title: Adipose tissue-derived soluble fms-like tyrosine kinase 1 is an obesity-relevant endogenous paracrine adipokine.
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-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.
authors.affiliation: Experimental and Clinical Research Center, Max-Delbrueck Center for Molecular Medicine, Charitè Campus Buch, Lindenbergerweg 80, 13125 Berlin, Germany. florian.herse@charite.de
authors.forename: Florian
authors.initials: F
authors.lastname: Herse
authors.forename: John N
authors.initials: JN
authors.lastname: Fain
authors.forename: Juergen
authors.initials: J
authors.lastname: Janke
authors.forename: Stefan
authors.initials: S
authors.lastname: Engeli
authors.forename: Christian
authors.initials: C
authors.lastname: Kuhn
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Weich
authors.forename: Astrid
authors.initials: A
authors.lastname: Bergmann
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
authors.forename: Anne C
authors.initials: AC
authors.lastname: Staff
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
mesh_terms: D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D054392:Adipokines / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D015992:Body Mass Index; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D012313:RNA / Q000235:genetics*; D051381:Rats; D055647:Rats, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D054392:Adipokines; D012313:RNA; D040281:Vascular Endothelial Growth Factor Receptor-1