title: Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet.
abstract: OBJECTIVE
  Elevated serum levels of the lymphangiogenic factors VEGF-C and -D have been observed in obese individuals but their relevance for the metabolic syndrome has remained unknown.
  
  
  METHODS
  K14-VEGFR-3-Ig (sR3) mice that constitutively express soluble-VEGFR-3-Ig in the skin, scavenging VEGF-C and -D, and wildtype (WT) mice were fed either chow or high-fat diet for 20 weeks. To assess the effect of VEGFR-3 blockage on adipose tissue growth and insulin sensitivity, we evaluated weight gain, adipocyte size and hepatic lipid accumulation. These results were complemented with insulin tolerance tests, FACS analysis of adipose tissue macrophages, in vitro 3T3-L1 differentiation assays and in vivo blocking antibody treatment experiments.
  
  
  RESULTS
  We show here that sR3 mice are protected from obesity-induced insulin resistance and hepatic lipid accumulation. This protection is associated with enhanced subcutaneous adipose tissue hyperplasia and an increased number of alternatively-activated (M2) macrophages in adipose tissue. We also show that VEGF-C and -D are chemotactic for murine macrophages and that this effect is mediated by VEGFR-3, which is upregulated on M1 polarized macrophages. Systemic antibody blockage of VEGFR-3 in db/db mice reduces adipose tissue macrophage infiltration and hepatic lipid accumulation, and improves insulin sensitivity.
  
  
  CONCLUSIONS
  These results reveal an unanticipated role of the lymphangiogenic factors VEGF-C and -D in the mediation of metabolic syndrome-associated adipose tissue inflammation. Blockage of these lymphangiogenic factors might constitute a new therapeutic strategy for the prevention of obesity-associated insulin resistance.
authors: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland.
authors: Sinem
authors: S
authors: Karaman
authors: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland.
authors: Maija
authors: M
authors: Hollmén
authors: Wihuri Research Institute and Translational Cancer Biology Program, Institute for Molecular Medicine Finland and Helsinki University Central Hospital, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
authors: Marius R
authors: MR
authors: Robciuc
authors: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland.
authors: Annamari
authors: A
authors: Alitalo
authors: Wihuri Research Institute and Translational Cancer Biology Program, Institute for Molecular Medicine Finland and Helsinki University Central Hospital, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
authors: Harri
authors: H
authors: Nurmi
authors: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland.
authors: Bettina
authors: B
authors: Morf
authors: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland.
authors: Dorina
authors: D
authors: Buschle
authors: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland.
authors: H Furkan
authors: HF
authors: Alkan
authors: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland.
authors: Alexandra M
authors: AM
authors: Ochsenbein
authors: Wihuri Research Institute and Translational Cancer Biology Program, Institute for Molecular Medicine Finland and Helsinki University Central Hospital, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
authors: Kari
authors: K
authors: Alitalo
authors: Institute of Food, Nutrition and Health, Swiss Federal Institute of Technology, ETH Zurich, 8603 Schwerzenbach, Switzerland.
authors: Christian
authors: C
authors: Wolfrum
authors: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland.
authors: Michael
authors: M
authors: Detmar
keywords: Adipose tissue; CM, conditioned medium; EWAT, epididymal white adipose tissue; HFD, high-fat diet; Inflammation; Macrophages; Obesity; SWAT, subcutaneous white adipose tissue; Vegfc; sR3, soluble-VEGFR-3