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

Nature Medicine volume 19, pages 313–321 (2013)Cite this article

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Abstract

Emerging evidence suggests that inflammation provides a link between obesity and insulin resistance. The noncanonical IκB kinases IKK-ɛ 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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Figure 1: Induction of IKK-ɛ and TBK1 in obese mice is a result of increased inflammation.
Figure 2: Amlexanox is a specific inhibitor of IKK-ɛ and TBK1.
Figure 3: Daily amlexanox gavage both prevents and reverses diet-induced or genetic obesity.
Figure 4: Amlexanox treatment improves insulin sensitivity and glucose tolerance.
Figure 5: Amlexanox treatment reverses hepatic steatosis.
Figure 6: Amlexanox reduces inflammation and increases energy expenditure in adipose tissue.

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Acknowledgements

We thank J. Hung and X. Peng for excellent technical assistance and members of the Saltiel laboratory for helpful discussions. This work was supported by US National Institutes of Health grants DK60597 and 60591 to A.R.S., F32DK09685101 to S.M.R., F30DK089687 to J.M. and R24DK090962 to A.R.S., J.M.O. and R.M.E. R.M.E., M.D. and R.T.Y. are supported by the Leona M. and Harry B. Helmsley Charitable Trust. We thank S. Akira (Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan) for providing MEFs. We also acknowledge support from the Michigan Diabetes Research and Training Center (DK020572), Michigan Institute for Clinical and Health Research (UL1-RR024986), Nathan Shock Center, Michigan Metabolic Phenotyping Core and Michigan Nutritional Obesity Research Center (DK089503).

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Author notes

  1. Shian-Huey Chiang, Nicole M White & Irit Hochberg

    Present address: Present addresses: Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, North Carolina, USA (S.-H.C.), Institute of Endocrinology, Diabetes and Metabolism, Rambam Health Care Campus, Haifa, Israel (N.M.W.) and Medical Oncology Division, Washington University School of Medicine, Saint Louis, Missouri, USA (I.H.).,

  2. Shannon M Reilly and Shian-Huey Chiang: These authors contributed equally to this work.

Authors and Affiliations

  1. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA

    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 & Alan R Saltiel

  2. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Maeran Uhm, Jonathan Mowers & Alan R Saltiel

  3. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA

    Maeran Uhm, Jonathan Mowers & Alan R Saltiel

  4. Gene Expression Laboratory, Salk Institute for Biological Sciences, La Jolla, California, USA

    Michael Downes, Ruth T Yu, Christopher Liddle & Ronald M Evans

  5. Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia

    Christopher Liddle

  6. Howard Hughes Medical Institute, Salk Institute for Biological Sciences, La Jolla, California, USA

    Ronald M Evans

  7. Department of Medicine, University of California San Diego, San Diego, California, USA

    Dayoung Oh, Pingping Li & Jerrold M Olefsky

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Contributions

A.R.S. and S.M.R. wrote the manuscript. S.M.R. created figures. S.M.R. produced the data in Figures 1e, 3e,i, 4f–i, 5c,f–h and 6c–j and in Supplementary Figures 1, 2c–h, 5b,e,g,h and 6a,b. S.-H.C. produced the data in Figures 3a–d,f–h,j, 4a–e, 5a,c–e and 6a,b and in Supplementary Figures 2a,b, 3 and 5a,d,f. S.J.D. and M.J.L. performed the screen identifying amlexanox as an IKK-ɛ inhibitor. L.C. and S.J.D. produced the data in Figures 1b and 2b,c,f. M.U. produced the data in Figures 1a and 2e and in Supplementary Figures 5c and 6c–e. J.R.R. produced the images in Figure 1d. J.M. produced the data in Figure 1c. N.M.W. produced the data in Supplementary Figure 4a–d. I.H. produced the data in Supplementary Figure 4e. M.D., R.T.Y., C.L. and R.M.E. contributed data not shown, which was instrumental in generating Figure 5f–h. D.O. produced the data in Figure 1d and the samples for Figure 1e. P.L. produced the data in Figure 1f under the guidance of J.M.O.

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Correspondence to Alan R Saltiel.

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Reilly, S., Chiang, SH., Decker, S. et al. An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice. Nat Med 19, 313–321 (2013). https://doi.org/10.1038/nm.3082

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