Adipose Tissue-Derived Soluble Fms-Like Tyrosine Kinase 1 Is an Obesity-Relevant Endogenous Paracrine Adipokine

Adipose tissue growth depends on angiogenesis. We tested the hypothesis that adipose tissue produces factors relevant to angiogenesis. We obtained fat biopsies in 2 different patient cohorts, cultured adipose-derived stem cells and studied mature adipocytes. We performed microarray, RT-PCR, and Western blotting; studied a rat obesity/metabolic syndrome model; and conducted viral gene transfer experiments in leptin-deficient mice. The microarray identified the splice variant of the vascular endothelial growth factor receptor, the soluble fms-like tyrosine kinase 1 (sFlt-1), as an antiangiogenesis candidate. We verified the expression findings and found that sFlt-1 was secreted by isolated mature human adipocytes. Tumor necrosis factor-α decreased sFlt-1 expression in mature adipocytes, whereas hypoxia had no effect. Separating cells from adipose tissue showed that the highest sFlt-1 expression was present in adipose-tissue nonfat cells rather than in the adipocytes themselves. We also found that sFlt-1 expression and sFlt-1 release by adipose-tissue explants were inversely correlated with body mass index of the corresponding patients but was directly correlated with adiponectin expression. In the obesity/metabolic syndrome rat model, we observed that circulating sFlt-1 levels and sFlt-1 expression in adipose tissue were also inversely correlated with body weight. To model our putative antiangiogenic factor further, we next overexpressed sFlt-1 by viral transfer in a mouse genetic model of leptin deficiency and observed that the transfected mice gained less weight than controls. We suggest that sFlt-1 could act as a paracrine factor inhibiting adipose tissue growth. Local sFlt-1 may regulate angiogenic potential and thereby influence adipose tissue mass.