Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet

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Karaman , S , Hollmen , M , Robciuc , M R , Alitalo , A , Nurmi , H , Morf , B , Buschle , D , Alkan , H F , Ochsenbein , A M , Alitalo , K , Wolfrum , C & Detmar , M 2015 , ' Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet ' , Molecular metabolism , vol. 4 , no. 2 , pp. 93-105 . https://doi.org/10.1016/j.molmet.2014.11.006

Title: Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet
Author: Karaman, Sinem; Hollmen, Maija; Robciuc, Marius R.; Alitalo, Annamari; Nurmi, Harri; Morf, Bettina; Buschle, Dorina; Alkan, H. Furkan; Ochsenbein, Alexandra M.; Alitalo, Kari; Wolfrum, Christian; Detmar, Michael
Contributor: University of Helsinki, Swiss Federal Institute of Technology
University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
University of Helsinki, Research Programs Unit
Date: 2015-02
Language: eng
Number of pages: 13
Belongs to series: Molecular metabolism
ISSN: 2212-8778
URI: http://hdl.handle.net/10138/175977
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-3eIg 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. (C) 2014 The Authors. Published by Elsevier GmbH.
Subject: Vegfc
Obesity
Adipose tissue
Inflammation
Macrophages
INSULIN-RESISTANCE
MACROPHAGE POLARIZATION
SKIN CARCINOGENESIS
T-CELLS
OBESITY
LYMPHANGIOGENESIS
ACTIVATION
PREADIPOCYTES
ADIPOGENESIS
RECRUITMENT
3111 Biomedicine
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