Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet
Identifieur interne : 004218 ( Pmc/Curation ); précédent : 004217; suivant : 004219Blockade 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.
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DOI: 10.1016/j.molmet.2014.11.006
PubMed: 25685697
PubMed Central: 4314545
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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></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></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></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></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25685697</idno><idno type="pmc">4314545</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314545</idno><idno type="RBID">PMC:4314545</idno><idno type="doi">10.1016/j.molmet.2014.11.006</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">004219</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004219</idno><idno type="wicri:Area/Pmc/Curation">004218</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">004218</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet</title><author><name sortKey="Karaman, Sinem" sort="Karaman, Sinem" uniqKey="Karaman S" first="Sinem" last="Karaman">Sinem Karaman</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></affiliation></author><author><name sortKey="Hollmen, Maija" sort="Hollmen, Maija" uniqKey="Hollmen M" first="Maija" last="Hollmén">Maija Hollmén</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></affiliation></author><author><name sortKey="Robciuc, Marius R" sort="Robciuc, Marius R" uniqKey="Robciuc M" first="Marius R." last="Robciuc">Marius R. 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></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></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></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></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></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></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></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></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></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></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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<front><journal-meta><journal-id journal-id-type="nlm-ta">Mol Metab</journal-id><journal-id journal-id-type="iso-abbrev">Mol Metab</journal-id><journal-title-group><journal-title>Molecular Metabolism</journal-title></journal-title-group><issn pub-type="epub">2212-8778</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25685697</article-id><article-id pub-id-type="pmc">4314545</article-id><article-id pub-id-type="publisher-id">S2212-8778(14)00200-2</article-id><article-id pub-id-type="doi">10.1016/j.molmet.2014.11.006</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Karaman</surname><given-names>Sinem</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Hollmén</surname><given-names>Maija</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Robciuc</surname><given-names>Marius R.</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Alitalo</surname><given-names>Annamari</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Nurmi</surname><given-names>Harri</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Morf</surname><given-names>Bettina</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Buschle</surname><given-names>Dorina</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Alkan</surname><given-names>H. Furkan</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Ochsenbein</surname><given-names>Alexandra M.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Alitalo</surname><given-names>Kari</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Wolfrum</surname><given-names>Christian</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Detmar</surname><given-names>Michael</given-names></name><email>michael.detmar@pharma.ethz.ch</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich, Switzerland</aff><aff id="aff2"><label>2</label>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</aff><aff id="aff3"><label>3</label>Institute of Food, Nutrition and Health, Swiss Federal Institute of Technology, ETH Zurich, 8603 Schwerzenbach, Switzerland</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author. Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Vladimir-Prelog-Weg 3, HCI H303, CH-8093 Zurich, Switzerland. Tel.: +41 44 633 7361; fax: +41 44 633 1364. <email>michael.detmar@pharma.ethz.ch</email></corresp></author-notes><pub-date pub-type="pmc-release"><day>04</day><month>12</month><year>2014</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="collection"><month>2</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>04</day><month>12</month><year>2014</year></pub-date><volume>4</volume><issue>2</issue><fpage>93</fpage><lpage>105</lpage><history><date date-type="received"><day>10</day><month>11</month><year>2014</year></date><date date-type="rev-recd"><day>24</day><month>11</month><year>2014</year></date><date date-type="accepted"><day>27</day><month>11</month><year>2014</year></date></history><permissions><copyright-statement>© 2014 The Authors</copyright-statement><copyright-year>2014</copyright-year><license license-type="CC BY-NC-ND" xlink:href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><license-p>This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).</license-p></license></permissions><abstract><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></abstract><kwd-group><title>Keywords</title><kwd>Vegfc</kwd><kwd>Obesity</kwd><kwd>Adipose tissue</kwd><kwd>Inflammation</kwd><kwd>Macrophages</kwd></kwd-group><kwd-group><title>Abbreviations</title><kwd>sR3, soluble-VEGFR-3</kwd><kwd>HFD, high-fat diet</kwd><kwd>SWAT, subcutaneous white adipose tissue</kwd><kwd>EWAT, epididymal white adipose tissue</kwd><kwd>CM, conditioned medium</kwd></kwd-group></article-meta></front><floats-group><fig id="fig1"><label>Figure 1</label><caption><p>Comparable weight gain, fat distribution and intestinal lipid uptake in sR3 mice. (A) Compared to WT mice, sR3 mice lack podoplanin positive dermal lymphatic vessels in the tail. Whole-mount imaging of intestinal villi of WT and sR3 mice revealed no differences in lacteal or blood vessel structure. Scale bars = 100 μm. (B) sVEGFR-3–Ig expression does not influence weight gain or adipose tissue distribution during chow diet or HFD (<italic>n</italic> = 8–13, data analyzed with repeated measures ANOVA; genotype effect on weight gain <italic>P</italic> = 0.30). (C) CT scan analyses and further calculation showed comparable adipose tissue weights in mice on HFD (<italic>n</italic> = 5–6). (D) Determination of BODIPY fluorescence in the serum 1 h after oral ingestion revealed similar lipid uptake in WT and sR3 mice (<italic>n</italic> = 3–4, two-tailed Student's <italic>t</italic>-test). All data are mean ± SD.</p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>sR3 mice have smaller subcutaneous adipocytes and are more insulin sensitive. (A) Compared to WT controls sR3 mice have smaller SWAT adipocytes under chow diet and HFD. (B) EWAT adipocyte size is not altered. Scale bars = 100 μm. (C) Cumulative distribution plot of SWAT adipocyte sizes between the groups shows a leftward shift in sR3 mice, both on chow and on HFD (***<italic>P</italic> < 0.001; two-sample Kolmogorov–Smirnov test). (D, E) Insulin tolerance test (ITT) showing increased insulin sensitivity of sR3 mice under chow (<italic>n</italic> = 7 each) and HFD (<italic>n</italic> = 5 each) in response to insulin stimulation. Blood glucose levels of sR3 mice and WT controls before i.p. administration of insulin were set to 100% (curves are compared using a two-way ANOVA, effect of genotype is shown; *<italic>P</italic> < 0.05 and **<italic>P</italic> < 0.01 compared to WT control at the same time point with two-tailed Student's <italic>t</italic>-test). All data are mean ± SD.</p></caption><graphic xlink:href="gr2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>sR3 mice exhibit reduced ectopic lipid accumulation after HFD. (A) Representative appearance of steatotic livers of WT and sR3 mice after 20 weeks on HFD, note the reduction in liver steatosis in the sR3 mice. Scale bars = 1 cm. (B) Oil red O staining of liver sections confirmed a reduction in lipid accumulation in the livers of sR3 mice under both chow and HFD for 20 weeks, compared to WT mice. Scale bar = 100 μm. (C) Triglyceride content measurements of the livers showed a slight reduction in the livers of sR3 mice on chow (<italic>P</italic> = 0.098), and a highly significant reduction under HFD (<italic>n</italic> = 8–13, two-tailed Student's <italic>t</italic>-test, ***<italic>P</italic> < 0.001). (D) Immunofluorescence stains for CD31 (red) and (E) subsequent image analysis showed similar coverage of liver sections with blood vessels and unaltered sinusoidal morphology. Scale bar = 100 μm. (F) Representative western blot analysis and (G) quantification of insulin-stimulated AKT phosphorylation of liver samples, showing increased AKT phosphorylation in the sR3 mice as compared to WT controls under HFD. Phospho-AKT levels were normalized to respective total AKT (<italic>n</italic> = 4–6, two-tailed Student's <italic>t</italic>-test, *<italic>P</italic> < 0.05). All data are mean ± SD.