Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation
| Autor: | Sander M. Houten, Antonio C. Bianco, Brian W. Kim, Johan Auwerx, Tatsuhiko Kodama, Nadia Messaddeq, Chikage Mataki, John W. Harney, Kristina Schoonjans, Marcelo A. Christoffolete, Mitsuhiro Watanabe, Osamu Ezaki, Hiroyuki Sato |
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| Přispěvatelé: | Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Paediatric Metabolic Diseases, Laboratory Genetic Metabolic Diseases |
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
MESH: Muscle Cells
MESH: Receptors G-Protein-Coupled MESH: Carbon Dioxide Receptors G-Protein-Coupled Mice 0302 clinical medicine Adipose Tissue Brown Cyclic AMP Homeostasis MESH: Animals MESH: Oxygen Consumption Receptor MESH: Cyclic AMP Adiposity 0303 health sciences MESH: Muscle Skeletal Multidisciplinary MESH: Energy Metabolism G protein-coupled bile acid receptor Liver MESH: Homeostasis MESH: Dietary Fats 030220 oncology & carcinogenesis Small heterodimer partner MESH: Cholic Acid Signal transduction Thyroid Hormones medicine.medical_specialty MESH: Iodide Peroxidase education Cholic Acid MESH: Bile Acids and Salts Biology Iodide Peroxidase MESH: Adipose Tissue Brown Bile Acids and Salts 03 medical and health sciences Oxygen Consumption MESH: Mice Inbred C57BL MESH: Thyroid Hormones Internal medicine medicine Animals Humans Muscle Skeletal MESH: Mice 030304 developmental biology MESH: Adiposity Muscle Cells MESH: Humans FGF15 Body Weight [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Carbon Dioxide Dietary Fats MESH: Body Weight Mice Inbred C57BL Endocrinology Nuclear receptor MESH: Gene Deletion Iodothyronine deiodinase Farnesoid X receptor Energy Metabolism Gene Deletion MESH: Liver |
| Zdroj: | Nature Nature, Nature Publishing Group, 2006, 439 (7075), pp.484-9. ⟨10.1038/nature04330⟩ Nature, 439(7075), 484-489. Nature Publishing Group |
| ISSN: | 0028-0836 1476-4679 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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