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The Function of the RBP4 Receptor Stra6 during Retinol Saturase Regulated Adipocyte Differentiation

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Retinol metabolism impacts fat regulation

Metabolic disorders such as diabetes and obesity are considered as modern epidemics. Understanding the mechanistic aetiology of these conditions is central for designing interventions or preventative measures.

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Retinol is the form of vitamin A that is absorbed when eating animal food sources, and its transport in the circulation depends on retinol binding protein 4 (RBP4). Accumulating evidence indicates that RBP4 is engaged in many other processes, including the differentiation of adipocytes as well as in glucose and fatty acid metabolism. Adipocyte differentiation is further promoted by the enzyme retinol saturase (RetSat). The recent discovery of the membrane receptor STRA6 that mediates retinol transport triggered further interest on delineating its association with RBP4 and the known pro-adipogenic factor RetSat. Towards this goal, the EU-funded project STRA6 (The function of the RBP4 receptor Stra6 during retinol saturase regulated adipocyte differentiation) investigated the association between RBP4 and STRA6 during adipocyte differentiation. In this context, they performed STRA6 gain- and loss-of-function studies, and also explored the components implicated in the transcriptional regulation of STRA6. Results identified STRA6 as an important link between RBP4-mediated retinol transport and the control of adipocyte differentiation. STRA6 was able to mediate retinol influx or efflux in adipocyte precursor cells depending on the presence of either RBP4 isoforms. This interaction also affected the activity of retinoic acid receptor alpha (RARalpha), a known negative regulator of adipocyte differentiation. Disruption of part of the STRA6 gene in vivo was compensated by increased expression of an alternative splice variant, while STRA6-dependent retinoid homeostasis was not a major determinant of RetSat function. Furthermore, scientists established mouse models with modified expression of RBP4 in liver and metabolically characterised these mice. Surprisingly, they found that these mice showed signs of altered activity of a related hormonal system. Collectively, the data of the STRA6 project enhance existing knowledge on the molecular determinants of retinol metabolism and fat regulation. Long term, this is expected to lead to the identification of novel targets against metabolic diseases and the design of therapeutic interventions.

Keywords

Retinol, metabolism, fat regulation, RBP4, adipocyte differentiation, retinol saturase, STRA6

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