</p></caption><graphic xlink:href="gr3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>sR3 mice have an increased ratio of M2/M1 polarized macrophages in subcutaneous adipose tissue. (A) Representative FACS plots. (B) FACS analyses showed that sR3 mice had an increase in CD11b<sup>+</sup>/F4/80<sup>+</sup> macrophages, as well as higher ratios of M2/M1 polarized macrophages. This difference was due to decreased expression of MHCII and increased expression of CD206 in the CD11b<sup>+</sup>/F4/80<sup>+</sup> macrophages within the stromal-vascular fraction (<italic>n</italic> = 3–7, two-tailed Student's <italic>t</italic>-test, *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01). All data are mean ± SD.</p></caption><graphic xlink:href="gr4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Conditioned media (CM) from WT, but not sR3 SWAT macrophages inhibit adipogenic differentiation of 3T3-L1 cells. (A) Images of terminally differentiated 3T3-L1 adipocytes stained with BODIPY 493/503 (green, lipid droplets), Syto60 (red, cytosol) and Hoechst (blue, nuclei, scale bar = 100 μm). (B) Quantification showed a significant decrease in adipogenic differentiation of the adipocytes treated with CM from WT macrophages, compared to adipocytes treated with sR3 macrophage CM (<italic>n</italic> = 4 each, two-tailed Student's <italic>t</italic>-test, **<italic>P</italic> < 0.01, ***<italic>P</italic> < 0.001). (C) Decreased (IL-6) or absent (IL-17, GM-CSF, IL-1α) proinflammatory cytokines in CM of sR3 SWAT macrophages. IL-10 (a Th2 cytokine) was only detectable in sR3 macrophage CM (<italic>n</italic> = 4 each). All data are mean ± SD.</p></caption><graphic xlink:href="gr5"></graphic></fig><fig id="fig6"><label>Figure 6</label><caption><p>VEGF-C and VEGF-D are chemotactic for macrophages. (A) The mRNA expression of <italic>Vegfc</italic> and <italic>Vegfd</italic> was increased in the adipocytes of WT mice after 20 weeks on HFD (<italic>n</italic> = 4 each). (B) Increased migration of peritoneal macrophages towards VEGF-C and VEGF-D (200 ng/mL, <italic>n</italic> = 3 mice per group, representative results from three independent experiments). (C) Real-time PCR demonstrated expression of VEGF-C/-D receptors and co-receptors in adipose tissue macrophages (average Ct value for <italic>Rplp0</italic> is 20.1). (D, E) Blockage of neuropilin-1 or -2 did not influence macrophage migration towards VEGF-C or VEGF-D. Blockage of VEGFR-2 had no effect on macrophage migration towards VEGF-C and VEGF-D but migration was strongly inhibited by an anti-VEGFR-3 antibody and by sVEGFR-3–Ig (sR3 protein). *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01, ***<italic>P</italic> < 0.001. All data are mean ± SD.</p></caption><graphic xlink:href="gr6"></graphic></fig><fig id="fig7"><label>Figure 7</label><caption><p>Induction of polarization related markers upon M1 or M2 polarization. (A) M1 polarization associated increase in the expression of <italic>Inos</italic> and <italic>Tnf</italic> mRNA. (B) M2 polarization increases the expression of the mRNA levels of <italic>Mrc1</italic>, <italic>Arg1</italic> and <italic>Ym1</italic>. <italic>Vegfr3</italic> mRNA expression is upregulated in M1, and downregulated in M2 polarized macrophages. Representative data from 5 independent experiments performed with 4 biological replicates per experimental group. Dashed line represents expression level in unstimulated macrophages. *<italic>P</italic> < 0.05, **<italic>P</italic> < 0.01. All data are mean ± SD.</p></caption><graphic xlink:href="gr7"></graphic></fig><fig id="fig8"><label>Figure 8</label><caption><p>VEGFR-3 blocking antibody treatment impedes obesity-associated adipose tissue inflammation in db/db mice. (A) No difference in weight gain and (B) %SWAT and %EWAT after 2 weeks of treatment. (C) Insulin tolerance test, (curves are compared with two-way ANOVA (effect of treatment is shown); *<italic>P</italic> < 0.05 compared to IgG control at the same time point with two-tailed Student's <italic>t</italic>-test). (D) Hematoxylin staining showing smaller SWAT adipocytes in MF4 treated db/db mice, whereas EWAT adipocyte size was not changed. (E) FACS results of CD11b<sup>+</sup>/F4/80<sup>+</sup> cells in stromal-vascular fraction of SWAT and EWAT. (F) Relative gene expression levels of <italic>CD11b</italic>, <italic>Tnf</italic> and <italic>Il6</italic> in SWAT and EWAT. (G) Reduced ectopic lipid accumulation in the livers of MF4 treated mice as compared to IgG treated mice as shown by Oil Red O staining and triglyceride measurements. Scale bars = 100 μm *<italic>P</italic> < 0.05 (Two-tailed Student's <italic>t</italic>-test compared to IgG control). All data are mean ± SD.</p></caption><graphic xlink:href="gr8"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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