Once the uncertainties regarding the divergent preclinical findings on VEGF-B’s role in metabolism are sorted out, a careful clinical approach should determine the clinical relevance of the endothelial signalling in the context of metabolic syndrome, thus providing greater insights that may ultimately lead to therapeutic advances against the increasing burden of the obesity pandemic and associated metabolic derangements. This evidence concerns the gene VEGFB and obesity due to melanocortin 4 receptor deficiency.