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Final Report Summary - STRA6 (The Function of the RBP4 Receptor Stra6 during Retinol Saturase Regulated Adipocyte Differentiation)

This CIG proposal was aimed at the integration of my newly established research group at the Charité-Universitätsmedizin Berlin after spending 5 years in the United States at the University of Pennsylvania in Philadelphia. It supported me to establish myself as an independent researcher. The researched topic addressed the influence of the specific transport protein for Vitamin A (retinol) in serum, retinol binding protein 4 (RBP4), towards the differentiation of adipocytes and glucose and fatty acid metabolism in general. Specifically, it investigated whether RBP4 affects the differentiation of these cells by interacting with its newly identified membrane receptor STRA6 that mediates retinol transport. In addition, it addressed whether RBP4 and STRA6 are linked to the oxidoreductase called Retinol Saturase (RetSat), a known pro-adipogenic factor (Schupp et al. PNAS 2009), whose biological role is a central interests of my newly established group. During the first funding period of this proposal we were able to identify STRA6 as an important link between RBP4-mediated retinol transport and the control of adipocyte differentiation. RBP4 could inhibit or enhance differentiation, depending on whether it was associated with retinol (holo-RBP4) or not (apo-RBP4). This was dependent on the presence of STRA6 and affected activity of Retinoic Acid Receptor alpha (RARalpha), a known negative regulator of adipocyte differentiation. We conclude that STRA6 can mediate retinol in-or efflux in adipocyte precursor cells depending on the presence of either RBP4 isoforms, thus controlling RARalpha activity and the differentiation process. These findings were published in a prestigious peer-reviewed journal (Muenzner et al. MCB, 2013) with both first and last authorships from my group, demonstrating the independent research capacities of my laboratory. During the second funding period, we established mouse models with modified expression of RBP4 in liver and metabolically characterized these mice. Surprisingly, we found that these mice showed signs of altered activity of a related hormonal system. A manuscript with these results is currently under revision and should hopefully be published within the next months. In addition, we acquired mice with targeted disruption of some elements of the STRA6 gene and found interesting compensations by an alternative STRA6 splice variant. We also found that STRA6-dependent retinoid homeostasis is not a major determinant of RetSat function, suggesting that RetSat has cellular effects independent of its effects on retinol. We presented our findings at a variety of international conferences such as the 2012 EASD meeting in Berlin, the 2012 Benzon Symposium 'Adipocyte Tissue in Health and Disease' in Copenhagen, at the 2013 'First international Retinoids meeting' in Rende, Italy, and 2015 at the 'EMBO conference for Nuclear Receptors' in Ajaccio, Corse. In addition, I was invited to present on this topic to several national research institutions and conferences during the last years including the German Institute for Human Nutrition in Potsdam-Rebrücke, a meeting of the German Society for Obesity in Hannover, and the University of Leipzig. We also published a review article on the metabolic role of STRA6 and RBP4 (Fedders et al. HMBCI, 2015) and another original article on a novel link between adipocyte differentiation and lipid metabolism (Witte et al. ENDOCRINOLOGY, 2015), both with me as the last corresponding author. To reach out, we showed our facilities and some visually interesting experiments to a wider public during the Berlin 'Lange Nacht der Wissenschaften' (Science for the entire night) and 'Open Door Day' of the Charite. My re-integration has been well progressed. We actively participate in the seminar series of our institution and I am associated with an interdisciplinary research network (Clinical Research Groups, funded by the DFG). In addition, I was appointed Associated Professor in 2013 at the Institute of Pharmacology of the Charité for the next 5 years, and I have been thoroughly involved in the teaching curriculum for our medical students. In summary, we have made great progress in establishing our independent research group and the re-integration into the scientific environment and institutional structures here in Berlin, with a major contribution coming from this CIG.

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CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Germany
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