Obesity is associated with a state of chronic low-grade inflammation. Immune cells accumulate in white adipose tissue (WAT). The vascular endothelium plays an interactive role in these infiltration- and inflammatory processes. Mature and hypertrophic adipocytes are considered as the major adipogenic cell type secreting pro-inflammatory cytokines in WAT. In contrast, the pro-inflammatory capacity of preadipocytes and their role in endothelial cell activation have been neglected so far. To gain new insights into this molecular and cellular cross-talk, we examined the pro-inflammatory expression and secretion of normoxia, hypoxia and TNF--treated human preadipocytes and adipocytes (SGBS cells) and their impact on human microvascular endothelial cell (HMEC-1) function. In this study, stimulation of HMEC-1 with conditioned media (CM) from preadipocytes increased endothelial ICAM-1 expression and monocyte adhesion but not adipocyte-CM. After hypoxia and TNF--stimulation of SGBS cells, adipocyte-CM induced and preadipocyte-CM enhanced the monocyte adhesion. Concordantly, the expression of pro-inflammatory adipokines was considerably higher in preadipocytes than in adipocytes. SGBS-CM up-regulated the phosphorylation of three MAPK pathways, STAT-1/3 and c-Jun in HMEC-1 whereas the NF-B pathway was not affected. Inhibitor experiments showed that monocyte-endothelial cell-cell adhesion and endothelial ICAM-1 expression was JNK and JAK-1/STAT-1/3 pathway dependent and revealed IL-6 as a major mediator in CM increasing monocyte-endothelial cell-cell adhesion via the STAT-1/3 pathway. Our study shows that preadipocytes rather than adipocytes operate as potent activators of endothelial cells. This can be enhanced in preadipocytes and induced in adipocytes by TNF- and hypoxia as it may occur in WAT in the etiology of obesity.