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Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation - Nature

  • ️Auwerx, Johan
  • ️Sun Jan 08 2006

Abstract

While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways1,2, are ligands for the G-protein-coupled receptor (GPCR) TGR53,4 and activate nuclear hormone receptors such as farnesoid X receptor α (FXR-α; NR1H4)5,6,7. FXR-α regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2)8,9 that inhibits the activity of other nuclear receptors. The FXR-α-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c10. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-α, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA–TGR5–cAMP–D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.

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Acknowledgements

We thank S. Iwasaki, A. Izumi, T. Taniguchi, K. Sakai, G. Tsujimoto, Y. Kawamata, H. Overmars, T. Sorg, M.-F. Champy and the staff of the Institut Clinique de la Souris for technical assistance and discussions. We also thank Seahorse Bioscience for the collaborative studies of oxygen consumption and extracellular acidification rate in the human skeletal myocytes. Work in the laboratories of the authors is supported by grants from CNRS, INSERM, ULP, FRM, the Hôpital Universitaire de Strasbourg, the NIH, EMBO and the EU. Author Contributions M.W. and S.M.H. were involved in project planning, experimental work and data analysis; C.M., M.A.C., B.W.K., H.S., N.M., J.W.H., O.E., T.K. and K.S. performed experimental work; and A.C.B. and J.A. were involved in project planning and data analysis.

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Author notes

  1. Mitsuhiro Watanabe and Sander M. Houten: *These authors contributed equally to this work

Authors and Affiliations

  1. Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, 67404, Illkirch, France

    Mitsuhiro Watanabe, Sander M. Houten, Chikage Mataki, Hiroyuki Sato, Nadia Messaddeq, Kristina Schoonjans & Johan Auwerx

  2. Department of Medicine, Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Massachusetts, 02115, Boston, USA

    Marcelo A. Christoffolete, Brian W. Kim, John W. Harney & Antonio C. Bianco

  3. Division of Clinical Nutrition, National Institute of Health and Nutrition, 1-23-1 Toyama, 162-8636, Shinjuku-ku, Tokyo, Japan

    Osamu Ezaki

  4. Laboratory for Systems Biology and Medicine, RCAST, University of Tokyo, 153-8904, Tokyo, Japan

    Tatsuhiko Kodama

  5. Institut Clinique de la Souris, 67404, Illkirch, France

    Johan Auwerx

Authors

  1. Mitsuhiro Watanabe

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  2. Sander M. Houten

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  3. Chikage Mataki

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  4. Marcelo A. Christoffolete

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  5. Brian W. Kim

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  6. Hiroyuki Sato

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  7. Nadia Messaddeq

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  8. John W. Harney

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  9. Osamu Ezaki

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  10. Tatsuhiko Kodama

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  11. Kristina Schoonjans

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  12. Antonio C. Bianco

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  13. Johan Auwerx

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Corresponding author

Correspondence to Johan Auwerx.

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Supplementary information

Supplementary Notes

This file contains Supplementary Tables 1 and 2, Supplementary Methods and Supplementary Figure Legends. (DOC 59 kb)

Supplementary Figure 1

A comparison of results after the different diets. (PDF 98 kb)

Supplementary Figure 2

a, Hematoxylin and eosin stained epWAT and BAT sections in animals treated with the indicated diets. b, Osmium tetroxide stained BAT sections of wildtype and D2-/- mice. (PDF 844 kb)

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Watanabe, M., Houten, S., Mataki, C. et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484–489 (2006). https://doi.org/10.1038/nature04330

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  • Received: 11 April 2005

  • Accepted: 19 October 2005

  • Published: 08 January 2006

  • Issue Date: 26 January 2006

  • DOI: https://doi.org/10.1038/nature04330

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Editorial Summary

Turn up the heat

Bile acids are known to mediate dietary lipid absorption and cholesterol catabolism, and recently an important signalling role emerged. Now they have been found to increase energy expenditure in brown adipose tissue and human skeletal muscle. As bile acid signalling may drive diet-induced heat production, it is a possible therapeutic target for the control of energy homeostasis.

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