Obesity-related metabolic disorders such as type 2 diabetes reach epidemic proportions in most industrialized countries. Retinol binding protein 4 (RBP4), the only specific serum protein for the delivery of retinol to tissues, is increased in obesity and contributes to the development of insulin resistance and type 2 diabetes. The protein encoding stimulated by retinoic acid gene 6 (stra6) was recently identified as the membrane receptor for RBP4, mediating cellular retinol uptake. We discovered that another putative component of retinol metabolism, the oxidoreductase Retinol Saturase (RetSat), promotes adipocyte differentiation, presumably through the generation of a pro-adipogenic enzymatic product. Whether RBP4 and stra6 play a role in the metabolic actions of RetSat is unknown.
This proposal is aimed at identifying stra6 as a potential link between RBP4 and RetSat's function in adipocyte differentiation. We will determine if adipocyte stra6 is transcriptionally regulated by the Peroxisome Proliferator-Activated Receptor gamma, the target of anti-diabetic thiazolidinedione drugs, and by weight gain in mice, as is known for RBP4 and RetSat. Furthermore, stra6 gain-and loss-of-function studies will be applied to precursor cells to understand its functions during adipocyte differentiation. Analyzing the retinoid composition after these manipulations will identify retinol derivatives regulating the adipogenic potential. Next, we will investigate whether stra6 is required for the pro-adipogenic effects of RetSat by overexpressing RetSat in stra6 depleted precursor cells and if this is dependent on the presence of RBP4.
The findings from this proposal will allow me to supplement my ongoing research on RetSat by exploring its dependence on stra6 mediated retinol uptake. Moreover, they may identify which components of the RBP4/stra6/RetSat axis could present potential therapeutic targets to treat obesity and related metabolic disorders.
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