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 path- ways1,2, are ligands for the G-protein-coupled receptor (GPCR) TGR53,4 and activate nuclear hormone receptors such as farnesoid X receptor a (FXR-a; NR1H4)5–7. FXR-a regulates the entero- hepatic 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-a-mediated SHP induction also underlies the downregula- tion of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regu- latory-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 adminis- tration 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 D22/2 mice. Treatment of brown adipocytes and human skeletal myo- cytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-a, 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 specifi- cally 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.
Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.
Mitsuhiro Watanabe, Sander M. Houten, Chikage Mataki, Marcelo A. Christoffolete, Brian W. Kim, Hiroyuki Sato, Nadia Messaddeq, John W. Harney, Osamu Ezaki, Tatsuhiko Kodama, Kristina Schoonjans, Antonio C. Bianco & Johan Auwerx. Journal of Biological Chemistry. January 26, 2006. doi:10.1038/nature04330