ABSTRACT:There is ample discussion of the relevance of the metabolic syndrome, the definition criteria, and predictive power. Nevertheless, along with the increasing prevalence of childhood obesity, the prevalence of the metabolic syndrome in obese children is reported at 30%, irrespective of the definition applied. Because children are otherwise relatively free of co-morbidities, they constitute an interesting population in which to study the sequence of events of obesity-related pathology. The adipocytokines appear to be important in this respect. Leptin was initially suggested as a promising "antiobesity" hormone. New concepts indicate that, in humans, leptin and its soluble receptor may be more important in states of energy deficiency rather than a predictor of the metabolic syndrome. Adiponectin, on the other hand, is not only related to obesity and insulin resistance, but appears to be the strongest predictor for metabolic syndrome, even in children. In newborns and infants, both adipocytokines occur in high concentrations, even though this cannot completely explain the increased risk for ensuing metabolic disease later in life. Finally, low-grade systemic inflammation may underlie the clustering of metabolic risk factors, but their role in children remains to be specified. Overall factors from the adipose tissue may constitute not only markers but also mediators of metabolic sequelae of obesity. T he metabolic syndrome in children is not only a scientifically and clinically relevant issue but also a controversial and complex issue with many questions not satisfactorily answered, such as, "What is the metabolic syndrome?" "How is the situation in children?" "How can we predict it?" and "Does the adipose tissue contribute to it?" TERMS AND DEFINITION OF THE METABOLIC SYNDROMEThe term and concept of the metabolic syndrome was first introduced by Reaven in 1988 (1), when he noticed, from the analysis of experimental, clinical, and epidemiologic studies, the simultaneous occurrence of hyperinsulinemia with several other cardiovascular risk factors in the same patient and that this clustering results in a markedly higher cardiovascular morbidity. He already assumed that there might be one common underlying mechanism for those risk factors-insulin resistance. Certainly, obesity seems to be another strong predisposing factor for all those components. The concept of the metabolic syndrome was then defined and institutionalized and was widely applied in clinical medicine (2-4). However, recent re-evaluation lead to a critical appraisal of the term and questioned the concept of the metabolic syndrome. In a joint statement of the American Diabetes Association and the European Association of the Study of Diabetes, the clarity and accuracy of the existing definition was questioned (5). Some criteria used are ambiguous or incomplete, and it has not been proven that the predictive value of the "syndrome" over the predictive value of the single components themselves is actually higher. In addition, ongoing research has id...

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BackgroundThe adipokine leptin realizes signal transduction via four different membrane-anchored leptin receptor (Ob-R) isoforms in humans. However, the amount of functionally active Ob-R is affected by constitutive shedding of the extracellular domain via a so far unknown mechanism. The product of the cleavage process the so-called soluble leptin receptor (sOb-R) is the main binding protein for leptin in human blood and modulates its bioavailability. sOb-R levels are differentially regulated in metabolic disorders like type 1 diabetes mellitus or obesity and can, therefore, enhance or reduce leptin sensitivity.Methodology/Principal FindingsTo describe mechanisms of Ob-R cleavage and to investigate the functional significance of differential sOb-R levels we established a model of HEK293 cells transiently transfected with different human Ob-R isoforms. Using siRNA knockdown experiments we identified ADAM10 (A Disintegrin And Metalloproteinase 10) as a major protease for constitutive and activated Ob-R cleavage. Additionally, the induction of lipotoxicity and apoptosis led to enhanced shedding shown by increased levels of the soluble leptin receptor (sOb-R) in cell supernatants. Conversely, high leptin concentrations and ER stress reduced sOb-R levels. Decreased amounts of sOb-R due to ER stress were accompanied by impaired leptin signaling and reduced leptin binding.ConclusionsLipotoxicity and apoptosis increased Ob-R cleavage via ADAM10-dependent mechanisms. In contrast high leptin levels and ER stress led to reduced sOb-R levels. While increased sOb-R concentrations seem to directly block leptin action, reduced amounts of sOb-R may reflect decreased membrane expression of Ob-R. These findings could explain changes of leptin sensitivity which are associated with variations of serum sOb-R levels in metabolic diseases.

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