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

Abstract

Abstract-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-␣ 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.

Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms

“…These data suggest that adipose tissue may contribute to the circulating pool of sFlt-1. Data from Herse and colleagues (66) showed that mature adipocytes isolated from humans do express and release sFlt-1 (Fig. 6).…”

“…A study comparing obese versus lean pregnant women demonstrated that obesity was associated with elevated blood pressure and reduced endothelium-dependent vasorelaxation in skin arteries (142,173). It was not shown whether this was dependent on reductions in NO levels or activity of the endothelial enzyme that produces NO (endothe- (66). Bottom: stimulation with AT1-AA promotes sFlt-1 release from adipose tissue explants isolated from normal pregnant (NP) Sprague-Dawley rats.…”

Redefining Preeclampsia Using Placenta-Derived Biomarkers

“…First, the placenta is the predominant source of circulating PlGF, whereas endothelial cells, peripheral blood mononuclear cells, and even adipose tissue also are sources of circulating sFlt1. [99][100][101] Second, alterations in circulating PlGF concentration can be detected in the first trimester of pregnancy in women destined to develop preeclampsia, before notable changes in sFlt1. 102 Finally, in most studies PlGF is a more sensitive and precise predictor of preeclampsia and FGR than any other single biomarker.…”

Impact of obesity on angiogenic and inflammatory markers in the Finnish Genetics of Pre-eclampsia Consortium (FINNPEC) cohort

“…42 Multiple angiogenic factors have been recognised in adipose tissue including sFlt-1, sEng and PlGF. 41,43,44 Interestingly, Herse et al 44 have shown that lean non-PE women have higher sFlt-1 levels in adipose tissue and that TNF-α could downregulate sFlt-1. Therefore high levels of sFlt-1 might restrain adipose tissue growth via inhibition of local angiogenesis.…”