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Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation

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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Figure 1: CA decreases adiposity of mice fed a HF diet.
Figure 2: CA increases energy expenditure.
Figure 3: BAs signal by means of D2.
Figure 4: In vitro effects of BAs.

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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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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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