Cited by 2,220Adipose Tissue and MetabolismDrug Transport and Resistance MechanismsCholesterol and Lipid Metabolism

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Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation

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Watanabe, Mitsuhiro, Houten, Sander M., Mataki, Chikage, Christoffolete, Marcelo A., Kim, Brian W., Sato, Hiroyuki, Messaddeq, Nadia, Harney, John W., Ezaki, Osamu, Kodama, Tatsuhiko, Schoonjans, Kristina, Bianco, Antonio C., Auwerx, Johan·2006·Nature

DOI 10.1038/nature04330

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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 pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-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 1c. 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-alpha, 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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Authors: Watanabe, M., Houten, S. M., Mataki, C., Christoffolete, M. A., Kim, B. W., Sato, H., Messaddeq, N., Harney, J. W., Ezaki, O., Kodama, T., Schoonjans, K., Bianco, A. C., & Auwerx, J.
Affiliations: Centre National de la Recherche Scientifique (FR)
Brigham and Women's Hospital (US)
National Institute of Health and Nutrition (JP)
The University of Tokyo (JP)
Corresponding author: Auwerx, Johan
ORCID: Houten, Sander M.
Christoffolete, Marcelo A.
Kim, Brian W.
Messaddeq, Nadia
Ezaki, Osamu
Kodama, Tatsuhiko
Schoonjans, Kristina
Bianco, Antonio C.
Auwerx, Johan
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2006-01
Volume: 439
Issue: 7075
Pages: 484-489
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature04330
OpenAlex: W2081028309
Cited by: 2,220
References: 26
Citations by year: 2026: 108 · 2025: 112 · 2024: 118 · 2023: 121 · 2022: 140 · 2021: 150 · 2020: 135 · 2019: 128 · 2018: 132 · 2017: 144 · 2016: 126 · 2015: 131 · 2014: 101 · 2013: 102 · 2012: 87
FWCI: 47.28
Type: journal article
Language: en
Open access: green
infoscience.epfl.ch
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
HAL (submittedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
Pure Amsterdam UMC (submittedVersion)
Funders: Centre National de la Recherche Scientifique
Topics: Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Keywords: bile acids, energy expenditure, thyroid hormone activation, TGR5, cAMP signaling, brown adipose tissue, thermogenesis, obesity, insulin resistance, enterohepatic circulation, metabolic homeostasis
MeSH terms: Iodothyronine Deiodinase Type II, Cyclic AMP, Animals, Bile Acids and Salts, Body Weight, Adipose Tissue, Brown, Carbon Dioxide, Dietary Fats, Energy Metabolism, Homeostasis, Humans, Iodide Peroxidase, Liver, Mice, Inbred C57BL, Oxygen Consumption, Thyroid Hormones, Gene Deletion, Muscle, Skeletal, Cholic Acid, Muscle Cells, Receptors, G-Protein-Coupled, Adiposity, Mice

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Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation

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