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Original Research
Glucagon-receptor Signaling Regulates Energy Metabolism Via Hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21
Teayoun Kim, Shelly Nason, Cassie Holleman, Mark Pepin, Landon Wilson, Taylor F Berryhill, Adam R. Wende, Chad Steele, Martin E. Young, Stephen Barnes, Daniel J. Drucker, Brian Finan, Richard DiMarchi, Diego Perez-Tilve, Matthias Tschoep, Kirk M Habegger
Diabetes 2018 Jun; db171502. https://doi.org/10.2337/db17-1502
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Abstract

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss, in part through potentiation of fibroblast-growth factor 21 (FGF21) secretion. However, FGF21 is only a partial mediator of metabolic actions ensuing from GcgR-activation, prompting us to search for additional pathways. Intriguingly, chronic GcgR agonism increases plasma bile acid levels. We hypothesized that GcgR agonism regulates energy metabolism, at least in part, through farnesoid X receptor (FXR). To test this hypothesis, we studied whole body and liver-specific FXR knockout (Fxr∆liver) mice. Chronic GcgR agonist (IUB288) administration in diet-induced obese (DIO) Gcgr, Fgf21 and Fxr whole body or liver-specific knockout (∆liver) mice failed to reduce body weight (BW) when compared to wildtype (WT) mice. IUB288 increased energy expenditure and respiration in DIO WT mice, but not FXR∆liver mice. GcgR agonism increased [14C]-palmitate oxidation in hepatocytes isolated from WT mice in a dose-dependent manner, an effect blunted in hepatocytes from Fxr∆liver mice. Our data clearly demonstrate that control of whole body energy expenditure by GcgR agonism requires intact FXR signaling in the liver. This heretofore-unappreciated aspect of glucagon biology has implications for the use of GcgR agonism in the therapy of metabolic disorders.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db17-1502.

  • Received December 12, 2017.
  • Accepted June 11, 2018.
  • © 2018 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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Glucagon-receptor Signaling Regulates Energy Metabolism Via Hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21
Teayoun Kim, Shelly Nason, Cassie Holleman, Mark Pepin, Landon Wilson, Taylor F Berryhill, Adam R. Wende, Chad Steele, Martin E. Young, Stephen Barnes, Daniel J. Drucker, Brian Finan, Richard DiMarchi, Diego Perez-Tilve, Matthias Tschoep, Kirk M Habegger
Diabetes Jun 2018, db171502; DOI: 10.2337/db17-1502

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Glucagon-receptor Signaling Regulates Energy Metabolism Via Hepatic Farnesoid X Receptor and Fibroblast Growth Factor 21
Teayoun Kim, Shelly Nason, Cassie Holleman, Mark Pepin, Landon Wilson, Taylor F Berryhill, Adam R. Wende, Chad Steele, Martin E. Young, Stephen Barnes, Daniel J. Drucker, Brian Finan, Richard DiMarchi, Diego Perez-Tilve, Matthias Tschoep, Kirk M Habegger
Diabetes Jun 2018, db171502; DOI: 10.2337/db17-1502
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© 2019 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.