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GRK 1482 Jahrbuch 2011-2014

Abstract Supplementing cholic acid to a high fat diet effectively impedes diet- induced obesity in C57BL/6J mice. It has been suggested that this effect is caused by NST in brown adipose tissue as bile acids bind to the G-protein-coupled BA receptor TGR5 and thereby induce thermo- genesis in brown adipocytes [2]. As NST in brown adipose tissue is critically dependant on UCP1, we will utilize the UCP1 ko mouse model to assess the relevance of UCP1 for the protective effect of BAs. Introduction Bile acids (BAs) are the main products of choleste- rol catabolism and function to emulsify and facili- tate the absorption of dietary lipids and fat-soluble vitamins. There are four major types of BAs: cholic acid (CA) and chenodeoxy-cholic acid (CDCA) are primary BAs, which are synthesized in the liver from cholesterol, as well as deoxycholic acid (DCA) and lithocholic acid (LCA), the secondary BAs, which are converted from primary BAs by bacterial enzymes in the intestine. Approximately 95% of BAs are re- absorbed and transported back to the liver from the ileum. Beyond the well characterized enterohepatic recy- cling, a new role for circulating BAs has emerged during the last years: a spillover from the liver into systemic blood circulation allows BAs to function as signalling molecules and regulate gene expres- sion in a number of peripheral target tissues. Se- veral of these novel BA effects are not mediated by the classical, nuclear farnesoid X receptor α (FXRα) but by the ubiquitously expressed G-protein coup- led BA receptor (GPBAR1) formerly known as TGR5 (reviewed in [1]). In 2006, Watanabe and colleagues hypothesized, that BA binding to TGR5 in brown adipose tissue (BAT) may induce thermogenesis [2] via thyroid hormone activation by means of the T4-converting enzyme deiodinase-2 [1]. A dietary supplementa- tion of cholic acid was proven to increase luminal absorption of BAs as well as circulating BA con- centration which in turn leads to elevated energy expenditure. By this mechanism C57BL/6J mice are prevented from diet-induced obesity (DIO) [2]. Nonshivering thermogenesis (NST) largely depends onthemitochondrialuncouplingprotein1(UCP1)[3], a protein that dissipates energy as heat and there- by contributes to a negative energy balance. While brown adipocytes in BAT have been implicated in this context, the involvement of brown adipocytes in white adipose tissues (brite) and the contribution of UCP1-mediated NST has yet to be proven. PhD FELLOWS Page 52 | GRK Progress Report 2011-2014 Kristina Hüttinger (M.Sc.) Molecular Nutritional Medicine PhD 11/2 Bile acids: from gut to liver to adipose tissue differentiation and functions