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 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.

Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes: a population-based cohort study

“…As bile acids were shown to increase the metabolic rate in mice, it can be speculated that FXR (NR1H4), which is activated by bile acids, may influence body weight through an effect on energy expenditure. 46 This study showed a very high BMI and waist in the four women with the SMARCA2 intron 9 AA genotype. All of them were overweight and three were obese.…”

The bile salt export pump

“…Since FXR requires bile salt binding to act to control expression target genes, Bsep may, by controlling bile salt concentration in systemic circulation, become an important control element in body energy and lipid homeostasis. And finally, bile salts have recently been shown to control energy expenditure by controlling intracellular thyroid hormone action by binding to the G protein-coupled receptor TGR5 [43,101].…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…Thus, mice fed bile acids in conjunction with a high fat diet (HFD) are resistant to diet-induced obesity, but D2KO mice are not. This appears to be dependent upon increased D2 expression induced by bile acids in BAT during a high fat diet, although D2 in other tissues may have a role in this as well (49). A potential metabolic role for D2 has also been suggested in human studies in patients receiving replacement doses of T4; in these subjects basal metabolic rate correlates directly with free T4 and inversely with serum TSH but not with free T3 (50).…”