ABSTRACT
Bile acids can function in the postprandial state as circulating signaling molecules in the regulation of glucose and lipid metabolism via the transmembrane receptor TGR5 and nuclear receptor FXR. Both receptors are present in the central nervous system, but their function in the brain is unclear. Therefore, we investigated the effects of intracerebroventricular (i.c.v.) administration of taurolithocholate (tLCA), a strong TGR5 agonist, and GW4064, a synthetic FXR agonist, on energy metabolism. We determined the effects of chronic i.c.v. infusion of tLCA, GW4064, or vehicle on energy expenditure, body weight and composition as well as tissue specific fatty acid uptake in mice equipped with osmotic minipumps. We found that i.c.v. administration of tLCA (final concentration in cerebrospinal fluid: 1â µM) increased fat oxidation (tLCA group: 0.083â ±â 0.006 vs control group: 0.036â ±â 0.023â kcal/h, Fâ =â 5.46, Pâ =â 0.04) and decreased fat mass (after 9 days of tLCA infusion: 1.35â ±â 0.13 vs controls: 1.96â ±â 0.23â g, Pâ =â 0.03). These changes were associated with enhanced uptake of triglyceride-derived fatty acids by brown adipose tissue and with browning of subcutaneous white adipose tissue. I.c.v. administration of GW4064 (final concentration in cerebrospinal fluid: 10â µM) did not affect energy metabolism, body composition nor bile acid levels, negating a role of FXR in the central nervous system in metabolic control. In conclusion, bile acids such as tLCA may exert metabolic effects on fat metabolism via the brain.
Subject(s)
Brain/drug effects , Lipid Metabolism/drug effects , Taurolithocholic Acid/administration & dosage , Animals , Body Composition/drug effects , Brain/metabolism , Drug Administration Schedule , Energy Metabolism/drug effects , Homeostasis/drug effects , Infusions, Intraventricular , Male , Mice , Mice, Inbred C57BL , Oxidation-Reduction/drug effects , Time Factors , Triglycerides/metabolismABSTRACT
To define the metabolism of 7-ketolithocholic acid in man, studies were carried out in gallstone patients with normal liver function. 7-[24-14C]ketolithocholic acid or its glycine or taurine conjugates were injected intravenously, and the chemical form of radioactivity appearing in bile was determined to define hepatic biotransformation. To study intestinal absorption 7-[24-14C]ketolithocholic acid was infused into the jejunum and ileum, respectively, and the chemical form of radioactivity appearing in peripheral blood and bile was assessed. 7-Ketolithocholic acid was extensively reduced in the liver to chenic acid and, to lesser extent, to ursodeoxycholic acid. Hepatic reduction was similar for both unconjugated as well as glycine- and taurine-conjugated 7-ketolithocholic acid. 7-Ketolithocholic acid was well absorbed. There was no biotransformation in the small intestinal lumen or during absorption, because all radioactivity recovered from the lumen or in peripheral blood was in unchanged 7-ketolithocholic acid. Biotransformation products in bile after jejunal infusion were similar to those after intravenous injection. The studies indicate that 7-ketolithocholic acid is likely to be a physiological precursor of ursodeoxycholic acid in healthy man.
