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GRK 1482 Jahrbuch 2011-2014

Publications [1] Thomas C, Auwerx J and Schoonjans K. Bile acids and the membrane bile acid receptor TGR5 - Connecting nutrition and metabolism. Thyroid. 2008, 18:167-174. [2] Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, KodamaT,SchoonjansK,BiancoAC&AuwerxJ.Bileacids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006, 439(7075): 484-9. [3] Meyer CW, Willershäuser M, Jastroch M, Rourke B, Fromme T, Oelkrug R, Heldmaier G, Klingenspor M. Adaptive thermogenesis and thermal conductance in wild-type and UCP1-KO mice. Am J Physiol Regul Integr Comp Physiol. 2010, 299(5): R1396-406. PhD FELLOWS GRK Progress Report 2011-2014 | Page 53 Aim The aims of our study are i) to investigate the relevance of brown and brite adipocytes within this context, and ii) to identify the role of UCP1 for BAs’ effects on body fat storage. We expect that UCP1 ablated mice, other than wildtype mice, are not protected by BAs from diet-induced obesity. With such a result we could prove that BAs target nonshivering thermoge- nesis in BAT and thereby mediate DIO resistance. Methods and Results We compared the two different mouse strains C57BL/6J (B6) and 129/Sv ev Tac (129Sv) in respect to their propensity to re- cruit brite adipocytes. The mice were assigned to one of four different purified diet groups: A low fat control diet (C), a high fat diet (HF) or one of both diets supplemented with 0.5% (w/w) cholic acid (+Ch). Despite equal energy resorption we observed substantial diffe- rences in body mass development both between mouse strains as well as the diet groups. As described in the literature, B6 mice were protected from DIO by cholic acid supplementation of the high fat diet. Intriguingly we found that this effect is strain spe- cific, as it did not occur in 129Sv mice. This strain difference was also reflected in body composition, as total body fat mass of HF+Ch- fed B6 mice was low and comparable to C-fed mice, but in the 129Sv mice accumulated irrespective of cholic acid supplementation. Histological analyses of inguinal white adipo- se tissue (iWAT) demonstrated that adipocytes from HF+Ch-fed B6 mice were not only smaller compared to HF-fed B6 mice, but also multilocular in appearance. Quantitative PCR revealed that these cells are brite adipocytes, as mRNA levels of several brown adipocyte markers were increased. Moreover, immuno- histochemistry demonstrated increased number of UCP1- immunoreactive adipocytes in iWAT of HF+Ch-fed B6 mice. The differential effects of BA supplementation on energy ba- lance and adipose tissue in the two inbred strains is most likely explained by differential BA spillover into systemic circulation, as in B6, but not in 129Sv, BA levels are increased due to HF+Ch feeding. The molecular mechanisms responsible for this strain difference remain to be resolved. The main goal of the ongoing present project, however, is to verify the role of UCP1 in brown and brite adipocytes for the DIO-protective effect of BAs. Outlook BA measurements in the enterohepatic organs as well as BA transporter analyses in the intestine and liver of both mouse strains will help to further elucidate the underlying mecha- nisms of strain specific differences. In order to clarify the question whether BAT is essential for the DIO-protective effects of BAs we will use the UCP1 ko mouse model. We expect that UCP1 ko mice lack the protective action of BAs. This would directly prove that BAs target NST in brown adipocytes. In case the effect of BAs on energy balance persists in UCP1 ko mice we will search for other target tissues of BAs. We will scrutinize the tissue responsible for the UCP1-indepen- dent thermogenesis, e.g. by measuring mitochondrial content and complex IV activity in a panel of all tissues. Figure: Proposed mechanism of bile acid effects on nonshivering ther- mogenesis in brown adipose tissue (on the basis of [2]). Supervisors Prof. Dr. Martin Klingenspor I TUM I Molecular Nutritional Medicine Prof. Dr. Hannelore Daniel I TUM I Physiology of Human Nutrition Start of project: August 2011 Academic background: Studies of Nutritional Science at Technische Universität München