Retinol binding protein 4 and its membrane receptors: a metabolic perspective

Nearly a decade of intense research has passed since the first report linking circulating retinol binding protein 4 (RBP4) to the development of insulin resistance. By now, a variety of underlying mechanisms have been identified; some of them are adherent to the canonical role of this circulating protein, which is to transport and deliver retinol to target tissues, and others that seem rather independent of retinol transport. Despite all these efforts, a consensus in the basic principles of RBP4’s metabolic effects has not been reached and some controversy remains. Using this as an opportunity, we here review and discuss current data on RBP4’s action on insulin sensitivity and its dependency on retinol homeostasis. We pay special attention to the involvement of RBP4 membrane receptors that were identified during these years, such as ‘stimulated by retinoic acid 6’ (STRA6), and whose identification added another layer of complexity to RBP4’s diverse actions. A better understanding of RBP4’s functions might allow its therapeutic exploitations, urgently needed in our period that is defined by an epidemic increase in metabolic diseases such as obesity and type 2 diabetes.