An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice', Nature medicine, vol. 19, no. 3, pp. 313-321. https://doi.org/10.1038/nm.3082

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title = "An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice",

abstract = "Emerging evidence suggests that inflammation provides a link between obesity and insulin resistance. The noncanonical IκB kinases IKK-Eε and TANK-binding kinase 1 (TBK1) are induced in liver and fat by NF-κB activation upon high-fat diet feeding and in turn initiate a program of counterinflammation that preserves energy storage. Here we report that amlexanox, an approved small-molecule therapeutic presently used in the clinic to treat aphthous ulcers and asthma, is an inhibitor of these kinases. Treatment of obese mice with amlexanox elevates energy expenditure through increased thermogenesis, producing weight loss, improved insulin sensitivity and decreased steatosis. Because of its record of safety in patients, amlexanox may be an interesting candidate for clinical evaluation in the treatment of obesity and related disorders.",

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An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice

Abstract

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