Endothelial dysfunction is a systemic and early event in the natural history of atherosclerosis [1]. The mechanisms eliciting endothelial dysfunction are still incompletely known, although an involvement of oxidative stress and reactive-oxygen species generating enzymes, such as NADPH oxidase, as well as nitric oxide bioavailability, have been implicated [2, 3]. The interaction between endothelial dysfunction and visceral fat is not novel: in this regard, it has been recently reported that flow-mediated dilatation (FMD) is blunted after modest weight gain and recovers after restoration of normal weight [4], thus suggesting the reversibility of the process and its dependence on visceral fat. The originality of the manuscript by Angelico et al. [5], published in this issue of IEM, stands in the clinical setting where this issue was challenged, i.e. metabolic syndrome (MS), and in their effort to dissect the underlying pathogenic cascade. Indeed, this study provides a mechanistic explanation for the association between MS and FMD, described in a large group of 2,123 Framingham Offspring Cohort participants [6]. In this US cohort, endothelial dysfunction progressively deteriorates with an increasing number of MS components. In the study by Angelico et al., patients with MS were compared with patients not fulfilling the criteria for MS. The choice of a control group of ‘‘nonhealthy’’ subjects, encompassing different degrees of cardiovascular burden, instead of healthy subjects, further strengthens the relevance of the biochemical abnormalities found in patients presenting with the clustering of MS perturbations in the cross-sectional comparison. The authors postulate that NOX-2, the catalytic core of NADPH oxidase, is overactivated in MS, elicits oxidative stress, as reflected by enhanced isoprostane formation, and that NOX-2-generated oxidative stress, in turn, impairs endothelial function. This pathway is reversible, at least in part, by successful weight loss achieved with a restrictedcalorie, Mediterranean-type diet. A small in vitro study on platelets of healthy subjects unravelled an involvement of adiponectin up-regulation associated with weight loss [7] in the reversal of oxidative stress, and thereby, of endothelial dysfunction. Interestingly, platelets have been suggested to play a central role as triggers of the entire process. In fact, previous observations by the same group, show that adiponectin reduces translocation of p47 subunit of NADPH oxidase to platelet membrane, thus decreasing NOX-2 activation [8], and that about one-third of circulating NOX-2 stems from platelet activation, with ensuing release of NOX-2 in the medium. These findings, coupled with the inverse relationship between adiponectin and NOX-2 in MS patients, prompted the authors to assess the effect of physiologic concentrations of adiponectin on NADPH oxidase activation, showing that adiponectin dose-dependently lowers NOX-2 cleavage from platelet membrane and NOX-2 concentration in the supernatant of arachidonic acid-activated platelets. It is of interest that both platelet activation and endothelial dysfunction are early events in the natural history of atherosclerosis. The cross talk between platelets and endothelial cells dates back to the bone marrow, where haematopoietic precursors, megakaryocytes, and sinusoidal endothelium interact directly [9]. The hypothesis that platelet oxygen free radicals may trigger a cascade of events ultimately leading to endothelial dysfunction is supported by previous observations by the same authors showing a progressive decrease in platelet formation of G. Davi (&) F. Santilli Internal Medicine, University of Chieti, Chieti, Italy e-mail: gdavi@unich.it