Nature, 2006-01, Vol.439 (7075), p.484-489
2006
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation
- Ist Teil von
- Nature, 2006-01, Vol.439 (7075), p.484-489
- Ort / Verlag
- London: Nature Publishing
- Erscheinungsjahr
- 2006
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 α (FXR-α; NR1H4). FXR-α 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-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 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-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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687, 1476-4679DOI: 10.1038/nature04330Titel-ID: cdi_hal_primary_oai_HAL_hal_00188183v1
- Format
- –
- Schlagworte
- Absorption, Adipose tissue, Adipose Tissue, Brown, Adipose Tissue, Brown - drug effects, Adipose Tissue, Brown - enzymology, Adipose Tissue, Brown - metabolism, Adiposity, Adiposity - drug effects, Animals, Bile, Bile Acids and Salts, Bile Acids and Salts - pharmacology, Biochemistry, Molecular Biology, Biological and medical sciences, Biosynthesis, Body Weight, Body Weight - drug effects, Carbon Dioxide, Carbon Dioxide - metabolism, Cholesterol, Cholic Acid, Cholic Acid - pharmacology, Cyclic AMP, Cyclic AMP - biosynthesis, Dietary Fats, Dietary Fats - administration & dosage, Dietary Fats - pharmacology, Energy Metabolism, Energy Metabolism - drug effects, Fatty acids, Fundamental and applied biological sciences. Psychology, Gene Deletion, Gene expression, Homeostasis, Homeostasis - drug effects, Hormones, Humans, Insulin, Iodide Peroxidase, Iodide Peroxidase - deficiency, Iodide Peroxidase - genetics, Iodide Peroxidase - metabolism, Iodothyronine Deiodinase Type II, Life Sciences, Liver, Liver - drug effects, Liver - metabolism, Liver. Bile. Biliary tracts, Metabolism, Mice, Mice, Inbred C57BL, Molecular biology, Muscle Cells, Muscle Cells - drug effects, Muscle Cells - enzymology, Muscle Cells - metabolism, Muscle, Skeletal, Muscle, Skeletal - cytology, Obesity, Oxygen Consumption, Oxygen Consumption - drug effects, Receptors, G-Protein-Coupled, Receptors, G-Protein-Coupled - genetics, Receptors, G-Protein-Coupled - metabolism, Rodents, Thyroid, Thyroid gland, Thyroid Hormones, Thyroid Hormones - metabolism, Vertebrates: digestive system, Weight control