Chronic infusion of taurolithocholate into the brain increases fat oxidation in mice

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: 1 μM) increased fat oxidation (tLCA group: 0.083 ± 0.006 vs control group: 0.036 ± 0.023 kcal/h, = 5.46, = 0.04) and decreased fat mass (after 9 days of tLCA infusion: 1.35 ± 0.13 vs controls: 1.96 ± 0.23 g, = 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: 10 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.

A human-like bile acid pool induced by deletion of hepatic Cyp2c70 modulates effects of FXR activation in mice

“…BAs in plasma and bile were measured by ultra (U)HPLC-MS/ MS on a Nexera X2 UHPLC system (Shimadzu, Kyoto, Japan), coupled to a SCIEX QTRAP 4500 MD triple quadrupole mass spectrometer (SCIEX, Framingham, MA) and quantified using D4-labeled BAs as internal standards (26). For fecal BA measurements, feces were dried and thoroughly ground.…”

Low production of 12α-hydroxylated bile acids prevents hepatic steatosis in Cyp2c70−/− mice by reducing fat absorption

“…Liquid chromatography-tandem mass spectrometry technique (LCMS) was applied for quantification of individual BA species in plasma and bile using a Nexera X2 Ultra High Performance Liquid Chromatography system (SHIMADZU, Kyoto, Japan), coupled to a SCIEX QTRAP 4500 MD triple J o u r n a l P r e -p r o o f 7 quadrupole mass spectrometer (SCIEX, Framingham, MA, USA) (UHPLC-MS/MS), as previously described (24).…”

Impaired Bile Acid Metabolism and Gut Dysbiosis in Mice Lacking Lysosomal Acid Lipase

“…BA measurements were performed in WT and LAL-KO mice fed a WTD for 4 weeks. Biliary BA concentrations were determined by (U)HPLC-MS/MS coupled to a SCIEX QTRAP 4500 MD triple quadrupole mass spectrometer and quantified using D4-labeled BA as internal standards [35]. For fecal BA measurements, BA in dried and grounded feces was methylated and trimethylsilylated prior to quantification by gas-liquid chromatography using 5ß-cholanic acid-7α,12α-diol as internal standard [36].…”