Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Top
  • View PDF
  • Download citation information
  • Send a letter
  • Share this article
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal
  • Top
  • Abstract
  • Supplemental material
  • Version history
  • Article usage
  • Citations to this article

Advertisement

ResearchIn-Press PreviewMetabolism Free access | 10.1172/JCI145546

FGF21 is required for the metabolic benefits of IKKε/TBK1 inhibition

Shannon M. Reilly,1 Mohammad Abu-Odeh,1 Magdalene Ameka,2 Julia H. DeLuca,1 Meghan C. Naber,3 Benyamin Dadpey,1 Nima Ebadat,1 Andrew V. Gomez,1 Xiaoling Peng,4 BreAnne Poirier,4 Elyse Walk,1 Matthew J. Potthoff,3 and Alan R. Saltiel1

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by Reilly, S. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by Abu-Odeh, M. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by Ameka, M. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by DeLuca, J. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by Naber, M. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by Dadpey, B. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by Ebadat, N. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by Gomez, A. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by Peng, X. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by Poirier, B. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by Walk, E. in: JCI | PubMed | Google Scholar

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by Potthoff, M. in: JCI | PubMed | Google Scholar |

1Department of Medicine, University of California, San Diego, La Jolla, United States of America

2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, United States of America

3Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, United States of America

4Life Sciences Institute, The University of Michigan, Ann Arbor, United States of America

Find articles by Saltiel, A. in: JCI | PubMed | Google Scholar |

Published April 6, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI145546.
Copyright © 2021, American Society for Clinical Investigation
Published April 6, 2021 - Version history
View PDF
Abstract

The protein kinases IKK-epsilon and TBK1 are activated in liver and fat in mouse models of obesity. We have previously demonstrated that treatment with the IKK-epsilon/TBK1 inhibitor, amlexanox, produces weight loss and relieves insulin resistance in obese animals and patients. While amlexanox treatment caused a transient reduction in food intake, long-term weight loss was attributable to increased energy expenditure via FGF21-dependent beiging of WAT. Amlexanox increased FGF21 synthesis and secretion in several tissues. Interestingly, while hepatic secretion determined circulating levels, it was dispensable for regulating energy expenditure. In contrast, adipocyte-secreted FGF21 may have acted as an autocrine factor that leads to adipose tissue browning and weight loss in obese mice. Moreover, increased energy expenditure was an important determinant of improved insulin sensitivity by amlexanox. Conversely, the immediate reductions in fasting blood glucose observed with acute amlexanox treatment were mediated by suppression of hepatic glucose production via the activation of STAT3 by adipocyte-secreted IL-6. These findings demonstrate that amlexanox improved metabolic health via FGF21 action in adipocytes to increase energy expenditure via WAT beiging, and an endocrine role of adipocyte-derived IL-6 to decrease gluconeogenesis via hepatic STAT3 activation, thereby producing a coordinated improvement in metabolic parameters.

Graphical Abstract
graphical abstract
Supplemental material

View

Version history
  • Version 1 (April 6, 2021): In-Press Preview

Article tools

  • View PDF
  • Download citation information
  • Send a letter
  • Share this article
  • Terms of use
  • Standard abbreviations
  • Need help? Email the journal

Metrics

  • Article usage
  • Citations to this article

Go to

  • Top
  • Abstract
  • Supplemental material
  • Version history
Advertisement
Advertisement

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts