Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet
Identifieur interne : 002D09 ( Main/Exploration ); précédent : 002D08; suivant : 002D10Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet
Auteurs : Sinem Karaman [Suisse] ; Maija Hollmén [Suisse] ; Marius R. Robciuc [Finlande] ; Annamari Alitalo [Suisse] ; Harri Nurmi [Finlande] ; Bettina Morf [Suisse] ; Dorina Buschle [Suisse] ; H. Furkan Alkan [Suisse] ; Alexandra M. Ochsenbein [Suisse] ; Kari Alitalo [Finlande] ; Christian Wolfrum [Suisse] ; Michael Detmar [Suisse]Source :
- Molecular Metabolism [ 2212-8778 ] ; 2014.
Abstract
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.
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,
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.
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.
Url:
DOI: 10.1016/j.molmet.2014.11.006
PubMed: 25685697
PubMed Central: 4314545
Affiliations:
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Robciuc</name><affiliation wicri:level="1"><nlm:aff id="aff2">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</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>00014 Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Alitalo, Annamari" sort="Alitalo, Annamari" uniqKey="Alitalo A" first="Annamari" last="Alitalo">Annamari Alitalo</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich</wicri:regionArea><wicri:noRegion>8093 Zurich</wicri:noRegion></affiliation></author><author><name sortKey="Nurmi, Harri" sort="Nurmi, Harri" uniqKey="Nurmi H" first="Harri" last="Nurmi">Harri Nurmi</name><affiliation wicri:level="1"><nlm:aff id="aff2">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</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>00014 Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Morf, Bettina" sort="Morf, Bettina" uniqKey="Morf B" first="Bettina" last="Morf">Bettina Morf</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich</wicri:regionArea><wicri:noRegion>8093 Zurich</wicri:noRegion></affiliation></author><author><name sortKey="Buschle, Dorina" sort="Buschle, Dorina" uniqKey="Buschle D" first="Dorina" last="Buschle">Dorina Buschle</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich</wicri:regionArea><wicri:noRegion>8093 Zurich</wicri:noRegion></affiliation></author><author><name sortKey="Alkan, H Furkan" sort="Alkan, H Furkan" uniqKey="Alkan H" first="H. Furkan" last="Alkan">H. Furkan Alkan</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich</wicri:regionArea><wicri:noRegion>8093 Zurich</wicri:noRegion></affiliation></author><author><name sortKey="Ochsenbein, Alexandra M" sort="Ochsenbein, Alexandra M" uniqKey="Ochsenbein A" first="Alexandra M." last="Ochsenbein">Alexandra M. Ochsenbein</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich</wicri:regionArea><wicri:noRegion>8093 Zurich</wicri:noRegion></affiliation></author><author><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name><affiliation wicri:level="1"><nlm:aff id="aff2">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</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>00014 Helsinki</wicri:noRegion><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName><orgName type="university">Université d'Helsinki</orgName></affiliation></author><author><name sortKey="Wolfrum, Christian" sort="Wolfrum, Christian" uniqKey="Wolfrum C" first="Christian" last="Wolfrum">Christian Wolfrum</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Food, Nutrition and Health, Swiss Federal Institute of Technology, ETH Zurich, 8603 Schwerzenbach, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Food, Nutrition and Health, Swiss Federal Institute of Technology, ETH Zurich, 8603 Schwerzenbach</wicri:regionArea><wicri:noRegion>8603 Schwerzenbach</wicri:noRegion></affiliation></author><author><name sortKey="Detmar, Michael" sort="Detmar, Michael" uniqKey="Detmar M" first="Michael" last="Detmar">Michael Detmar</name><affiliation wicri:level="1"><nlm:aff id="aff1">Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea>Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich</wicri:regionArea><wicri:noRegion>8093 Zurich</wicri:noRegion></affiliation></author></analytic><series><title level="j">Molecular Metabolism</title><idno type="eISSN">2212-8778</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Objective</title><p>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.</p></sec><sec><title>Methods</title><p>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, <italic>in vitro</italic> 3T3-L1 differentiation assays and <italic>in vivo</italic> blocking antibody treatment experiments.</p></sec><sec><title>Results</title><p>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.</p></sec><sec><title>Conclusions</title><p>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.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y. Wang</name></author><author><name sortKey="Beydoun, M A" uniqKey="Beydoun M">M.A. Beydoun</name></author><author><name sortKey="Liang, L" uniqKey="Liang L">L. Liang</name></author><author><name sortKey="Caballero, B" uniqKey="Caballero B">B. Caballero</name></author><author><name sortKey="Kumanyika, S K" uniqKey="Kumanyika S">S.K. 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Neufeld</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Finlande</li><li>Suisse</li></country><region><li>Uusimaa</li></region><settlement><li>Helsinki</li></settlement><orgName><li>Université d'Helsinki</li></orgName></list><tree><country name="Suisse"><noRegion><name sortKey="Karaman, Sinem" sort="Karaman, Sinem" uniqKey="Karaman S" first="Sinem" last="Karaman">Sinem Karaman</name></noRegion><name sortKey="Alitalo, Annamari" sort="Alitalo, Annamari" uniqKey="Alitalo A" first="Annamari" last="Alitalo">Annamari Alitalo</name><name sortKey="Alkan, H Furkan" sort="Alkan, H Furkan" uniqKey="Alkan H" first="H. Furkan" last="Alkan">H. Furkan Alkan</name><name sortKey="Buschle, Dorina" sort="Buschle, Dorina" uniqKey="Buschle D" first="Dorina" last="Buschle">Dorina Buschle</name><name sortKey="Detmar, Michael" sort="Detmar, Michael" uniqKey="Detmar M" first="Michael" last="Detmar">Michael Detmar</name><name sortKey="Hollmen, Maija" sort="Hollmen, Maija" uniqKey="Hollmen M" first="Maija" last="Hollmén">Maija Hollmén</name><name sortKey="Morf, Bettina" sort="Morf, Bettina" uniqKey="Morf B" first="Bettina" last="Morf">Bettina Morf</name><name sortKey="Ochsenbein, Alexandra M" sort="Ochsenbein, Alexandra M" uniqKey="Ochsenbein A" first="Alexandra M." last="Ochsenbein">Alexandra M. Ochsenbein</name><name sortKey="Wolfrum, Christian" sort="Wolfrum, Christian" uniqKey="Wolfrum C" first="Christian" last="Wolfrum">Christian Wolfrum</name></country><country name="Finlande"><noRegion><name sortKey="Robciuc, Marius R" sort="Robciuc, Marius R" uniqKey="Robciuc M" first="Marius R." last="Robciuc">Marius R. Robciuc</name></noRegion><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name><name sortKey="Nurmi, Harri" sort="Nurmi, Harri" uniqKey="Nurmi H" first="Harri" last="Nurmi">Harri Nurmi</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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